Dietary Factors

Some of the listed dietary factors (i.e., L-carnitine, coenzyme Q10, and lipoic acid) can be synthesized by the body.

L-Carnitine

Summary

  • L-carnitine supplementation is indicated for the treatment of primary and secondary carnitine deficiencies. (More information)
  • Healthy individuals, including strict vegetarians, generally synthesize enough L-carnitine to prevent deficiency. (More information)
  • Hemodialysis patients with selected symptoms that do not respond to standard therapy may benefit from a trial of L-carnitine supplementation. (More information)
  • Propionyl-L-carnitine supplementation appears promising as a treatment for intermittent claudication in peripheral arterial disease. (More information)
  • The roles of L-carnitine supplementation as an adjunct to standard medical therapy in myocardial infarction, heart failure, angina pectoris, Alzheimer's disease, and HIV infection require further research. (More information)
  • Although studies in rats suggest acetyl-L-carnitine supplementation may be beneficial in preventing age-related declines in energy metabolism and memory, it is not known whether acetyl-L-carnitine supplementation will help prevent such age-related declines in humans. (More information)
  • There is little evidence that L-carnitine supplementation improves athletic performance in healthy people. (More information)
  • If you choose to take carnitine supplements, the Linus Pauling Institute recommends acetyl-L-carnitine at a daily dose of 500 to 1,000 mg.

Introduction

L-carnitine is a derivative of the amino acid, lysine. Its name is derived from the fact that it was first isolated from meat (carnis) in 1905. Only the L-isomer of carnitine (Figure 1) is biologically active (1). L-carnitine appeared to act as a vitamin in the mealworm (Tenebrio molitor) and was therefore termed vitamin BT (2). Vitamin BT, however, is actually a misnomer because humans and other higher organisms can synthesize L-carnitine (see Metabolism and Bioavailability). Under certain conditions, the demand for L-carnitine may exceed an individual's capacity to synthesize it, making it a conditionally essential micronutrient (3, 4).

Figure 1. Chemical Structures of L-Carnitine, Acetyl-L-Carnitine, and Propionyl L-Carnitine.

Metabolism and Bioavailability

In healthy people, carnitine homeostasis (balance) is maintained through endogenous biosynthesis of L-carnitine, absorption of carnitine from dietary sources, and elimination and reabsorption of carnitine by the kidneys (5).

Endogenous biosynthesis

Humans can synthesize L-carnitine from the amino acids lysine and methionine in a multi-step process. Specifically, protein-bound lysine is enzymatically methylated to form episilon-N-trimethyllysine; three molecules of methionine provide the methyl groups for the reaction. Epsilon-N-trimethyllysine is released for carnitine synthesis by protein hydrolysis (5, 6). Several enzymes are involved in endogenous L-carnitine biosynthesis. The enzyme γ-butyrobetaine hydroxylase, however, is absent from cardiac and skeletal muscle but highly expressed in human liver, testes, and kidney (7). The rate of L-carnitine biosynthesis in humans was studied in vegetarians and is estimated to be 1.2 μmol/kg of body weight/day (8). Changes in dietary carnitine intake or renal reabsorption do not appear to affect the rate of endogenous carnitine synthesis (1).

Absorption of exogenous L-carnitine

Dietary L-carnitine

The bioavailability of L-carnitine from food can vary depending on dietary composition. For instance, one study reported that bioavailability of L-carnitine in individuals adapted to low-carnitine diets (i.e., vegetarians; 66%-86%) is higher than those adapted to high-carnitine diets (i.e., regular red meat eaters; 54%-72%) (9).

L-carnitine supplements

While bioavailability of L-carnitine from the diet is quite high (see Dietary L-carnitine), absorption from oral L-carnitine supplements is considerably lower. According to one study, bioavailability of L-carnitine from oral supplements (0.5-6 gram dosage) ranges from 14%-18% of the total dose (5). Less is known regarding the metabolism of the acetylated form of L-carnitine, acetyl-L-carnitine (ALCAR); however, bioavailability of ALCAR is thought to be higher than L-carnitine. The results of in vitro experiments suggest that ALCAR is partially hydrolyzed upon intestinal absorption (10). In humans, administration of 2 grams of ALCAR per day for 50 days increased plasma ALCAR levels by 43%, suggesting that some acetyl-L-carnitine is absorbed without hydrolysis or that L-carnitine is reacetylated in the enterocyte (5).

Elimination and reabsorption

L-carnitine and short-chain acylcarnitines (esters of L-carnitine), such as acetyl-L-carnitine, are excreted by the kidneys. Renal reabsorption of L-carnitine is normally very efficient; in fact, an estimated 95% is thought to be reabsorbed by the kidneys (1). Therefore, carnitine excretion by the kidney is normally very low. However, several conditions can decrease carnitine reabsorption efficiency and, correspondingly, increase carnitine excretion. Such conditions include high-fat (low-carbohydrate) diets, high-protein diets, pregnancy, and certain disease states (see Primary systemic carnitine deficiency) (11). In addition, when circulating L-carnitine levels increase, as in the case of oral supplementation, renal reabsorption of L-carnitine becomes saturated, resulting in increased urinary excretion of L-carnitine (5). Dietary or supplemental L-carnitine that is not absorbed by enterocytes is degraded by colonic bacteria to form two principal products, trimethylamine and γ-butyrobetaine. γ-butyrobetaine is eliminated in the feces; trimethylamine is efficiently absorbed and metabolized to trimethylamine-N-oxide, which is excreted in the urine (9).

Biological Activities

Mitochondrial oxidation of long-chain fatty acids

L-carnitine is synthesized primarily in the liver but also in the kidneys and then transported to other tissues. It is most concentrated in tissues that use fatty acids as their primary fuel, such as skeletal and cardiac (heart) muscle. In this regard, L-carnitine plays an important role in energy production by conjugating fatty acids for transport into the mitochondria (1).

L-carnitine is required for mitochondrial β-oxidation of long-chain fatty acids for energy production (1). Long-chain fatty acids must be in the form of esters of L-carnitine (acylcarnitines) in order to enter the mitochondrial matrix where β-oxidation occurs (Figure 2). Proteins of the carnitine-acyl transferase family transport acylcarnitines into the mitochondrial matrix. On the outer mitochondrial membrane, carnitine-palmitoyl transferase I (CPTI) catalyzes the transfer of long-chain fatty acids into the cytosol from coenzyme A (CoA) to L-carnitine, the rate-limiting step in fatty acid oxidation (12). A transport protein called carnitine:acylcarnitine translocase (CACT) facilitates the transport of acylcarnitine esters across the inner mitochondrial membrane. On the inner mitochondrial membrane, carnitine-palmitoyl transferase II (CPTII) catalyzes the transfer of fatty acids from L-carnitine to free CoA in the mitochondrial matrix, where they are metabolized through β-oxidation, ultimately yielding propionyl-CoA and acetyl-CoA (1).

Figure 2. The Mitochondrial Carnitine System. L-carnitine is required for mitochondrial β-oxidation of long-chain fatty acids for energy production. Long-chain fatty acids must be in the form of esters of L-carnitine (acylcarnitines) in order to enter the mitochondrial matrix where beta-oxidation occurs . Proteins of the carnitine-acyl transferase family transport acylcarnitines into the mitochondrial matrix. On the outer mitochondrial membrane, carnitine-palmitoyl transferase I (CPTI) catalyzes the transfer of long-chain fatty acids into the cytosol from coenzyme A (CoA) to L-carnitine, the rate-limiting step in fatty acid oxidation. A transport protein called carnitine:acylcarnitine translocase (CACT) facilitates the transport of acylcarnitine esters across the inner mitochondrial membrane. On the inner mitochondrial membrane, carnitine-palmitoyl transferase II (CPTII) catalyzes the transfer of fatty acids from L-carnitine to free CoA in the mitochondrial matrix, where they are metabolized through beta-oxidation, ultimately yielding propionyl-CoA and acetyl-CoA.

Regulation of energy metabolism through modulation of acyl CoA:CoA ratio

CoA is required as a cofactor for numerous cellular reactions (1). Within the mitochondrial matrix, carnitine acetyl transferase (CAT) catalyzes the trans-esterification (transfer) of short- and medium-chain fatty acids from CoA to carnitine (see Figure 2 above). The acylcarnitine esters can then be exported from the mitochondria via CACT, and the resulting free CoA can participate in other reactions. For example, pyruvate dehydrogenase (PDH) catalyzes the formation of acetyl-CoA from pyruvate and free CoA (13). Acetyl-CoA, in turn, can be oxidized to produce energy (ATP) in the tricarboxylic acid (TCA) cycle. Carnitine facilitates the oxidation of glucose by removing acyl groups generated by fatty acid β-oxidation and freeing CoA to participate in the PDH reaction (1).

Deficiency

Nutritional carnitine deficiencies have not been identified in healthy people without metabolic disorders, suggesting that most people can synthesize enough L-carnitine (1). Even strict vegetarians (vegans) show no signs of carnitine deficiency, despite the fact that most dietary carnitine is derived from animal sources (8). Infants, particularly premature infants, are born with low stores of L-carnitine, which could put them at risk of deficiency given their rapid rate of growth. One study reported that infants fed carnitine-free, soy-based formulas grew normally and showed no signs of a clinically relevant carnitine deficiency; however, some biochemical measures related to lipid metabolism differed significantly from infants fed the same formula supplemented with L-carnitine (14). Soy-based infant formulas are now fortified with the amount of L-carnitine normally found in human milk (15).

Primary systemic carnitine deficiency

Primary systemic carnitine deficiency is a rare, autosomal recessive disorder caused by mutations in the gene for the carnitine transporter protein OCTN2 (16, 17). Afflicted individuals have poor intestinal absorption of dietary L-carnitine and impaired L-carnitine reabsorption by the kidneys, i.e., increased urinary loss of L-carnitine (4). The disorder usually presents in early childhood and is characterized by low plasma carnitine, progressive cardiomyopathy, skeletal myopathy, hypoglycemia, and hypoammonemia (1, 4, 16). Without treatment, primary systemic carnitine deficiency is fatal. Treatment consists of pharmacological doses of L-carnitine; such therapy corrects the cardiomyopathy and muscle weakness (17).

Myopathic carnitine deficiency

Primary myopathic carnitine deficiency is a rare genetic disorder in which the carnitine deficiency is limited to skeletal and cardiac muscle. Symptoms, including muscle pain and progressive muscle weakness, begin in childhood or adolescence (4). Serum carnitine levels, however, are usually normal (18). In general, the myopathic form of primary carnitine deficiency is less severe than the systemic form (4).

Secondary carnitine deficiency or depletion

Secondary carnitine deficiency or depletion may result from either genetic or acquired conditions. Hereditary causes include genetic defects in amino acid degradation (e.g., propionic aciduria) and lipid metabolism (e.g., medium chain acyl-CoA dehydrogenase deficiency) (19). Such inherited disorders can lead to a build-up of organic acids, which are subsequently removed from the body via urinary excretion of acylcarnitine esters. Increased urinary losses of carnitine can lead to a systemic depletion of carnitine (1). Systemic carnitine depletion can also occur in disorders of impaired renal reabsorption. For instance, Fanconi's syndrome is a hereditary or acquired condition in which the proximal tubular reabsorption function of the kidneys is impaired (20). Malfunction of the kidney consequently results in increased urinary losses of carnitine. One example of an exclusively acquired carnitine deficiency involves chronic use of pivalate-conjugated antibiotics. Pivalate is a branched-chain fatty acid that is metabolized to form an acylCoA ester that is transesterified to carnitine and subsequently excreted in the urine as pivaloyl carnitine. Urinary losses of carnitine via this route can be 10-fold greater than the sum of daily carnitine intake and biosynthesis (see Safety); thus, systemic carnitine depletion can result (17). Further, patients with renal disease who undergo hemodialysis are at risk for secondary carnitine deficiency because hemodialysis removes carnitine from the blood (see Hemodialysis) (21).

Regardless of etiology, a secondary carnitine deficiency is characterized clinically by low plasma concentrations of free carnitine (less than 20 μmol/L) and increased acylcarnitine/free carnitine ratios (greater than 0.4) (19, 22). Secondary deficiencies are more common than the rare, primary carnitine disorders.

Nutrient interactions

Endogenous biosynthesis of L-carnitine is catalyzed by the concerted action of five different enzymes. This process requires two essential amino acids (lysine and methionine), iron (Fe2+), vitamin B6, niacin in the form of nicotinamide adenine dinucleotide (NAD), and may also require vitamin C (4). One of the earliest symptoms of vitamin C deficiency is fatigue, thought to be related to decreased synthesis of L-carnitine (23).

Disease Prevention

Aging

Age-related declines in mitochondrial function and increases in mitochondrial oxidant production are thought to be important contributors to the adverse effects of aging. Tissue L-carnitine levels have been found to decline with age in humans and animals (24). One study found that feeding aged rats acetyl-L-carnitine (ALCAR) reversed the age-related declines in tissue L-carnitine levels and also reversed a number of age-related changes in liver mitochondrial function; however, high doses of ALCAR increased liver mitochondrial oxidant production (25). ALCAR supplementation in rats has also been shown to improve or reverse age-related mitochondrial declines in skeletal and cardiac muscle (26, 27). Studies have found that supplementing aged rats with either ALCAR or α-lipoic acid, a mitochondrial cofactor and antioxidant, improved mitochondrial energy metabolism, decreased oxidative stress, and improved memory (28, 29). Interestingly, co-supplementation of ALCAR and α-lipoic acid resulted in even greater improvements than either compound administered alone. Likewise, several studies have reported that supplementing rats with both L-carnitine and α-lipoic acid blunts the age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in a variety of tissues (heart, skeletal muscle, and brain). Improvements in mitochondrial enzyme and respiratory chain activities and decreased apoptosis have also been observed (30-39). While these findings are very exciting, it is important to realize that these studies used relatively high doses of the compounds and only for a short time. Co-supplementation of aged rats with ALCAR and α-lipoic acid for a longer time period (three months) improved both the number of total and intact mitochondria and mitochondrial ultrastructure of neurons in the hippocampus (39). It is not yet known whether taking relatively high doses of these two naturally occurring substances will have similar effects in humans. Clinical trials in humans are planned, but it will be several years before the results are available.

Disease Treatment

Cardiovascular disease

In the studies discussed below it is important to note that treatment with L-carnitine or propionyl-L-carnitine was used as an adjunct (in addition) to appropriate medical therapy, not in place of it.

Myocardial infarction (heart attack)

Myocardial infarction (MI) occurs when an atherosclerotic plaque in a coronary artery ruptures. The resultant clot can obstruct the blood supply to the heart muscle, causing injury or damage to the heart. L-carnitine treatment has been found to reduce injury to heart muscle resulting from ischemia in several animal models (40). In humans, L-carnitine administration immediately after MI diagnosis has improved clinical outcomes in several, small clinical trials. In one trial, half of 160 men and women diagnosed with a recent MI were randomly assigned to receive 4 grams/day of oral L-carnitine in addition to standard pharmacological treatment. After one year of treatment, mortality was significantly lower in the L-carnitine supplemented group compared to the control group (1.2% vs. 12.5%), and angina attacks were less frequent (41). In a controlled clinical trial in 96 cardiac patients, treatment with intravenous L-carnitine (5 gram bolus followed by 10 g/day for three days) following a MI resulted in lower levels of creatine kinase-MB and troponin-I, two markers of cardiac injury (42). However, not all clinical trials have found L-carnitine supplementation to be beneficial after MI. In a randomized, double-blind, placebo-controlled trial, 60 men and women diagnosed with an acute MI were treated with either intravenous L-carnitine (6 grams/day) for seven days followed by oral L-carnitine (3 grams/day) for three months or placebo (43). After three months, mortality did not differ between the two groups, nor did echocardiographic measures of cardiac function. In a larger placebo-controlled trial, 472 patients treated in an intensive care unit within 24 hours of having their first MI were randomly assigned to either intravenous L-carnitine therapy (9 grams/day) for five days followed by oral L-carnitine (6 grams/day) for 12 months or a placebo; both groups also received standard medical therapy (44, 45). Although there were no significant differences in mortality or the incidence of congestive heart failure (CHF), left ventricular volumes were significantly lower in the L-carnitine treated group at the end of one year, suggesting that L-carnitine therapy may limit adverse effects of acute MI on the heart muscle. Based on these findings, a randomized placebo-controlled trial in 2,330 patients with acute MI was undertaken to determine the effect of L-carnitine therapy on the incidence of heart failure six months after MI. L-carnitine therapy (9 grams/day intravenously for five days, then 4 grams/day orally for six months) did not affect the incidence of heart failure and death in this study (46).

Heart failure

Heart failure is described as the heart's inability to pump enough blood for all of the body's needs. In coronary artery disease, accumulation of atherosclerotic plaque in the coronary arteries may prevent heart regions from getting adequate circulation, ultimately resulting in cardiac damage and impaired pumping ability. Myocardial infarction (MI) may also damage the heart muscle, which could potentially lead to heart failure. Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure. Echocardiography is also used to determine the left ventricular ejection fraction (LVEF), an objective measure of the heart's pumping ability. A LVEF of less than 40% is indicative of systolic heart failure (47).

Addition of L-carnitine to standard medical therapy for heart failure has been evaluated in several clinical trials. A randomized, placebo-controlled study in 70 heart failure patients found that three-year survival was significantly higher in the group receiving oral L-carnitine (2 grams/day) compared to the group receiving placebo (48). In a randomized, single-blind, placebo-controlled trial in 30 heart failure patients, oral administration of 1.5 grams/day of propionyl-L-carnitine for one month resulted in significantly improved measures of exercise tolerance and a slight but significant decrease in left ventricular size compared to placebo (49). A larger randomized, double-blind, placebo-controlled trial compared the addition of propionyl-L-carnitine (1.5 grams/day for six months) to the treatment regimen of 271 heart failure patients to a placebo group consisting of 266 patients (50). Overall, exercise tolerance was not different between the two groups. However, in patients with higher LVEF values (greater than 30%), exercise tolerance was significantly improved in the propionyl-L-carnitine versus placebo group, suggesting that propionyl-L-carnitine may help improve exercise tolerance in higher functioning heart failure patients. A recent study in 29 patients with mild diastolic heart failure (LVEF > 45%) found that 1.5 grams/day of oral L-carnitine for three months improved some measures of diastolic function compared to baseline (51).

Angina pectoris

Angina pectoris is chest pain that occurs when the coronary blood supply is insufficient to meet the metabolic needs of the heart muscle (ischemia). The addition of oral L-carnitine or propionyl-L-carnitine to pharmacologic therapy for chronic stable angina has been found to modestly improve exercise tolerance and decrease electrocardiographic signs of ischemia during exercise testing in a limited number of angina patients. One randomized, placebo-controlled study in 200 patients with exercise-induced stable angina found that supplementing conventional medical therapy with 2 grams/day of L-carnitine for six months significantly reduced the incidence of premature ventricular contractions at rest and also improved exercise tolerance (52). In addition, a randomized, placebo-controlled cross-over trial in 44 men with chronic stable angina found that administering 2 grams/day of L-carnitine for four weeks significantly increased the exercise workload tolerated prior to the onset of angina and decreased ST segment depression (electrocardiographic evidence of ischemia) during exercise compared to placebo (53). In a more recent randomized, placebo-controlled trial in 47 men and women with chronic stable angina, the addition of 2 grams/day of L-carnitine for three months significantly improved exercise duration and decreased the time required for exercise-induced ST segment changes to return to baseline compared to placebo (54). One study examined the effect of propionyl-L-carnitine on ischemia in men with myocardial dysfunction and angina pectoris by measuring hemodynamic and angiographic variables before, during, and after administering intravenous propionyl-L-carnitine (15 mg/kg body weight). In this study, propionyl-L-carnitine decreased myocardial ischemia, evidenced by significant reductions in ST-segment depression and left ventricular end-diastolic pressure (55). Although these results are promising, large-scale studies are needed to determine whether L-carnitine or propionyl-L-carnitine is a beneficial therapy for angina pectoris.

Intermittent claudication in peripheral arterial disease

In peripheral arterial disease, atherosclerosis of the arteries that supply the lower extremities may diminish blood flow to the point that the metabolic needs of exercising muscles are not sufficiently met, thereby leading to ischemic leg or hip pain known as claudication (56). Several clinical trials have found that treatment with propionyl-L-carnitine improves exercise tolerance in some patients with intermittent claudication (IC). In a double-blind, placebo-controlled, dose-titration study, 1-3 grams/day of oral propionyl-L-carnitine for 24 weeks was well tolerated and improved maximal walking distance in IC patients (57). In a randomized, placebo-controlled study of 495 patients with IC, 2 grams/day of propionyl-L-carnitine for 12 months significantly increased maximal walking distance and the distance walked prior to the onset of claudication in patients whose initial maximal walking distance was less than 250 meters (58). However, no significant response to propionyl-L-carnitine treatment was observed in more mildly affected patients whose initial maximal walking distance was greater than 250 meters. In a double-blind, randomized, placebo-controlled trial of 155 patients with disabling claudication in the US and Russia, administration of 2 grams/day of propionyl-L-carnitine for six months significantly improved walking distance and claudication onset time compared to placebo (59). More recently, a clinical trial in 74 patients with peripheral arterial disease associated with type 2 diabetes found that 2 g/day of oral propionyl-L-carnitine for 12 months improved pain-free walking distance and the ankle-brachial index, a diagnostic measure of peripheral arterial disease (60).

One study compared the efficacy of L-carnitine and propionyl-L-carnitine administered intravenously for the treatment of IC and concluded that propionyl-L-carnitine was more effective than L-carnitine when the same amount of carnitine was provided (61). Moreover, propionyl-L-carnitine has been reported to be a vasodilator (62); thus, the results mentioned above may in part be due to this compound's ability to affect endothelial function. In fact, a recent double-blind, placebo-controlled, cross-over study in 21 peripheral arterial disease patients found that intravenous infusion of propionyl-L-carnitine (6 grams/day) increased flow-mediated dilation of the brachial artery (63).

End-stage renal disease/hemodialysis

L-carnitine and many of its precursors are removed from the circulation during hemodialysis. Impaired L-carnitine synthesis by the kidneys may also contribute to the potential for carnitine deficiency in patients with end-stage renal disease undergoing hemodialysis. The US Food and Drug Administration (FDA) has approved the use of L-carnitine in hemodialysis patients for the prevention and treatment of carnitine deficiency (64). Carnitine depletion may lead to a number of conditions observed in dialysis patients, including muscle weakness and fatigue, plasma lipid abnormalities, and refractory anemia. A systematic review that examined the results of 18 randomized trials, including a total of 482 dialysis patients, found that L-carnitine treatment improved hemoglobin levels in studies performed before recombinant erythropoietin (EPO) was routinely used to treat anemia in dialysis patients, and that L-carnitine treatment decreased EPO dose and resistance to EPO in studies performed when patients routinely received EPO (65). Although some uncontrolled studies found that L-carnitine treatment improved blood lipid profiles in hemodialysis patients (66), a 2002 systematic review of randomized controlled trials found no evidence that L-carnitine improved lipid profiles (65). Moreover, two recent studies associated carnitine therapy by hemodialysis with reduced hospitalization (67, 68). The National Kidney Foundation (NKF) does not recommend routine administration of L-carnitine to all dialysis patients (69). However, the NKF and other consensus groups suggest a trial of L-carnitine for hemodialysis patients with selected symptoms that do not respond to standard therapy. Those symptoms include persistent muscle cramps or hypotension (low blood pressure) during dialysis, severe fatigue, skeletal muscle weakness or myopathy, cardiomyopathy, and anemia requiring large doses of EPO (69). In general, intravenous L-carnitine therapy (20 mg/kg body weight) at the end of a dialysis session has been recommended for patients on hemodialysis (70). Oral carnitine is not advised for hemodialysis patients due to the possible accumulation of potentially toxic metabolites (see Safety) (71).

Alzheimer's disease (dementia)

Several small, controlled clinical trials conducted in the 1990s suggested that acetyl-L-carnitine (ALCAR) treatment (2-3 grams/day for 6-12 months) might slow the cognitive decline in patients clinically diagnosed with Alzheimer's disease (72-74). However, a larger multicenter, randomized controlled trial involving 417 Alzheimer's disease patients found ALCAR treatment (3 grams/day for 12 months) was no different than placebo with respect to cognitive decline (75). Subsequent statistical analyses of the data from that study suggested that patients with early-onset Alzheimer's disease (65 years and younger) experienced a more rapid cognitive decline that was significantly slowed by ALCAR treatment (76, 77). However, a multicenter, randomized controlled trial involving 167 early-onset Alzheimer's disease patients between 45 and 65 years of age found that ALCAR treatment (3 grams/day for 12 months) had no effect on most measures of cognitive decline except ALCAR treatment was associated with a non-significant reduction in the attention-related decline compared to placebo (76).

HIV/AIDS

One of the hallmarks of infection with the HIV retrovirus is a progressive decline in the numbers of critical immune cells known as CD4 T lymphocytes (CD4 cells), ultimately leading to the development of AIDS. Lymphocytes of HIV-infected individuals inappropriately undergo programmed cell death (apoptosis). Limited evidence in cell culture experiments and in humans suggests that L-carnitine supplementation may help slow or prevent HIV-induced lymphocyte apoptosis. In an uncontrolled trial, 11 asymptomatic HIV-infected patients, who had refused antiretroviral treatment despite progressively declining CD4 cell counts, were treated with 6 grams/day of L-carnitine intravenously for four months (78). After four months of L-carnitine therapy, CD4 cell counts increased significantly and markers of lymphocyte apoptosis decreased, although there was no significant change in plasma levels of the HIV virus. Long-term outcomes were not reported in these patients. In a more recent study, 20 HIV-infected individuals were randomly assigned to receive the antiretroviral agents, zidovudine (AZT) and didanosine (DDI), with or without supplemental L-carnitine (79). Although CD4 cell counts and plasma HIV levels were not different between the two groups after seven months of therapy, indicators of CD4 cell apoptosis were significantly lower in the group taking L-carnitine.

Some antiretroviral agents (nucleoside analogues) used to treat HIV-infection appear to cause a secondary L-carnitine deficiency that may lead to some of their toxic side effects (see Drug interactions) (80). A small cross-sectional study found that nerve concentrations of acetyl-L-carnitine were significantly lower in HIV patients who developed peripheral neuropathy while taking nucleoside analogues than in control subjects (79). Ten out of 16 HIV patients with painful neuropathies reported improvement after three weeks of intravenous or intramuscular acetyl-L-carnitine (ALCAR) treatment (81). In a small study of 20 patients with antiretroviral-induced neuropathy, oral ALCAR (2 grams/day) for four weeks significantly reduced the subjects' mean pain intensity score but did not affect any of the measured neurophysiological parameters (82). In a double-blind, placebo-controlled trial in 90 HIV patients with symptomatic distal symmetrical polyneuropathy, intramuscular injection of 1,000 mg/day of ALCAR for two weeks had no benefit compared to placebo in the intention-to-treat analysis, but ALCAR provided some pain relief in the group of 66 patients who completed the trial (83). Results from two recent trials suggest that long-term (two to four years) ALCAR supplementation may be a beneficial adjunct to antiretroviral therapy in some HIV-infected individuals (84, 85). However, large-scale, controlled studies are needed before any conclusions can be drawn.

Decreased sperm motility

L-carnitine is concentrated in the epididymis, where sperm mature and acquire their motility (86). Two uncontrolled trials of L-carnitine supplementation in more than 100 men diagnosed with decreased sperm motility found that oral L-carnitine supplementation (3 grams/day) for three to four months significantly improved sperm motility (87, 88). However, no information on subsequent fertility was reported. A cross-sectional study of 101 fertile and infertile men found that L-carnitine concentrations in semen were positively correlated with the number of sperm, the percentage of motile sperm, and the percentage of normal appearing sperm in the sample (89), suggesting that L-carnitine levels in semen may be useful in evaluating male infertility. More recently, a placebo-controlled, double-blind, cross-over trial in 86 patients with male infertility found that L-carnitine (2 grams/day) supplementation for two months led to significantly improvements in sperm quality, evidenced by increases in sperm concentration and motility (90). Similar improvements in sperm motility were observed in a subsequent placebo-controlled, double-blind, randomized study conducted by the same group, but the patients received combination therapy consisting of L-carnitine (2 grams/day) and acetyl-L-carnitine (1 gram/day) for six months (91). Interestingly, in both studies, the most dramatic carnitine-induced improvements were noted in patients with the lowest baseline sperm motility measures (i.e., most severe cases) (90, 91). Another group of researchers also reported improved sperm motility following combined carnitine therapy. In this placebo-controlled, double-blind, randomized study, 44 patients with idiopathic asthenozoospermia (reduced sperm motility) received placebo, L-carnitine (3 grams/day), acetyl-L-carnitine (3 grams/day), or a combination of L-carnitine (2 grams/day) and acetyl-L-carnitine (1 gram/day). The combination therapy as well as acetyl-L-carnitine, alone, resulted in significant increases in sperm motility (92). Together, these data suggest that carnitine therapy may be useful in disorders of sperm motility and male infertility; however, large-scale clinical trials are undoubtedly necessary.

Performance

Physical performance

Interest in the potential of L-carnitine supplementation to improve athletic performance is related to its important roles in energy metabolism. A number of small, uncontrolled studies have reported that either acute (dose given one hour before exercise bout) or short-term (two to three weeks) L-carnitine supplementation (2 to 4 grams/day) was associated with increases in maximal oxygen uptake and decreases in plasma lactate (93-96). Most studies to date have shown no effect of L-carnitine supplementation on physical performance (97). However, conclusions that can be drawn from this research are limited due to small numbers of participants, short duration of supplementation, and lack of appropriate control groups in most studies. In a recent double-blind, placebo-controlled trial in 32 healthy adults, propionyl-L-carnitine (1 gram/day or 3 grams/day) for eight weeks did not improve aerobic or anaerobic exercise performance (98). Several studies have shown that carnitine supplementation increases plasma carnitine levels (99-103), but studies have failed to demonstrate that carnitine supplementation increases levels of carnitine within skeletal or cardiac muscle (27, 98, 104). Thus, while carnitine supplementation in theory might work, the available data suggest that carnitine supplementation does not affect athletic performance in healthy individuals.

Sources

Biosynthesis

The normal rate of L-carnitine biosynthesis in humans ranges from 0.16 to 0.48 mg/kg of body weight/day (4). Thus, a 70 kg (154 lb) person would synthesize between 11 and 34 mg of carnitine per day. This rate of synthesis combined with efficient (95%) L-carnitine reabsorption by the kidneys is sufficient to prevent deficiency in generally healthy people, including strict vegetarians (105).

Food sources

Meat, poultry, fish, and dairy products are the richest sources of L-carnitine, while fruit, vegetables, and grains contain relatively little L-carnitine. Omnivorous diets have been found to provide 20 to 200 mg/day of L-carnitine for a 70 kg person, while strict vegetarian diets may provide as little as 1 mg/day for a 70 kg person. Between 63% and 75% of L-carnitine from food is absorbed, compared to 14%-20% from oral supplements (1, 105, 106). Non-milk-based infant formulas (e.g., soy formulas) should be fortified so that they contain 11 mg of L-carnitine/liter. Some carnitine-rich foods and their carnitine content in milligrams (mg) are listed in Table 1 (105).

Table 1. L-Carnitine Content of Selected Foods
Food Serving L-Carnitine (mg)
Beef steak 3 ounces* 81
Ground beef 3 ounces 80 
Pork 3 ounces  24 
Canadian bacon 3 ounces  20 
Milk (whole) 8 fluid ounces (1 cup) 
Fish (cod) 3 ounces 
Chicken breast 3 ounces 
Ice cream 4 ounces (½ cup) 
Avocado 1 medium 
American cheese 1 ounce 
Whole-wheat bread 2 slices  0.2 
Asparagus 6 spears (½ cup) 0.2
*A three-ounce serving of meat is about the size of a deck of cards.

Supplements

Intravenous L-carnitine is available by prescription only for the treatment of primary and secondary L-carnitine deficiencies.

Oral L-carnitine is available by prescription for the treatment of primary and secondary L-carnitine deficiencies. It is also available without a prescription as a nutritional supplement; supplemental doses usually range from 500 to 2,000 mg/day.

Acetyl-L-carnitine is available without a prescription as a nutritional supplement. In addition to providing L-carnitine, it provides acetyl groups, which may be used in the formation of the neurotransmitter, acetylcholine. Supplemental doses usually range from 500 to 2,000 mg/day (107).

Propionyl-L-carnitine provides L-carnitine as well as propionate, which may be utilized as an intermediate during energy metabolism (106).

See Figure 1 for the chemical structures of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine.

Safety

Adverse effects

In general, L-carnitine appears to be well tolerated; toxic effects related to high-dose L-carnitine have not been reported. L-carnitine supplementation may cause mild gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea. Supplements providing more than 3,000 mg/day may cause a "fishy" body odor. Acetyl-L-carnitine has been reported to increase agitation in some Alzheimer's disease patients and to increase seizure frequency and/or severity in some individuals with seizure disorders (107). Only the L-isomer of carnitine is biologically active, and the D-isomer may actually compete with L-carnitine for absorption and transport, thereby increasing the risk of L-carnitine deficiency (4). Supplements containing a mixture of the D- and L-isomers (D, L-carnitine) have been associated with muscle weakness in patients with kidney disease. Controlled studies examining the safety of L-carnitine supplementation in pregnant and breast-feeding women are lacking (107).

Drug interactions

The anticonvulsant, valproic acid, and nucleoside analogues used in the treatment of HIV infection, including zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), and stavudine (d4T), may produce a secondary L-carnitine deficiency. Pivalic acid-containing antibiotics used in Europe (pivampicillin, pivmecillinam, and pivcephalexin) may also produce a secondary L-carnitine deficiency (105, 107). Additionally, two cancer chemotherapy agents, ifosfamide and cisplatin, may increase the risk of secondary L-carnitine deficiency. Further, there is limited evidence that L-carnitine supplementation may help prevent cardiomyopathy induced by doxorubicin (adriamycin) therapy (80).


Authors and Reviewers

Originally written in 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in April 2012 by:
Tory M. Hagen, Ph.D.
Principal Investigator, Linus Pauling Institute
Professor, Dept. of Biochemistry and Biophysics
Burgess and Elizabeth Jamieson Endowed Chair in Healthspan Research
Oregon State University

Copyright 2002-2017  Linus Pauling Institute


References

1.  Rebouche CJ. Carnitine. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Philadelphia: Lippincott, Williams & Wilkins; 2006:537-544.

2.  Fraenkel G, Friedman S. Carnitine. Vitam Horm. 1957;15:73-118.

3.  De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3(4):223-231.  (PubMed)

4.  Seim H, Eichler K, Kleber H. L(-)-Carnitine and its precursor, gamma-butyrobetaine. In: Kramer K, Hoppe P, Packer L, eds. Nutraceuticals in Health and Disease Prevention. New York: Marcel Dekker, Inc.; 2001:217-256. 

5.  Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci. 2004;1033:30-41.  (PubMed)

6.  Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6(15):3379-3386.  (PubMed)

7.  Rebouche CJ. Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr. 1991;54(6 Suppl):1147S-1152S.  (PubMed)

8.  Lombard KA, Olson AL, Nelson SE, Rebouche CJ. Carnitine status of lactoovovegetarians and strict vegetarian adults and children. Am J Clin Nutr. 1989;50(2):301-306.  (PubMed)

9.  Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr. 1991;121(4):539-546.  (PubMed)

10.  Gross CJ, Henderson LM, Savaiano DA. Uptake of L-carnitine, D-carnitine and acetyl-L-carnitine by isolated guinea-pig enterocytes. Biochim Biophys Acta. 1986;886(3):425-433.  (PubMed)

11.  Rebouche CJ, Lombard KA, Chenard CA. Renal adaptation to dietary carnitine in humans. Am J Clin Nutr. 1993;58(5):660-665.  (PubMed)

12.  Foster DW. The role of the carnitine system in human metabolism. Ann N Y Acad Sci. 2004;1033:1-16.  (PubMed)

13.  McGrane MM. Carbohydrate metabolism--synthesis and oxidation. In: Stipanuk MH (ed). Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co; 2000:158-210. 

14.  Olson AL, Nelson SE, Rebouche CJ. Low carnitine intake and altered lipid metabolism in infants. Am J Clin Nutr. 1989;49(4):624-628.  (PubMed)

15.  American Academy of Pediatrics, Committee on Nutrition. Soy protein-based formulas: recommendations for use in infant feeding. Pediatrics. 1998;101(1):148-152.  (PubMed)

16.  Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet. 1999;21(1):91-94.  (PubMed)

17.  Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci. 2004;1033:42-51.  (PubMed)

18.  Kerner J, Hoppel C. Genetic disorders of carnitine metabolism and their nutritional management. Annu Rev Nutr. 1998;18:179-206.  (PubMed)

19.  Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol. 1995;10 Suppl 2:S8-24.  (PubMed)

20.  Gregory MJ, Schwartz GJ. Diagnosis and treatment of renal tubular disorders. Semin Nephrol. 1998;18(3):317-329.  (PubMed)

21.  Calvani M, Benatti P, Mancinelli A, et al. Carnitine replacement in end-stage renal disease and hemodialysis. Ann N Y Acad Sci. 2004;1033:52-66.  (PubMed)

22.  Winter SC, Szabo-Aczel S, Curry CJ, Hutchinson HT, Hogue R, Shug A. Plasma carnitine deficiency. Clinical observations in 51 pediatric patients. Am J Dis Child. 1987;141(6):660-665.  (PubMed)

23.  Food and Nutrition Board, Institute of Medicine. Vitamin C. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington D.C.: National Academy Press; 2000:95-185.  (National Academy Press)

24.  Costell M, O'Connor JE, Grisolia S. Age-dependent decrease of carnitine content in muscle of mice and humans. Biochem Biophys Res Commun. 1989;161(3):1135-1143.  (PubMed)

25.  Hagen TM, Ingersoll RT, Wehr CM, et al. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci U S A. 1998;95(16):9562-9566.  (PubMed)

26.  Pesce V, Fracasso F, Cassano P, Lezza AM, Cantatore P, Gadaleta MN. Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis. Rejuvenation Res. 2010;13(2-3):148-151.  (PubMed)

27.  Gomez LA, Heath SH, Hagen TM. Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart. Mech Ageing Dev. 2012;133(2-3):99-106.  (PubMed)

28.  Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002;99(4):1870-1875.  (PubMed)

29.  Liu J, Head E, Gharib AM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A. 2002;99(4):2356-2361.  (PubMed)

30.  Muthuswamy AD, Vedagiri K, Ganesan M, Chinnakannu P. Oxidative stress-mediated macromolecular damage and dwindle in antioxidant status in aged rat brain regions: role of L-carnitine and DL-alpha-lipoic acid. Clin Chim Acta. 2006;368(1-2):84-92.  (PubMed)

31.  Kumaran S, Panneerselvam KS, Shila S, Sivarajan K, Panneerselvam C. Age-associated deficit of mitochondrial oxidative phosphorylation in skeletal muscle: role of carnitine and lipoic acid. Mol Cell Biochem. 2005;280(1-2):83-89.  (PubMed)

32.  Kumaran S, Subathra M, Balu M, Panneerselvam C. Supplementation of L-carnitine improves mitochondrial enzymes in heart and skeletal muscle of aged rats. Exp Aging Res. 2005;31(1):55-67.  (PubMed)

33.  Savitha S, Panneerselvam C. Mitochondrial membrane damage during aging process in rat heart: potential efficacy of L-carnitine and DL alpha lipoic acid. Mech Ageing Dev. 2006;127(4):349-355.  (PubMed)

34.  Savitha S, Sivarajan K, Haripriya D, Kokilavani V, Panneerselvam C. Efficacy of levo carnitine and alpha lipoic acid in ameliorating the decline in mitochondrial enzymes during aging. Clin Nutr. 2005;24(5):794-800.  (PubMed)

35.  Sethumadhavan S, Chinnakannu P. Carnitine and lipoic Acid alleviates protein oxidation in heart mitochondria during aging process. Biogerontology. 2006;7(2):101-109.  (PubMed)

36.  Sundaram K, Panneerselvam KS. Oxidative stress and DNA single strand breaks in skeletal muscle of aged rats: role of carnitine and lipoicacid. Biogerontology. 2006;7(2):111-118.  (PubMed)

37.  Sethumadhavan S, Chinnakannu P. L-carnitine and alpha-lipoic acid improve age-associated decline in mitochondrial respiratory chain activity of rat heart muscle. J Gerontol A Biol Sci Med Sci. 2006;61(7):650-659.  (PubMed)

38.  Tamilselvan J, Jayaraman G, Sivarajan K, Panneerselvam C. Age-dependent upregulation of p53 and cytochrome c release and susceptibility to apoptosis in skeletal muscle fiber of aged rats: role of carnitine and lipoic acid. Free Radic Biol Med. 2007;43(12):1656-1669.  (PubMed)

39.  Aliev G, Liu J, Shenk JC, et al. Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. J Cell Mol Med. 2009;13(2):320-333.  (PubMed)

40.  Lopaschuk G. Regulation of carbohydrate metabolism in ischemia and reperfusion. Am Heart J. 2000;139(2 Pt 3):S115-119.  (PubMed)

41.  Davini P, Bigalli A, Lamanna F, Boem A. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res. 1992;18(8):355-365.  (PubMed)

42.   Xue YZ, Wang LX, Liu HZ, Qi XW, Wang XH, Ren HZ. L-carnitine as an adjunct therapy to percutaneous coronary intervention for non-ST elevation myocardial infarction. Cardiovasc Drugs Ther. 2007;21(6):445-448.  (PubMed)

43.  Iyer R, Gupta A, Khan A, Hiremath S, Lokhandwala Y. Does left ventricular function improve with L-carnitine after acute myocardial infarction? J Postgrad Med. 1999;45(2):38-41.  (PubMed)

44.  Colonna P, Iliceto S. Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico. Am Heart J. 2000;139(2 Pt 3):S124-130.  (PubMed)

45.  Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol. 1995;26(2):380-387.  (PubMed)

46.  Tarantini G, Scrutinio D, Bruzzi P, Boni L, Rizzon P, Iliceto S. Metabolic treatment with L-Carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial. Cardiology. 2006;106(4):215-223.  (PubMed)

47.  Trupp RJ, Abraham WT. Congestive heart failure. In: Rakel RE, Bope ET, eds. Conn's Current Therapy. 54th ed. New York: W.B. Sunders Company 2002:306-313. 

48.  Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J. 2000;139(2 Pt 3):S120-123.  (PubMed)

49.  Anand I, Chandrashekhan Y, De Giuli F, et al. Acute and chronic effects of propionyl-L-carnitine on the hemodynamics, exercise capacity, and hormones in patients with congestive heart failure. Cardiovasc Drugs Ther. 1998;12(3):291-299.  (PubMed)

50.  Study on propionyl-L-carnitine in chronic heart failure. Eur Heart J. 1999;20(1):70-76.  (PubMed)

51.  Serati AR, Motamedi MR, Emami S, Varedi P, Movahed MR. L-carnitine treatment in patients with mild diastolic heart failure is associated with improvement in diastolic function and symptoms. Cardiology. 2010;116(3):178-182.   (PubMed)

52.  Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. Drugs Exp Clin Res. 1991;17(4):225-235.  (PubMed)

53.  Cherchi A, Lai C, Angelino F, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomized, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol. 1985;23(10):569-572.  (PubMed)

54.  Iyer RN, Khan AA, Gupta A, Vajifdar BU, Lokhandwala YY. L-carnitine moderately improves the exercise tolerance in chronic stable angina. J Assoc Physicians India. 2000;48(11):1050-1052.  (PubMed)

55.  Bartels GL, Remme WJ, Pillay M, Schonfeld DH, Kruijssen DA. Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol. 1994;74(2):125-130.  (PubMed)

56.  Mills JL. Peripheral arterial disease. In: Rakel RE, Bope ET, eds. Conn's Current Therapy. 54th ed. New York: W.B. Sunders Company; 2002:340-343. 

57.  Brevetti G, Perna S, Sabba C, Martone VD, Condorelli M. Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol. 1995;26(6):1411-1416.   (PubMed)

58.  Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol. 1999;34(5):1618-1624.  (PubMed)

59.  Hiatt WR. Carnitine and peripheral arterial disease. Ann N Y Acad Sci. 2004;1033:92-98.  (PubMed)

60.  Santo SS, Sergio N, Luigi DP, et al. Effect of PLC on functional parameters and oxidative profile in type 2 diabetes-associated PAD. Diabetes Res Clin Pract. 2006;72(3):231-237.  (PubMed)

61.  Brevetti G, Perna S, Sabba C, et al. Superiority of L-propionylcarnitine vs L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J. 1992;13(2):251-255.  (PubMed)

62.  Cipolla MJ, Nicoloff A, Rebello T, Amato A, Porter JM. Propionyl-L-carnitine dilates human subcutaneous arteries through an endothelium-dependent mechanism. J Vasc Surg. 1999;29(6):1097-1103.  (PubMed)

63.  Loffredo L, Marcoccia A, Pignatelli P, et al. Oxidative-stress-mediated arterial dysfunction in patients with peripheral arterial disease. Eur Heart J. 2007;28(5):608-612.  (PubMed)

64.  Guarnieri G, Situlin R, Biolo G. Carnitine metabolism in uremia. Am J Kidney Dis. 2001;38(4 Suppl 1):S63-67.  (PubMed)

65.  Hurot JM, Cucherat M, Haugh M, Fouque D. Effects of L-carnitine supplementation in maintenance hemodialysis patients: a systematic review. J Am Soc Nephrol. 2002;13(3):708-714.  (PubMed)

66.  Vesela E, Racek J, Trefil L, Jankovy'ch V, Pojer M. Effect of L-carnitine supplementation in hemodialysis patients. Nephron. 2001;88(3):218-223.  (PubMed)

67.  Kazmi WH, Obrador GT, Sternberg M, et al. Carnitine therapy is associated with decreased hospital utilization among hemodialysis patients. Am J Nephrol. 2005;25(2):106-115.  (PubMed)

68.  Weinhandl ED, Rao M, Gilbertson DT, Collins AJ, Pereira BJ. Protective effect of intravenous levocarnitine on subsequent-month hospitalization among prevalent hemodialysis patients, 1998 to 2003. Am J Kidney Dis. 2007;50(5):803-812.  (PubMed)

69.  Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney Foundation. American Journal of Kidney Diseases. 2000;35(6 Suppl 2):S1-140.  (PubMed)

70.  Eknoyan G, Latos DL, Lindberg J. Practice recommendations for the use of L-carnitine in dialysis-related carnitine disorder. National Kidney Foundation Carnitine Consensus Conference. Am J Kidney Dis. 2003;41(4):868-876.  (PubMed)

71.  Schreiber B. Safety of oral carnitine in dialysis patients. Semin Dial. 2002;15(1):71-72.  (PubMed)

72.  Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease. Neurobiol Aging. 1995;16(1):1-4.  (PubMed)

73.  Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology. 1991;41(11):1726-1732.  (PubMed)

74.  Sano M, Bell K, Cote L, et al. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Arch Neurol. 1992;49(11):1137-1141.  (PubMed)

75.  Thal LJ, Carta A, Clarke WR, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology. 1996;47(3):705-711.  (PubMed)

76.  Thal LJ, Calvani M, Amato A, Carta A. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology. 2000;55(6):805-810.  (PubMed)

77.  Brooks JO, 3rd, Yesavage JA, Carta A, Bravi D. Acetyl L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Int Psychogeriatr. 1998;10(2):193-203.  (PubMed)

78.  Moretti S, Alesse E, Di Marzio L, et al. Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: a pilot study. Blood. 1998;91(10):3817-3824.  (PubMed)

79.  Moretti S, Famularo G, Marcellini S, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal. 2002;4(3):391-403.  (PubMed)

80.  Arrigoni-Martelli E, Caso V. Carnitine protects mitochondria and removes toxic acyls from xenobiotics. Drugs Exp Clin Res. 2001;27(1):27-49.  (PubMed)

81.  Scarpini E, Sacilotto G, Baron P, Cusini M, Scarlato G. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst. 1997;2(3):250-252.  (PubMed)

82.  Osio M, Muscia F, Zampini L, et al. Acetyl-l-carnitine in the treatment of painful antiretroviral toxic neuropathy in human immunodeficiency virus patients: an open label study. J Peripher Nerv Syst. 2006;11(1):72-76.   (PubMed)

83.  Youle M, Osio M. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med. 2007;8(4):241-250.  (PubMed)

84.  Hart AM, Wilson AD, Montovani C, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. Aids. 2004;18(11):1549-1560.  (PubMed)

85.  Herzmann C, Johnson MA, Youle M. Long-term effect of acetyl-L-carnitine for antiretroviral toxic neuropathy. HIV Clin Trials. 2005;6(6):344-350.  (PubMed)

86.  Jeulin C, Lewin LM. Role of free L-carnitine and acetyl-L-carnitine in post-gonadal maturation of mammalian spermatozoa. Hum Reprod Update. 1996;2(2):87-102.  (PubMed)

87.  Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res. 1995;21(4):157-159.  (PubMed)

88.  Costa M, Canale D, Filicori M, D'Lddio S, Lenzi A. L-carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia. 1994;26(3):155-159.  (PubMed)

89.  Matalliotakis I, Koumantaki Y, Evageliou A, Matalliotakis G, Goumenou A, Koumantakis E. L-carnitine levels in the seminal plasma of fertile and infertile men: correlation with sperm quality. Int J Fertil Womens Med. 2000;45(3):236-240.  (PubMed)

90.  Lenzi A, Lombardo F, Sgro P, et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril. 2003;79(2):292-300.  (PubMed)

91.  Lenzi A, Sgro P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril. 2004;81(6):1578-1584.   (PubMed)

92.  Balercia G, Regoli F, Armeni T, Koverech A, Mantero F, Boscaro M. Placebo-controlled double-blind randomized trial on the use of L-carnitine, L-acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic asthenozoospermia. Fertil Steril. 2005;84(3):662-671.  (PubMed)

93.  Siliprandi N, Di Lisa F, Pieralisi G, et al. Metabolic changes induced by maximal exercise in human subjects following L-carnitine administration. Biochim Biophys Acta. 1990;1034(1):17-21.  (PubMed)

94.  Vecchiet L, Di Lisa F, Pieralisi G, et al. Influence of L-carnitine administration on maximal physical exercise. Eur J Appl Physiol Occup Physiol. 1990;61(5-6):486-490.  (PubMed)

95.  Dragan GI, Vasiliu A, Georgescu E, Dumas I. Studies concerning chronic and acute effects of L-carnitine on some biological parameters in elite athletes. Physiologie. 1987;24(1):23-28.  (PubMed)

96.  Marconi C, Sassi G, Carpinelli A, Cerretelli P. Effects of L-carnitine loading on the aerobic and anaerobic performance of endurance athletes. Eur J Appl Physiol Occup Physiol. 1985;54(2):131-135.  (PubMed)

97.  Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr. 2000;72(2 Suppl):618S-623S.  (PubMed)

98.  Smith WA, Fry AC, Tschume LC, Bloomer RJ. Effect of glycine propionyl-L-carnitine on aerobic and anaerobic exercise performance. Int J Sport Nutr Exerc Metab. 2008;18(1):19-36.  (PubMed)

99.  Natali A, Santoro D, Brandi LS, et al. Effects of acute hypercarnitinemia during increased fatty substrate oxidation in man. Metabolism. 1993;42(5):594-600.  (PubMed)

100.  Barnett C, Costill DL, Vukovich MD, et al. Effect of L-carnitine supplementation on muscle and blood carnitine content and lactate accumulation during high-intensity sprint cycling. Int J Sport Nutr. 1994;4(3):280-288.  (PubMed)

101.  Vukovich MD, Costill DL, Fink WJ. Carnitine supplementation: effect on muscle carnitine and glycogen content during exercise. Med Sci Sports Exerc. 1994;26(9):1122-1129.  (PubMed)

102.  Trappe SW, Costill DL, Goodpaster B, Vukovich MD, Fink WJ. The effects of L-carnitine supplementation on performance during interval swimming. Int J Sports Med. 1994;15(4):181-185.  (PubMed)

103.  Brass EP, Hoppel CL, Hiatt WR. Effect of intravenous L-carnitine on carnitine homeostasis and fuel metabolism during exercise in humans. Clin Pharmacol Ther. 1994;55(6):681-692.  (PubMed)

104.  Brass EP. Carnitine and sports medicine: use or abuse? Ann N Y Acad Sci. 2004;1033:67-78.  (PubMed)

105.  Rebouche CJ. Carnitine. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Philadelphia: Lippincott, Williams & Wilkins; 1999:505-512.

106.  Brass EP, Hiatt WR. The role of carnitine and carnitine supplementation during exercise in man and in individuals with special needs. J Am Coll Nutr. 1998;17(3):207-215.  (PubMed)

107.  In: Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc.; 2001.

Coenzyme Q10

Summary

Introduction

Coenzyme Q10 is a member of the ubiquinone family of compounds. All animals, including humans, can synthesize ubiquinones, hence, coenzyme Q10 cannot be considered a vitamin (1). The name ubiquinone refers to the ubiquitous presence of these compounds in living organisms and their chemical structure, which contains a functional group known as a benzoquinone. Ubiquinones are fat-soluble molecules with anywhere from one to 12 isoprene (5-carbon) units. The ubiquinone found in humans, ubidecaquinone or coenzyme Q10, has a "tail" of 10 isoprene units (a total of 50 carbon atoms) attached to its benzoquinone "head" (Figure 1(2).

Figure 1. Chemical Structure of Coenzyme Q10. Coenzyme Q can exist in three oxidation states: the fully reduced ubiquinol form (CoQH2), the radical semiquinone intermediate (CoQH·), and the fully oxidized ubiquinone form (CoQ). Chemical structures of these forms are shown.

Biological Activities

Coenzyme Q10 is soluble in lipids (fats) and is found in virtually all cell membranes, as well as lipoproteins (2). The ability of the benzoquinone head group of coenzyme Q10 to accept and donate electrons is a critical feature in its biochemical functions. Coenzyme Q10 can exist in three oxidation states (see Figure 1 above): (1) the fully reduced ubiquinol form (CoQ10H2), (2) the radical semiquinone intermediate (CoQ10H·), and (3) the fully oxidized ubiquinone form (CoQ10).

Mitochondrial ATP synthesis

The conversion of energy from carbohydrates and fats to adenosine triphosphate (ATP), the form of energy used by cells, requires the presence of coenzyme Q in the inner mitochondrial membrane. As part of the mitochondrial electron transport chain, coenzyme Q accepts electrons from reducing equivalents generated during fatty acid and glucose metabolism and then transfers them to electron acceptors. At the same time, coenzyme Q transfers protons outside the inner mitochondrial membrane, creating a proton gradient across that membrane. The energy released when the protons flow back into the mitochondrial interior is used to form ATP (2)

Lysosomal function

Lysosomes are organelles within cells that are specialized for the digestion of cellular debris. The digestive enzymes within lysosomes function optimally at an acid pH, meaning they require a permanent supply of protons. The lysosomal membranes that separate those digestive enzymes from the rest of the cell contain relatively high concentrations of coenzyme Q10. Research suggests that coenzyme Q10 plays an important role in the transport of protons across lysosomal membranes to maintain the optimal pH (2, 3)

Antioxidant functions

In its reduced form, CoQ10H2 is an effective fat-soluble antioxidant. The presence of a significant amount of CoQ10H2 in cell membranes, along with enzymes that are capable of reducing oxidized CoQ10 back to CoQ10H2, supports the idea that CoQ10H2 is an important cellular antioxidant (2). CoQ10H2 has been found to inhibit lipid peroxidation when cell membranes and low-density lipoproteins (LDL) are exposed to oxidizing conditions outside the body (ex vivo). When LDL is oxidized ex vivo, CoQ10H2 is the first antioxidant consumed. Moreover, the formation of oxidized lipids and the consumption of α-tocopherol (α-TOH, biologically the most active form of vitamin E) are suppressed while CoQ10H2 is present (4). In isolated mitochondria, coenzyme Q10 can protect membrane proteins and DNA from the oxidative damage that accompanies lipid peroxidation (1). In addition to neutralizing free radicals directly, CoQ10H2 is capable of regenerating α-TOH from its one-electron oxidation product, α-tocopheroxyl radical (α-TO·).

Nutrient interactions

Vitamin E

α-Tocopherol (vitamin E) and coenzyme Q10 are the principal fat-soluble antioxidants in membranes and lipoproteins. When α-TOH neutralizes a free radical, such as a lipid peroxyl radical (LOO·), it becomes oxidized itself, forming α-TO·, which can promote the oxidation of lipoprotein lipids under certain conditions in the test tube. When the reduced form of coenzyme Q10 (CoQ10H2) reacts with α-TO·, α-TOH is regenerated and the semiquinone radical (CoQ10H·) is formed. It is possible for CoQ10H· to react with oxygen (O2) to produce superoxide anion radical (O2·-), which is a much less oxidizing radical than LOO·. However, CoQ10H· can also reduce α-TO· back to α-TOH, resulting in the formation of fully oxidized coenzyme Q10 (CoQ10), which does not react with O2 to form O2·- (Figure 2(4, 5).

Figure 2. Potential Interactions Between Coenzyme Q and Alpha-Tocopherol. When alpha-tocopherol (α-TOH) neutralizes a free radical, such as a lipid peroxyl radical (LOO·), it becomes oxidized itself, forming the alpha-tocopheroxyl radical (α-TO·), which can promote the oxidation of lipoprotein lipids under certain conditions in the test tube (Reaction 1). When the reduced form of coenzyme Q (CoQH2) reacts with α-TO·, α-TOH is regenerated and the semiquinone radical (CoQH·) is formed (Reaction 2). It is possible for CoQH· to react with oxygen (O2) to produce superoxide (O2·-), which is a much less oxidizing radical than LOO· (Reaction 3a). Alternatively, CoQH· can also reduce α-TO· back to α-TOH, resulting in the formation of fully oxidized coenzyme Q (CoQ), which does not react with O2 to form O2·- (Reaction 3b).

Deficiency

Symptoms of coenzyme Q10 deficiency have not been reported in the general population, so it is generally assumed that normal biosynthesis and a varied diet provides sufficient coenzyme Q10 for healthy individuals (6). It has been estimated that dietary consumption contributes about 25% of plasma coenzyme Q10, but there are currently no specific dietary intake recommendations for coenzyme Q10 from the Institute of Medicine or other agencies (7). The extent to which dietary consumption contributes to tissue coenzyme Q10 levels is not clear. 

Primary coenzyme Q10 deficiency is a rare, autosomal recessive disorder caused by genetic defects in coenzyme Q10 biosynthesis. The resultant low tissue levels of coenzyme Q10 severely compromise neuronal and muscular function. Oral coenzyme Q10 supplementation has been shown to improve neurological and muscular symptoms in some patients with primary coenzyme Q10 deficiency (8). Coenzyme Q10 levels have been found to decline gradually with age in a number of different tissues (1, 9), but it is unclear whether this age-associated decline constitutes a deficiency (see Disease Prevention). Decreased plasma levels of coenzyme Q10 have been observed in individuals with diabetes, cancer, and congestive heart failure (see Disease Treatment). Lipid lowering medications that inhibit the activity of HMG-CoA reductase, a critical enzyme in both cholesterol and coenzyme Q10 biosynthesis, decrease plasma coenzyme Q10 levels (see HMG-CoA reductase inhibitors (statins) under Drug interactions), although it remains unclear whether this has clinical or symptomatic implications.

Disease Prevention

Aging

According to the free radical and mitochondrial theories of aging, oxidative damage of cell structures by reactive oxygen species (ROS) plays an important role in the functional declines that accompany aging (10). ROS are generated by mitochondria as a byproduct of ATP production. If not neutralized by antioxidants, ROS may damage mitochondria over time, causing them to function less efficiently and to generate more damaging ROS in a self-perpetuating cycle. Coenzyme Q10 plays an important role in mitochondrial ATP synthesis and functions as an antioxidant in mitochondrial membranes. Moreover, tissue levels of coenzyme Q10 have been reported to decline with age (9). One of the hallmarks of aging is a decline in energy metabolism in many tissues, especially liver, heart, and skeletal muscle. It has been proposed that age-associated declines in tissue coenzyme Q10 levels may play a role in this decline (11). In recent studies, lifelong dietary supplementation with coenzyme Q10 increased tissue concentrations of coenzyme Q10 but did not increase the lifespans of rats or mice (12, 13); however, one study showed that coenzyme Q10 supplementation attenuates the age-related increase in DNA damage (14). Presently, there is no scientific evidence that coenzyme Q10 supplementation prolongs life or prevents age-related functional declines in humans. 

Cardiovascular disease

Oxidative modification of low-density lipoproteins (LDL) in arterial walls is thought to represent an early event leading to the development of atherosclerosis. Reduced coenzyme Q10 (CoQ10H2) inhibits the oxidation of LDL in the test tube (in vitro) and works together with α-TOH to inhibit LDL oxidation by reducing the α-TO· back to α-TOH. In the absence of a co-antioxidant, such as CoQ10H2 (or vitamin C), α-TOH can, under certain conditions, promote the oxidation of LDL in vitro (4). Supplementation with coenzyme Q10 increases the concentration of CoQ10H2 in human LDL (15). Studies in apolipoprotein E-deficient mice, an animal model of atherosclerosis, found that coenzyme Q10 supplementation with supra-pharmacological amounts of coenzyme Q10 significantly inhibited the formation of atherosclerotic lesions (16). Interestingly, co-supplementation of these mice with α-TOH and coenzyme Q10 was more effective in inhibiting atherosclerosis than supplementation with either α-TOH or coenzyme Q10 alone (17). Another important step in the development of atherosclerosis is the recruitment of immune cells known as monocytes into the blood vessel walls. This recruitment is dependent in part on monocyte expression of cell adhesion molecules (integrins). Supplementation of 10 healthy men and women with 200 mg/day of coenzyme Q10 for 10 weeks resulted in significant decreases in monocyte expression of integrins, suggesting another potential mechanism for the inhibition of atherosclerosis by coenzyme Q10 (18). Although coenzyme Q10 supplementation shows promise as an inhibitor of LDL oxidation and atherosclerosis, more research is needed to determine whether coenzyme Q10 supplementation can inhibit the development or progression of atherosclerosis in humans.

Disease Treatment

Mitochondrial encephalomyopathies

Mitochondrial encephalomyopathies represent a diverse group of genetic disorders resulting from numerous inherited abnormalities in the function of the mitochondrial electron transport chain. Coenzyme Q10 supplementation has resulted in clinical and metabolic improvement in some patients with various types of mitochondrial encephalomyopathies (19). Neuromuscular and widespread tissue coenzyme Q10 deficiencies have been found in a very small subpopulation of individuals with mitochondrial encephalomyopathies (20, 21). In those rare individuals with genetic defects in coenzyme Q10 biosynthesis, coenzyme Q10 supplementation has resulted in substantial improvement (22, 23). It is not clear whether coenzyme Q10 supplementation might have therapeutic benefit in patients with other mitochondrial disorders; a phase III clinical trial investigating that question is currently under way (23)

Cardiovascular disease

Congestive heart failure

Impairment of the heart's ability to pump enough blood for all of the body's needs is known as congestive heart failure. In coronary artery disease, accumulation of atherosclerotic plaque in the coronary arteries may prevent parts of the heart muscle from getting adequate blood supply, ultimately resulting in cardiac damage and impaired pumping ability. Myocardial infarction (MI) may also damage the heart muscle, leading to heart failure. Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure. Echocardiography is also used to determine the left ventricular ejection fraction, an objective measure of the heart's pumping ability (25). The finding that myocardial coenzyme Q10 levels were lower in patients with more severe versus milder heart failure led to several clinical trials of coenzyme Q10 supplementation in heart failure patients (26). A number of small intervention trials that administered supplemental coenzyme Q10 (100-300 mg/day of coenzyme Q10 for one to three months) to congestive heart failure patients, in conjunction with conventional medical therapy, have demonstrated improvements in some cardiac function measures (27-29). However, other researchers have found that supplementing the diet with 100-200 mg/day of coenzyme Q10, along with conventional medical therapy, did not significantly improve left ventricular ejection fraction or exercise performance in heart failure patients (30, 31). A 2006 meta-analysis of 10 randomized controlled trials found that coenzyme Q10 supplementation (99-200 mg/day for one to six months) in heart failure patients resulted in a significant, 3.7% improvement in left ventricular ejection fraction; the effect was stronger in patients not taking angiotensin-converting enzyme inhibitors (32). A slight increase in cardiac output (0.28 L/min) was also found with coenzyme Q10 supplementation, but this analysis only included two trials (60 mg/day for one month or 200 mg/day for three months) (32). A recent study in 236 heart failure patients found that lower plasma coenzyme Q10 levels were associated with a heightened risk of mortality (33); however, a larger study of 1,191 heart failure patients found that plasma coenzyme Q10 level was a biomarker of advanced heart disease and not an independent predictor of clinical outcomes in heart failure patients (34). Although there is some evidence that coenzyme Q10 supplementation may be of benefit, large well-designed intervention trials are needed to determine whether coenzyme Q10 supplementation has value as an adjunct to conventional medical therapy in the treatment of congestive heart failure. One such large trial is presently being conducted.  

Myocardial infarction and cardiac surgery

The heart muscle may become oxygen-deprived (ischemic) as the result of myocardial infarction (MI) or during cardiac surgery. Increased generation of ROS when the heart muscle's oxygen supply is restored (reperfusion) is thought to be an important contributor to myocardial damage occurring during ischemia-reperfusion. Pretreatment of animals with coenzyme Q10 has been found to decrease myocardial damage due to ischemia-reperfusion (35). Another potential source of ischemia-reperfusion injury is aortic clamping during some types of cardiac surgery, such as coronary artery bypass graft (CABG) surgery. Three out of four placebo-controlled trials found that coenzyme Q10 pretreatment (100-300 mg/day for 7-14 days prior to surgery) provided some benefit in short-term outcome measures after CABG surgery (36, 37). In the placebo-controlled trial that did not find preoperative coenzyme Q10 supplementation to be of benefit, patients were treated with 600 mg of coenzyme Q10 12 hours prior to surgery (38), suggesting that preoperative coenzyme Q10 treatment may need to commence at least one week prior to CABG surgery in order to realize any benefit. Although the results are promising, these trials have included relatively few people and have only examined outcomes shortly after CABG surgery. 

Angina pectoris

Myocardial ischemia may also lead to chest pain known as angina pectoris. People with angina pectoris often experience symptoms when the demand for oxygen exceeds the capacity of the coronary circulation to deliver it to the heart muscle, e.g., during exercise. Five small placebo-controlled studies have examined the effects of oral coenzyme Q10 supplementation (60-600 mg/day) in addition to conventional medical therapy in patients with chronic stable angina (28). In most of the studies, coenzyme Q10 supplementation improved exercise tolerance and reduced or delayed electrocardiographic changes associated with myocardial ischemia compared to placebo. However, only two of the studies found significant decreases in symptom frequency and nitroglycerin consumption with coenzyme Q10 supplementation. Presently, there is only limited evidence suggesting that coenzyme Q10 supplementation would be a useful adjunct to conventional angina therapy. 

Hypertension

The results of several small, uncontrolled studies in humans suggest that coenzyme Q10 supplementation could be beneficial in the treatment of hypertension (37). More recently, two short-term placebo-controlled trials found that coenzyme Q10 supplementation resulted in moderate blood pressure decreases in hypertensive individuals. The addition of 120 mg/day of coenzyme Q10 to conventional medical therapy for eight weeks in patients with hypertension and coronary artery disease decreased systolic blood pressure by an average of 12 mm Hg and diastolic blood pressure by an average of 6 mm Hg, in comparison to a placebo containing B-complex vitamins (39). In patients with isolated systolic hypertension, supplementation with both coenzyme Q10 (120 mg/day) and vitamin E (300 IU/day) for 12 weeks resulted in an average decrease of 17 mm Hg in systolic blood pressure compared with 300 IU/day of vitamin E (300 IU/day) alone (40). A 2007 meta-analysis of 12 clinical trials, including 362 hypertensive patients, found that supplemental coenzyme Q10 reduces systolic blood pressure by 11-17 mm Hg and diastolic blood pressure by 8-10 mm Hg (41). The four randomized controlled trials included in this meta-analysis used doses of 100-120 mg/day of coenzyme Q10.

Vascular endothelial function (blood vessel dilation)

Normal function of the inner lining of blood vessels, known as the vascular endothelium, plays an important role in preventing cardiovascular disease (42). Atherosclerosis is associated with impairment of vascular endothelial function, thereby compromising the ability of blood vessels to relax and permit normal blood flow. Endothelium-dependent blood vessel relaxation (vasodilation) is impaired in individuals with elevated serum cholesterol levels as well as in patients with coronary artery disease or diabetes. One placebo-controlled trial found that coenzyme Q10 supplementation (200 mg/day) for 12 weeks improved endothelium-dependent vasodilation in diabetic patients with abnormal serum lipid profiles, although it did not restore vasodilation to levels seen in non-diabetic individuals (43). Another placebo-controlled study in 23 type 2 diabetics taking statins (HMG-CoA reductase inhibitors) found that 200 mg/day of coenzyme Q10 for 12 weeks improved flow-mediated dilatation, but not nitrate-mediated dilatation, of the brachial artery (44). However, a placebo-controlled trial in 80 type 2 diabetics found that this supplementation protocol did not improve endothelial function (45).

In a study of 12 individuals with high serum cholesterol levels and endothelial dysfunction who were otherwise healthy, supplementation with 150 mg/day of coenzyme Q10 did not affect endothelium-dependent vasodilation (46). A prospective, randomized cross-over study of 25 men with endothelial dysfunction found that coenzyme Q10 supplementation (150 mg/day) significantly improved endothelial function, similar to that of a lipid-lowering medication (47). Yet, it is important to mention that this study was not placebo-controlled and, importantly, the authors reported that the subjects' mean baseline for flow-mediated vasodilation was below zero. A randomized, double-blind, placebo-controlled trial in 22 patients with coronary artery disease found that 300 mg/day of coenzyme Q10 for one month improved endothelium-dependent vasodilation (48). Another randomized, double-blind, placebo-controlled trial in 56 patients with ischemic left ventricular systolic dysfunction reported that 300 mg/day of coenzyme Q10 for eight weeks significantly improved measures of endothelial dysfunction (49). A 2011 meta-analysis examining the results of five randomized controlled trials, including 194 subjects, found that supplemental coenzyme Q10 (150-300 mg/day for four to 12 weeks) resulted in a clinically significant, 1.7% increase in flow-dependent endothelial-mediated dilation (50). Large-scale studies are needed to further elucidate the therapeutic role of coenzyme Q10 in endothelial dysfunction. 

Diabetes mellitus

Diabetes mellitus is a condition of increased oxidative stress and impaired energy metabolism. Plasma levels of reduced coenzyme Q10 (CoQ10H2) have been found to be lower in diabetic patients than healthy controls when normalized to plasma cholesterol levels (51, 52). However, supplementation with 100 mg/day of coenzyme Q10 for three months neither improved glycemic (blood glucose) control nor decreased insulin requirements in type 1 (insulin-dependent) diabetics compared to placebo (53). Similarly, 200 mg/day of coenzyme Q10 supplementation for 12 weeks or six months did not improve glycemic control or serum lipid profiles in type 2 (non-insulin dependent) diabetics (45, 54). Because coenzyme Q10 supplementation did not influence glycemic control in either study, the authors of both studies concluded that coenzyme Q10 supplements could be used safely in diabetic patients as adjunct therapy for cardiovascular disease

Maternally inherited diabetes mellitus and deafness (MIDD) is the result of a mutation in mitochondrial DNA, which is inherited exclusively from one's mother. Although mitochondrial diabetes accounts for less than 1% of all diabetes, there is some evidence that long-term coenzyme Q10 supplementation (150 mg/day) may improve insulin secretion and prevent progressive hearing loss in these patients (55, 56)

Neurodegenerative diseases

Parkinson's disease

Parkinson's disease is a degenerative neurological disorder characterized by tremors, muscular rigidity, and slow movements. It is estimated to affect approximately 1% of Americans over the age of 65. Although the causes of Parkinson's disease are not all known, decreased activity of complex I of the mitochondrial electron transport chain and increased oxidative stress in a part of the brain called the substantia nigra are thought to play a role. Coenzyme Q10 is the electron acceptor for complex I as well as an antioxidant, and decreased ratios of reduced to oxidized coenzyme Q10 have been found in platelets of individuals with Parkinson's disease (57, 58). One study also found higher concentrations of oxidized coenzyme Q10 in the cerebrospinal fluid of patients with untreated Parkinson’s disease compared to healthy controls (59). Additionally, a study of coenzyme Q10 levels in postmortem Parkinson’s disease patients found lower levels of total coenzyme Q10 in the cortex region of the brain compared to age-matched controls, but no differences were seen in other brain areas, including the striatum, substantia nigra, and cerebellum (60). A 16-month randomized placebo-controlled trial evaluated the safety and efficacy of 300, 600, or 1,200 mg/day of coenzyme Q10 in 80 people with early Parkinson's disease (61). Coenzyme Q10 supplementation was well tolerated at all doses and was associated with slower deterioration of function in Parkinson's disease patients compared to placebo. However, the difference was statistically significant only in the group taking 1,200 mg/day. A smaller placebo-controlled trial showed that oral administration of 360 mg/day of coenzyme Q10 for four weeks moderately benefited Parkinson's disease patients (62). More recently, a randomized, double-blind, placebo-controlled trial in 106 patients with midstage Parkinson’s disease reported that 300 mg/day of nanoparticular coenzyme Q10 for three months had no therapeutic benefit (63). Another trial found that 2,400 mg/day of coenzyme Q10 for 12 months was not effective in early Parkinson’s disease (64). A phase III clinical trial of coenzyme Q10 (1,200-2,400 mg/day) and vitamin E (1,200 IU/day) supplementation in patients with Parkinson’s disease was recently terminated because it was unlikely that such a treatment was effective in treating Parkinson’s disease (65)

Huntington's disease

Huntington's disease is an inherited neurodegenerative disorder characterized by selective degeneration of nerve cells known as striatal spiny neurons. Symptoms, such as movement disorders and impaired cognitive function, typically develop in the fourth decade of life and progressively deteriorate over time. Animal models indicate that impaired mitochondrial function and glutamate-mediated neurotoxicity may play roles in the pathology of Huntington's disease. Coenzyme Q10 supplementation has been found to decrease brain lesion size in animal models of Huntington's disease and to decrease brain lactate levels in Huntington's disease patients (66, 67). Feeding a combination of coenzyme Q10 (0.2% of diet) and remacemide (0.007% of diet) to transgenic mice that express the Huntington's disease protein (HD-N171-82Q mice) resulted in improved motor performance and/or survival (68, 69). Remacemide is an antagonist of the neuronal receptor that is activated by glutamate.

It was recently shown that the R6/2 mouse model of Huntington's disease exhibits a progressive decline in behavioral and neurological symptoms similar to that of the human condition (70). Thus, R6/2 mice may be an ideal model to investigate potential therapies for Huntington's disease. Some, but not all, studies employing these mice have shown that dietary supplementation with coenzyme Q10 (0.2% of diet) improves motor performance and overall survival and helps to prevent body weight loss; coenzyme Q10 supplementation has also been associated with reductions in the various hallmarks of Huntington's disease, i.e., brain atrophy, ventricular enlargement, and striatal neuronal atrophy (68, 71). Interestingly, co-administration of coenzyme Q10 with remacemide, the antibiotic minocycline, or creatine has been shown to result in even greater improvements in most measured parameters (68, 71, 72).

To date, only one clinical trial has examined whether coenzyme Q10 might be efficacious in human patients with Huntington's disease. A 30-month, randomized, placebo-controlled trial of coenzyme Q10 (600 mg/day), remacemide, or both in 347 patients with early Huntington's disease found that neither coenzyme Q10 nor remacemide significantly altered the decline in total functional capacity, although coenzyme Q10 supplementation (with or without remacemide) resulted in a nonsignificant 13% decrease in the decline (73). A recent 20-week pilot trial examined the safety and tolerability of increasing dosages of coenzyme Q10 (1,200 mg/day, 2,400 mg/day, and 3,600 mg/day) in eight healthy subjects and in 20 patients with Huntington’s disease; 22 of the subjects completed the study (74). All dosages were generally well tolerated, with gastrointestinal symptoms being the most frequently reported adverse effect. Blood levels of coenzyme Q10 at the end of the study were not higher than the levels resulting from the intermediate dose, suggesting that the 2,400 mg/day effectively maximizes blood coenzyme Q10 levels and potentially avoid any side effects with higher dosages (74). A phase III clinical trial administering 2,400 mg/day of coenzyme Q10 or placebo for five years is currently recruiting participants with Huntington’s disease (75). At present, there is insufficient evidence to recommend coenzyme Q10 supplements to Huntington's disease patients.

Friedreich's ataxia

Friedreich's ataxia (FRDA) is an inherited, autosomal recessive neurodegenerative disease caused by mutations in the gene that encodes frataxin, a protein of unknown function that is primarily located in the mitochondria. Decreased expression of frataxin is associated with accumulation of iron within the mitochondria, thereby resulting in increased oxidative stress; imbalances in iron-sulfur containing proteins, including mitochondrial aconitase; and reduced activities of the mitochondrial respiratory chain (76). Clinically, FRDA is a progressive disease characterized by limb ataxia and CNS abnormalities that result from sensory nerve degeneration (77, 78). In addition, FRDA patients experience symptoms of hypertrophic cardiomyopathy and diabetes (79). A pilot study administering coenzyme Q10 (200 mg/day) and vitamin E (2,100 IU/day) to 10 FDRA patients found that energy metabolism of cardiac and skeletal muscle was improved after only three months of therapy (80). Follow-up assessments at 47 months indicated that cardiac and skeletal muscle improvements were maintained and that FRDA patients showed significant increases in fractional shortening, a measure of cardiac function. Moreover, the therapy was effective at preventing the progressive decline of neurological function (81). A recent study reported that both coenzyme Q10 and vitamin E deficiencies are quite common among FRDA patients and that cosupplementation with both compounds, at doses as low as 30mg/day of coenzyme Q10 and 4 IU/day of vitamin E, may improve disease symptoms (82). Large-scale randomized clinical trials are necessary to determine whether coenzyme Q10, in conjunction with vitamin E, has therapeutic benefit in FRDA.

Cancer

Interest in coenzyme Q10 as a potential therapeutic agent in cancer was stimulated by an observational study that found that individuals with lung, pancreas, and especially breast cancer were more likely to have low plasma coenzyme Q10 levels than healthy controls (83). Although a few case reports and an uncontrolled trial suggest that coenzyme Q10 supplementation may be beneficial as an adjunct to conventional therapy for breast cancer (84), the lack of controlled clinical trials makes it impossible to determine the effects, if any, of coenzyme Q10 supplementation in cancer patients.

Performance

Athletic performance

Although coenzyme Q10 supplementation has improved exercise tolerance in some individuals with mitochondrial encephalomyopathies (see Deficiency) (19), there is little evidence that it improves athletic performance in healthy individuals. At least seven placebo-controlled trials have examined the effects of 100-150 mg/day of coenzyme Q10 supplementation for three to eight weeks on physical performance in trained and untrained men. Most found no significant differences between groups taking coenzyme Q10 and groups taking placebos with respect to measures of aerobic exercise performance, such as maximal oxygen consumption (VO2 max) and exercise time to exhaustion (85-89). One study found the maximal cycling workload to be slightly (4%) increased after eight weeks of coenzyme Q10 supplementation compared to placebo, although measures of aerobic power were not increased (90). Two studies actually found significantly greater improvement in measures of anaerobic (86) and aerobic (85) exercise performance after supplementation with a placebo compared to coenzyme Q10. Studies on the effect of supplementation on physical performance in women are lacking, but there is little reason to suspect a gender difference in the response to coenzyme Q10 supplementation.

Sources

Biosynthesis

Coenzyme Q10 is synthesized in most human tissues. The biosynthesis of coenzyme Q10 involves three major steps: (1) synthesis of the benzoquinone structure from either tyrosine or phenylalanine, two amino acids; (2) synthesis of the isoprene side chain from acetyl-coenzyme A (CoA) via the mevalonate pathway; and (3) the joining or condensation of these two structures. The enzyme hydroxymethylglutaryl (HMG)-CoA reductase plays a critical role in the regulation of coenzyme Q10 synthesis, as well as the regulation of cholesterol synthesis (1, 6).

The first step in benzoquinone biosynthesis (the conversion of tyrosine to 4-hydroxyphenylpyruvic acid) requires vitamin B6 in the form of pyridoxal 5'-phosphate. Thus, adequate vitamin B6 nutrition is essential for coenzyme Q10 biosynthesis. A pilot study in 29 patients and healthy volunteers found significant positive correlations between blood levels of coenzyme Q10 and measures of vitamin B6 nutritional status (91). However, further research is required to determine the clinical significance of this association.

Food sources

Based on food frequency studies, the average dietary intake of coenzyme Q10 in Denmark was estimated to be 3-5 mg/day (6, 7). Most people probably have a dietary intake of less than 10 mg/day of coenzyme Q10. Rich sources of dietary coenzyme Q10 include mainly meat, poultry, and fish. Other relatively rich sources include soybean and canola oils, and nuts. Fruit, vegetables, eggs, and dairy products are moderate sources of coenzyme Q10. Approximately 14%-32% of coenzyme Q10 was lost during frying of vegetables and eggs, but the coenzyme Q10 content of these foods did not change when they were boiled. Some relatively rich dietary sources and their coenzyme Q10 content in milligrams (mg) are listed in Table 1 (92-94).

Table 1. Some Food Sources of Coenzyme Q10
Food Serving Coenzyme Q10 (mg)
Beef, fried  3 ounces*  2.6 
Herring, marinated  3 ounces  2.3 
Chicken, fried  3 ounces  1.4 
Soybean oil  1 tablespoon  1.3 
Canola oil  1 tablespoon  1.0 
Rainbow trout, steamed  3 ounces  0.9 
Peanuts, roasted  1 ounce  0.8 
Sesame seeds, roasted  1 ounce  0.7 
Pistachio nuts, roasted  1 ounce  0.6 
Broccoli, boiled  ½ cup, chopped  0.5 
Cauliflower, boiled  ½ cup, chopped  0.4 
Orange  1 medium  0.3 
Strawberries  ½ cup  0.1 
Egg, boiled  1 medium  0.1
*A three-ounce serving of meat or fish is about the size of a deck of cards.

Supplements

Coenzyme Q10 is available without a prescription as a dietary supplement in the US. Supplemental doses for adults range from 30-100 mg/day, which is considerably higher than normal dietary coenzyme Q10 intake. Therapeutic doses for adults generally range from 100-300 mg/day, although doses as high as 3,000 mg/day have been used to treat early Parkinson's disease under medical supervision (95). Absorption of coenzyme Q10 decreases with increasing supplemental dose; total intestinal absorption is likely less than 10% in humans. Coenzyme Q10 is fat-soluble and is best absorbed with fat in a meal. Doses higher than 100 mg/day are generally divided into two or three doses throughout the day (7, 96)

Does oral coenzyme Q10 supplementation increase tissue levels?

Oral supplementation with coenzyme Q10 is known to increase blood and lipoprotein concentrations of coenzyme Q10 in humans (2, 12, 15). However, it is not clear whether oral supplementation increases coenzyme Q10 concentrations in other tissues of individuals with normal endogenous coenzyme Q10 biosynthesis. Oral coenzyme Q10 supplementation of young healthy animals has not generally resulted in increased tissue concentrations, other than in the liver, spleen, and blood vessels (97, 98). Supplementation of healthy men with 120 mg/day for three weeks did not increase skeletal muscle concentrations of coenzyme Q10 (99). However, supplementation may increase coenzyme Q10 levels in tissues that are deficient. For example, oral supplementation of aged rats increased brain coenzyme Q10 concentrations (100), and a study of 24 older adults supplemented with 300 mg/day of coenzyme Q10 or placebo for at least seven days prior to cardiac surgery found that the coenzyme Q10 content of atrial tissue was significantly increased in those taking coenzyme Q10, especially in those over 70 years of age (36). Additionally, in a study of patients with left ventricular dysfunction, supplementation with 150 mg/day of coenzyme Q10 for four weeks before cardiac surgery increased coenzyme Q10 levels in the heart but not in skeletal muscle (101). Clearly, this is an area of research that requires further investigation.

Safety

Toxicity

There have been no reports of significant adverse side effects of oral coenzyme Q10 supplementation at doses as high as 1,200 mg/day for up to 16 months (61) and 600 mg/day for up to 30 months (73). In fact, 1,200 mg/day has recently been proposed as the observed safe level (OSL) for coenzyme Q10 (102). Some people have experienced gastrointestinal symptoms, such as nausea, diarrhea, appetite suppression, heartburn, and abdominal discomfort. These adverse effects may be minimized if daily doses higher than 100 mg are divided into two or three daily doses. Because controlled safety studies in pregnant and lactating women are not available, the use of coenzyme Q10 supplements by pregnant or breast-feeding women should be avoided (96, 103).

Drug interactions

Warfarin

Concomitant use of warfarin (Coumadin) and coenzyme Q10 supplements has been reported to decrease the anticoagulant effect of warfarin in at least four cases (104). An individual on warfarin should not begin taking coenzyme Q10 supplements without consulting the health care provider who is managing his or her anticoagulant therapy. If warfarin and coenzyme Q10 are to be used concomitantly, blood tests to assess clotting time (prothrombin time; PT/INR) should be monitored frequently, especially in the first two weeks. 

HMG-CoA reductase inhibitors (statins)

HMG-CoA reductase is an enzyme that plays a critical role in the regulation of cholesterol synthesis as well as coenzyme Q10 synthesis, although it is now recognized that there are additional rate-limiting steps in the biosynthesis of cholesterol and coenzyme Q10. HMG-CoA reductase inhibitors, also known as statins, are widely used cholesterol-lowering medications that may also decrease the endogenous synthesis of coenzyme Q10. Therapeutic use of statins, including simvastatin (Zocor), pravastatin (Pravachol), lovastatin (Mevacor, Altocor, Altoprev), rosuvastatin (Crestor), and atorvastatin (Lipitor), has been shown to decrease blood plasma or serum levels of coenzyme Q10 (105-114). However, it has been suggested that blood coenzyme Q10 concentrations should be reported only after normalizing to total lipid or cholesterol levels because coenzyme Q10 circulates with lipoproteins and levels of coenzyme Q10 are highly dependent upon levels of circulating lipids (115, 116). Given the lipid-lowering effects of statins, it is therefore unclear whether these drugs actually decrease coenzyme Q10 levels independent of a reduction in circulating lipids. Also, very few studies have examined coenzyme Q10 content in target organs; thus, it is not clear whether statin therapy affects coenzyme Q10 concentrations in the body's tissues (111, 113, 117). At present, more research is needed to determine whether coenzyme Q10 supplementation might be beneficial for those taking HMG-CoA reductase inhibitors.


Authors and Reviewers

Originally written in 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in February 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2012 by:
Roland Stocker, Ph.D.
Centre for Vascular Research
School of Medical Sciences (Pathology) and
Bosch Institute
Sydney Medical School
The University of Sydney
Sydney, New South Wales, Australia

Copyright 2003-2017  Linus Pauling Institute


References

1.  Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995;1271(1):195-204.  (PubMed)

2.  Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001;20(6):591-598.  (PubMed)

3.  Nohl H, Gille L. The role of coenzyme Q in lysosomes. In: Kagan VEQ, P. J. (ed). Coenzyme Q: Molecular Mechanisms in Health and Disease. Boca Raton: CRC Press; 2001:99-106.

4.  Thomas SR, Stocker R. Mechanisms of antioxidant action of ubiquinol-10 for low-density lipoprotein. In: Kagan VE, Quinn PJ,eds. Coenzyme Q: Molecular Mechanisms in Health and Disease. Boca Raton: CRC Press; 2001:131-150.

5.  Kagan VE, Fabisak JP, Tyurina YY. Independent and concerted antioxidant functions of coenzyme Q. In: Kagan VE, Quinn PJ, eds. Coenzyme Q: Molecular Mechanisms in Health and Disease. Boca Raton: CRC Press; 2001:119-130.

6.  Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999;53(10):764-770.  (PubMed)

7.  Weber C. Dietary intake and absorption of coenzyme Q. In: Kagan VE, Quinn PJ,eds. Coenzyme Q: Molecular Mechanisms in Health and Disease. Boca Raton: CRC Press; 2001:209-215.

8.  Rustin P, Munnich A, Rotig A. Mitochondrial respiratory chain dysfunction caused by coenzyme Q deficiency. Methods Enzymol. 2004;382:81-88.   (PubMed)

9.  Kalen A, Appelkvist EL, Dallner G. Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989;24(7):579-584.  (PubMed)

10.  Beckman KB, Ames BN. Mitochondrial aging: open questions. Ann N Y Acad Sci. 1998;854:118-127.  (PubMed)

11.  Alho H, Lonnrot K. Coenzyme Q supplementation and longevity. In: Kagan VE, Quinn PJ,eds. Coenzyme Q: Molecular Mechanisms in Health and Disease. Boca Raton: CRC Press; 2001:371-380.

12.  Singh RB, Niaz MA, Kumar A, Sindberg CD, Moesgaard S, Littarru GP. Effect on absorption and oxidative stress of different oral Coenzyme Q10 dosages and intake strategy in healthy men. Biofactors. 2005;25(1-4):219-224.  (PubMed)

13.  Sohal RS, Kamzalov S, Sumien N, et al. Effect of coenzyme Q10 intake on endogenous coenzyme Q content, mitochondrial electron transport chain, antioxidative defenses, and life span of mice. Free Radic Biol Med. 2006;40(3):480-487.  (PubMed)

14.  Quiles JL, Ochoa JJ, Battino M, et al. Life-long supplementation with a low dosage of coenzyme Q10 in the rat: effects on antioxidant status and DNA damage. Biofactors. 2005;25(1-4):73-86.  (PubMed)

15.  Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta. 1992;1126(3):247-254.  (PubMed)

16.  Witting PK, Pettersson K, Letters J, Stocker R. Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice. Free Radic Biol Med. 2000;29(3-4):295-305.  (PubMed)

17.  Thomas SR, Leichtweis SB, Pettersson K, et al. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001;21(4):585-593.   (PubMed)

18.  Turunen M, Wehlin L, Sjoberg M, et al. beta2-Integrin and lipid modifications indicate a non-antioxidant mechanism for the anti-atherogenic effect of dietary coenzyme Q10. Biochem Biophys Res Commun. 2002;296(2):255-260.  (PubMed)

19.  Shoffner JM. Oxidative phosphorylation diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D,eds. The metabolic and molecular bases of inherited disease. 8th ed. Volume 2. New York: McGraw-Hill; 2001:2367-2392.

20.  Rotig A, Appelkvist EL, Geromel V, et al. Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet. 2000;356(9227):391-395.  (PubMed)

21.  Boitier E, Degoul F, Desguerre I, et al. A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10 deficiency. J Neurol Sci. 1998;156(1):41-46.  (PubMed)

22.  Munnich A, Rotig A, Cormier-Daire V, Rustin P. Clinical presentation of respiratory chain deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D,eds. The metabolic and molecular bases of inherited disease. 8th ed. Volume 2. New York: McGraw-Hill; 2001:2261-2274.

23.  Horvath R, Gorman G, Chinnery PF. How can we treat mitochondrial encephalomyopathies? Approaches to therapy. Neurotherapeutics. 2008;5:558-568.   (PubMed)

24.  National Institutes of Health. Phase III Trial of Coenzyme Q10 in Mitochondrial Disease. ClinicalTrials.gov [Web page]. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00432744?term=coenzyme+Q10+AND+mitochondrial&rank=1. Accessed 2/23/12.

25.  Trupp RJ, Abraham WT. Congestive heart failure. In: Rakel RE, Bope ET,eds. Rakel: Conn's Current Therapy 2002. 54th ed. New York: W. B. Saunders Company; 2002:306-313.

26.  Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci U S A. 1985;82(3):901-904.  (PubMed)

27.  Belardinelli R, Mucaj A, Lacalaprice F, et al. Coenzyme Q10 and exercise training in chronic heart failure. Eur Heart J. 2006; 27(22):2675-2681.  (PubMed)

28.  Tran MT, Mitchell TM, Kennedy DT, Giles JT. Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy. 2001;21(7):797-806.  (PubMed)

29.  Belardinelli R, Mucaj A, Lacalaprice F, et al. Coenzyme Q10 improves contractility of dysfunctional myocardium in chronic heart failure. Biofactors. 2005;25(1-4):137-145.  (PubMed)

30.  Khatta M, Alexander BS, Krichten CM, et al. The effect of coenzyme Q10 in patients with congestive heart failure. Ann Intern Med. 2000;132(8):636-640.  (PubMed)

31. Watson PS, Scalia GM, Galbraith A, Burstow DJ, Bett N, Aroney CN. Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure. J Am Coll Cardiol. 1999;33(6):1549-1552.  (PubMed)

32.  Sander S, Coleman CI, Patel AA, Kluger J, White CM. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail. 2006;12:464-472.  (PubMed)

33.  Molyneux SL, Florkowski CM, George PM, et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008;52:1435-1441.  (PubMed)

34.  McMurray JJ, Dunselman P, Wedel H, et al. Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure). J Am Coll Cardiol. 2010;56:1196-1204.   (PubMed)

35.  Lonnrot K, Tolvanen JP, Porsti I, Ahola T, Hervonen A, Alho H. Coenzyme Q10 supplementation and recovery from ischemia in senescent rat myocardium. Life Sci. 1999;64(5):315-323.  (PubMed)

36.  Rosenfeldt FL, Pepe S, Linnane A, et al. The effects of ageing on the response to cardiac surgery: protective strategies for the ageing myocardium. Biogerontology. 2002;3(1-2):37-40.  (PubMed)

37.  Langsjoen PH, Langsjoen AM. Overview of the use of CoQ10 in cardiovascular disease. Biofactors. 1999;9(2-4):273-284.  (PubMed)

38.  Taggart DP, Jenkins M, Hooper J, et al. Effects of short-term supplementation with coenzyme Q10 on myocardial protection during cardiac operations. Ann Thorac Surg. 1996;61(3):829-833.  (PubMed)

39.  Singh RB, Niaz MA, Rastogi SS, Shukla PK, Thakur AS. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens. 1999;13(3):203-208.  (PubMed)

40.  Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J. 2001;94(11):1112-1117.  (PubMed)

41.  Rosenfeldt FL, Haas SJ, Krum H, et al. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens. 2007;21:297-306.   (PubMed)

42.  Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340(2):115-126.  (PubMed)

43.  Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002;45(3):420-426.  (PubMed)

44.  Hamilton SJ, Chew GT, Watts GF. Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients. Diabetes Care. 2009;32:810-812.  (PubMed)

45.  Lim SC, Lekshminarayanan R, Goh SK, et al. The effect of coenzyme Q10 on microcirculatory endothelial function of subjects with type 2 diabetes mellitus. Atherosclerosis. 2008;196:966-969.  (PubMed)

46.  Raitakari OT, McCredie RJ, Witting P, et al. Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance endothelial function in hypercholesterolemic young adults. Free Radic Biol Med. 2000;28(7):1100-1105.  (PubMed)

47.  Kuettner A, Pieper A, Koch J, Enzmann F, Schroeder S. Influence of coenzyme Q(10) and cerivastatin on the flow-mediated vasodilation of the brachial artery: results of the ENDOTACT study. Int J Cardiol. 2005;98(3):413-419.  (PubMed)

48.  Tiano L, Belardinelli R, Carnevali P, Principi F, Seddaiu G, Littarru GP. Effect of coenzyme Q10 administration on endothelial function and extracellular superoxide dismutase in patients with ischaemic heart disease: a double-blind, randomized controlled study. Eur Heart J. 2007;28:2249-2255.  (PubMed)

49.  Dai YL, Luk TH, Yiu KH, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis. 2011;216:395-401.  (PubMed)

50.  Gao L, Mao Q, Cao J, Wang Y, Zhou X, Fan L. Effects of coenzyme Q10 on vascular endothelial function in humans: A meta-analysis of randomized controlled trials. Atherosclerosis. 2011;221(2):311-316.  (PubMed)

51.  McDonnell MG, Archbold GP. Plasma ubiquinol/cholesterol ratios in patients with hyperlipidaemia, those with diabetes mellitus and in patients requiring dialysis. Clin Chim Acta. 1996;253(1-2):117-126.  (PubMed)

52.  Lim SC, Tan HH, Goh SK, et al. Oxidative burden in prediabetic and diabetic individuals: evidence from plasma coenzyme Q(10). Diabet Med. 2006;23:1344-1349.  (PubMed)

53.  Henriksen JE, Andersen CB, Hother-Nielsen O, Vaag A, Mortensen SA, Beck-Nielsen H. Impact of ubiquinone (coenzyme Q10) treatment on glycaemic control, insulin requirement and well-being in patients with Type 1 diabetes mellitus. Diabet Med. 1999;16(4):312-318.  (PubMed)

54.  Eriksson JG, Forsen TJ, Mortensen SA, Rohde M. The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus. Biofactors. 1999;9(2-4):315-318.  (PubMed)

55.  Alcolado JC, Laji K, Gill-Randall R. Maternal transmission of diabetes. Diabet Med. 2002;19(2):89-98.  (PubMed)

56.  Suzuki S, Hinokio Y, Ohtomo M, et al. The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation. Diabetologia. 1998;41(5):584-588.  (PubMed)

57.  Gotz ME, Gerstner A, Harth R, et al. Altered redox state of platelet coenzyme Q10 in Parkinson's disease. J Neural Transm. 2000;107(1):41-48.  (PubMed)

58.  Shults CW, Haas RH, Passov D, Beal MF. Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Ann Neurol. 1997;42(2):261-264.  (PubMed)

59.  Isobe C, Abe T, Terayama Y. Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2'-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson's disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. Neurosci Lett. 2010;469:159-63.  (PubMed)

60.  Hargreaves IP, Lane A, Sleiman PM. The coenzyme Q10 status of the brain regions of Parkinson's disease patients. Neurosci Lett. 2008;447:17-19.  (PubMed)

61.  Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541-1550.  (PubMed)

62.  Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease. Neurosci Lett. 2003;341(3):201-204.  (PubMed)

63.  Storch A, Jost WH, Vieregge P, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64:938-44.  (PubMed)

64.  A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007;68:20-28.  (PubMed)

65.  National Institutes of Health. Effects of Coenzyme Q10 (CoQ) in Parkinson Disease (QE3). ClinicalTrials.gov [Web page]. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00740714?term=coenzyme+Q&rank=2. Accessed 2/15/12.

66.  Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington's disease and effects of coenzyme Q10. Ann Neurol. 1997;41(2):160-165.  (PubMed)

67.  Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res. 2002;36(4):455-460.  (PubMed)

68.  Ferrante RJ, Andreassen OA, Dedeoglu A, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002;22(5):1592-1599.  (PubMed)

69.  Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci Lett. 2001;315(3):149-153.  (PubMed)

70.  Stack EC, Kubilus JK, Smith K, et al. Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice. J Comp Neurol. 2005;490(4):354-370.  (PubMed)

71.  Stack EC, Smith KM, Ryu H, et al. Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice. Biochim Biophys Acta. 2006;1762(3):373-380.  (PubMed)

72.  Yang L, Calingasan NY, Wille EJ, et al. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases. Journal Neurochem. 2009;109:1427-1439.  (PubMed)

73.  A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology. 2001;57(3):397-404.  (PubMed)

74.  Hyson HC, Kieburtz K, Shoulson I, et al. Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects. Mov Disord. 2010;25:1924-1928.  (PubMed)

75.  National Institutes of Health. Coenzyme Q10 in Huntington's Disease (HD) (2CARE). ClinicalTrials.gov [Web page]. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00608881?term=coenzyme+Q10+and+huntington&rank=1. Accessed 3/15/12.

76.  Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005;6(10):743-755.  (PubMed)

77.  Cooper JM, Schapira AH. Friedreich's Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy. Biofactors. 2003;18(1-4):163-171.  (PubMed)

78.  Taroni F, DiDonato S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci. 2004;5(8):641-655.  (PubMed)

79.  Lodi R, Tonon C, Calabrese V, Schapira AH. Friedreich's ataxia: from disease mechanisms to therapeutic interventions. Antioxid Redox Signal. 2006;8(3-4):438-443.  (PubMed)

80.  Lodi R, Hart PE, Rajagopalan B, et al. Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich's ataxia. Ann Neurol. 2001;49(5):590-596.  (PubMed)

81.  Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol. 2005;62(4):621-626.  (PubMed)

82.  Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH. Coenzyme Q10 and vitamin E deficiency in Friedreich's ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy. Eur J Neurol. 2008;15:1371-1379.  (PubMed)

83.  Folkers K, Osterborg A, Nylander M, Morita M, Mellstedt H. Activities of vitamin Q10 in animal models and a serious deficiency in patients with cancer. Biochem Biophys Res Commun. 1997;234(2):296-299.  (PubMed)

84.  Hodges S, Hertz N, Lockwood K, Lister R. CoQ10: could it have a role in cancer management? Biofactors. 1999;9(2-4):365-370.  (PubMed)

85.  Laaksonen R, Fogelholm M, Himberg JJ, Laakso J, Salorinne Y. Ubiquinone supplementation and exercise capacity in trained young and older men. Eur J Appl Physiol Occup Physiol. 1995;72(1-2):95-100.  (PubMed)

86.  Malm C, Svensson M, Ekblom B, Sjodin B. Effects of ubiquinone-10 supplementation and high intensity training on physical performance in humans. Acta Physiol Scand. 1997;161(3):379-384.  (PubMed)

87.  Weston SB, Zhou S, Weatherby RP, Robson SJ. Does exogenous coenzyme Q10 affect aerobic capacity in endurance athletes? Int J Sport Nutr. 1997;7(3):197-206.  (PubMed)

88.  Porter DA, Costill DL, Zachwieja JJ, et al. The effect of oral coenzyme Q10 on the exercise tolerance of middle-aged, untrained men. Int J Sports Med. 1995;16(7):421-427.  (PubMed)

89.  Braun B, Clarkson PM, Freedson PS, Kohl RL. Effects of coenzyme Q10 supplementation on exercise performance, VO2max, and lipid peroxidation in trained cyclists. Int J Sport Nutr. 1991;1(4):353-365.  (PubMed)

90.  Bonetti A, Solito F, Carmosino G, Bargossi AM, Fiorella PL. Effect of ubidecarenone oral treatment on aerobic power in middle-aged trained subjects. J Sports Med Phys Fitness. 2000;40(1):51-57.  (PubMed)

91.  Willis R, Anthony M, Sun L, Honse Y, Qiao G. Clinical implications of the correlation between coenzyme Q10 and vitamin B6 status. Biofactors. 1999;9(2-4):359-363.  (PubMed)

92.  Mattila P, Kumpulainen J. Coenzymes Q9 and Q10: Contents in foods and dietary intake. J Food Comp Anal. 2001;14(4):409-417.

93.  Kamei M, Fujita T, Kanbe T, et al. The distribution and content of ubiquinone in foods. Int J Vitam Nutr Res. 1986;56(1):57-63.  (PubMed)

94.  Weber C, Bysted A, Holmer G. Coenzyme Q10 in the diet--daily intake and relative bioavailability. Mol Aspects Med. 1997;18 Suppl:S251-254.  (PubMed)

95.  Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease. Exp Neurol. 2004;188(2):491-494.  (PubMed)

96.  Hendler SS, Rorvik DR (eds). PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

97.  Lonnrot K, Holm P, Lagerstedt A, Huhtala H, Alho H. The effects of lifelong ubiquinone Q10 supplementation on the Q9 and Q10 tissue concentrations and life span of male rats and mice. Biochem Mol Biol Int. 1998;44(4):727-737.  (PubMed)

98.  Zhang Y, Aberg F, Appelkvist EL, Dallner G, Ernster L. Uptake of dietary coenzyme Q supplement is limited in rats. J Nutr. 1995;125(3):446-453.  (PubMed)

99.  Svensson M, Malm C, Tonkonogi M, Ekblom B, Sjodin B, Sahlin K. Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism during high-intensity exercise. Int J Sport Nutr. 1999;9(2):166-180.  (PubMed)

100.  Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A. 1998;95(15):8892-8897.  (PubMed)

101.  Keith M, Mazer CD, Mikhail P, Jeejeebhoy F, Briet F, Errett L. Coenzyme Q10 in patients undergoing CABG: Effect of statins and nutritional supplementation. Nutr Metab Cardiovasc Dis.  (PubMed)

102.  Hathcock JN, Shao A. Risk assessment for coenzyme Q10 (Ubiquinone). Regul Toxicol Pharmacol. 2006;45(3):282-288.  (PubMed)

103.  Natural Medicines Comprehensive Database. Therapeutic Research Faculty [Web site]. 11/07/02. Available at: http://www.naturaldatabase.com. Accessed 11/07/02, 2002.

104.  Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000;57(13):1221-1227; quiz 1228-1230.  (PubMed)

105.  Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A. 1990;87(22):8931-8934.  (PubMed)

106.  Colquhoun DM, Jackson R, Walters M, et al. Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans. Eur J Clin Invest. 2005;35(4):251-258.  (PubMed)

107.  Mabuchi H, Higashikata T, Kawashiri M, et al. Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients. J Atheroscler Thromb. 2005;12(2):111-119.  (PubMed)

108.  Bargossi AM, Battino M, Gaddi A, et al. Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int J Clin Lab Res. 1994;24(3):171-176.  (PubMed)

109.  Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol. 1993;46(11):1055-1057.  (PubMed)

110.  Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993;33(3):226-229.  (PubMed)

111.  Laaksonen R, Jokelainen K, Laakso J, et al. The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol. 1996;77(10):851-854.  (PubMed)

112.  Laaksonen R, Ojala JP, Tikkanen MJ, Himberg JJ. Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol. 1994;46(4):313-317.  (PubMed)

113.  Elmberger PG, Kalen A, Lund E, et al. Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia. J Lipid Res. 1991;32(6):935-940.  (PubMed)

114.  Ashton E, Windebank E, Skiba M, et al. Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study. Int J Cardiol. 2011;146:404-407.  (PubMed)

115.  Hughes K, Lee BL, Feng X, Lee J, Ong CN. Coenzyme Q10 and differences in coronary heart disease risk in Asian Indians and Chinese. Free Radic Biol Med. 2002;32(2):132-138.  (PubMed)

116.  Hargreaves IP, Duncan AJ, Heales SJ, Land JM. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf. 2005;28(8):659-676.  (PubMed)

117.  Laaksonen R, Jokelainen K, Sahi T, Tikkanen MJ, Himberg JJ. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther. 1995;57(1):62-66.  (PubMed)

Lipoic Acid

Summary

Introduction

α-Lipoic acid (LA), also known as thioctic acid, is a naturally occurring compound that is synthesized in small amounts by plants and animals, including humans (1, 2). Endogenously synthesized LA is covalently bound to specific proteins, which function as cofactors for several important mitochondrial enzyme complexes (see Biological Activities). In addition to the physiological functions of protein-bound LA, there is increasing scientific and medical interest in potential therapeutic uses of pharmacological doses of free LA (3). LA contains two thiol (sulfur) groups, which may be oxidized or reduced (Figure 1). The reduced form is known as dihydrolipoic acid (DHLA), while the oxidized form is known as LA (4). LA also contains an asymmetric carbon, meaning there are two possible optical isomers that are mirror images of each other (R-LA and S-LA). Only the R- isomer is endogenously synthesized and bound to protein: R-LA occurs natural in foods (see Food sources). Free LA supplements may contain either R-LA or a 50/50 (racemic) mixture of R-LA and S-LA (see Supplements).

Figure 1. Chemical structures of lipoic acid: alpha-lipoic acid and dihydrolipoic acid. Lipoic has a chiral center, which means it can be found in two mirror image forms (S- and R-alpha-lipoic acid) that cannot be superimposed on each other.

Metabolism and Bioavailability

Endogenous biosynthesis

LA is synthesized de novo from an 8-carbon fatty acid (octanoic acid) in mitochondria, where protein-bound LA functions as an enzyme cofactor. Evidence suggests that LA can be synthesized “on site” from octanoic acid that is already covalently bound to LA-dependent enzymes (5, 6). The final step in LA synthesis is the insertion of two sulfur atoms into octanoic acid. This reaction is catalyzed by lipoyl synthase, an enzyme that contains iron-sulfur clusters, which are thought to act as sulfur donors to LA (7, 8). The gene for lipoyl synthase has been cloned, and research is under way to learn more about its regulation (9).

Dietary and supplemental α-lipoic acid

Exogenous LA from the diet can be activated with ATP or GTP by lipoate-activating enzyme, and transferred to LA-dependent enzymes by lipoyltransferase (10, 11). Consumption of LA from food has not yet been found to result in detectable increases of free LA in human plasma or cells (3, 12). In contrast, high oral doses of free LA (≥50 mg) result in significant but transient increases in free LA in plasma and cells. Pharmacokinetic studies in humans have found that about 30%-40% of an oral dose of LA (a 50/50 mixture of R-LA and S-LA) is absorbed (12, 13). Oral LA supplements are better absorbed on an empty stomach than with food: taking LA with food decreased peak plasma LA concentrations by about 30% and total plasma LA concentrations by about 20% compared to fasting (14). Additionally, the sodium salt of R-LA may be better absorbed than free LA, presumably because of its higher aqueous solubility (15).

There may also be differences in bioavailability of the two isomers of LA. After oral dosing with LA, peak plasma concentrations of R-LA were found to be 40%-50% higher than S-LA, suggesting that R-LA is better absorbed than S-LA (12, 14, 16). Following oral administration, both isomers are rapidly metabolized and excreted. Plasma LA concentrations generally peak in one hour or less and decline rapidly (12, 13, 16, 17). In cells, LA is quickly reduced to DHLA, and studies in vitro studies indicate that DHLA is rapidly exported from cells (3).

Biological Activities

Protein-bound α-lipoic acid

Enzyme cofactor

R-LA is an essential cofactor for several mitochondrial enzyme complexes that catalyze critical reactions related to energy production and the catabolism (breakdown) of α-keto acids and amino acids (18). In each case, R-LA is covalently bound to a specific lysine residue in one of the proteins of the enzyme complex. The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-coenzyme A (CoA), an important substrate for energy production via the citric acid cycle. The α-ketoglutarate dehydrogenase complex catalyzes the conversion of α-ketoglutarate to succinyl CoA, another important intermediate of the citric acid cycle. The activity of the branched-chain α-ketoacid dehydrogenase complex results in the catabolism of the branched-chain amino acids: leucine, isoleucine, and valine (19). The glycine cleavage system is a multi-enzyme complex that catalyzes the oxidation of glycine to form 5,10-methylene tetrahydrofolate, an important cofactor in the synthesis of nucleic acids (20).

Free α-lipoic acid

When considering the biological activities of supplemental free LA, it is important to keep in mind the limited and transient nature of the increases in plasma and tissue LA (see Metabolism and Bioavailability) (3).

Antioxidant activities

Scavenging reactive oxygen and nitrogen species: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive compounds with the potential to damage DNA, proteins, and lipids (fats) in cell membranes. Both LA and DHLA can directly scavenge (neutralize) physiologically relevant ROS and RNS in the test tube (reviewed in 3). However, it is not clear whether LA acts directly to scavenge ROS and RNS in vivo. The highest tissue concentrations of free LA likely to be achieved through oral supplementation are at least 10 times lower than those of other intracellular antioxidants, such as vitamin C and glutathione. Moreover, free LA is rapidly eliminated from cells, so any increases in direct radical scavenging activity are unlikely to be sustained.

Regeneration of other antioxidants: When an antioxidant scavenges a free radical, it becomes oxidized itself and is not able to scavenge additional ROS or RNS until it has been reduced. DHLA is a potent reducing agent with the capacity to reduce the oxidized forms of several important antioxidants, including vitamin C and glutathione (21). DHLA may also reduce the oxidized form of α-tocopherol (the α-tocopheroxyl radical), directly or indirectly, by reducing the oxidized form of vitamin C (dehydroascorbate), which is able to reduce the α-tocopheroxyl radical (22). Coenzyme Q10, an important component of the mitochondrial electron transport chain, also has antioxidant activity. DHLA can reduce oxidized forms of coenzyme Q10 (23), which may reduce the α-tocopheroxyl radical (24). Although DHLA has been found to regenerate oxidized antioxidants in the test tube, it is not known whether DHLA effectively regenerates other antioxidants under physiological conditions (3).

Metal chelation: Redox-active metal ions, such as free iron and copper, can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals (25). Compounds that chelate (bind) free metal ions in a way that prevents them from generating free radicals offer promise in the treatment of neurodegenerative diseases and other chronic diseases in which metal-induced oxidative damage may play a pathogenic role (26). Both LA and DHLA have been found to inhibit copper- and iron-mediated oxidative damage in the test tube (27, 28) and to inhibit excess iron and copper accumulation in animal models (29, 30).

Induction of glutathione synthesis: Glutathione is an important intracellular antioxidant that also plays a role in the detoxification and elimination of potential carcinogens and toxins. Studies in rodents have found that glutathione synthesis and tissue glutathione levels are significantly lower in aged animals compared to younger animals, leading to decreased ability of aged animals to respond to oxidative stress or toxin exposure (31). LA has been found to increase glutathione levels in cultured cells and in the tissues of aged animals fed LA (32, 33). Research suggests that LA may increase glutathione synthesis in aged rats by increasing the expression of γ-glutamylcysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis (34) and by increasing cellular uptake of cysteine, an amino acid required for glutathione synthesis (35).

Modulation of signal transduction

Insulin signaling: The binding of insulin to the insulin receptor (IR) triggers the autophosphorylation of several tyrosine residues on the IR. Activation of the IR in this manner stimulates a cascade of protein phosphorylations, resulting in the translocation of glucose transporters (GLUT4) to the cell membrane and thus increased cellular glucose uptake (3, 36). LA has been found to activate the insulin signaling cascade in cultured cells (3, 36, 37), increase GLUT4 translocation to cell membranes, and increase glucose uptake in cultured adipose (fat) and muscle cells (38, 39). A computer modeling study showed that LA binds to the tyrosine kinase domain of the IR and may stabilize the active form of the enzyme (37).

PKB/Akt-dependent signaling: In addition to insulin signaling, phosphorylation and dephosphorylation of other cell-signaling molecules affect a variety of cellular processes, including metabolism, stress responses, proliferation, and survival (3). One such molecule is protein kinase B, also known as Akt (PKB/Akt). LA has been found to activate PKB/Akt-dependent signaling in vitro (37, 40-42) and in vivo (42), inhibit apoptosis in cultured hepatocytes (37), and increase survival of cultured neurons (40). LA has also been shown to improve nitric oxide-dependent vasodilation in aged rats by increasing PKB/Akt-dependent phosphorylation of endothelial nitric oxide synthase (eNOS), which increases eNOS-catalyzed production of nitric oxide (43).

Redox-sensitive transcription factors: Transcription factors are proteins that bind to specific sequences of DNA and promote or repress the transcription of selected genes. Some transcription factors are sequestered outside the nucleus until some sort of signal induces their translocation to the nucleus. Oxidative stress or changes in the balance between oxidation and reduction (redox status) in a cell can trigger the translocation of redox-sensitive transcription factors to the nucleus. One such redox-sensitive transcription factor, known as nuclear factor-kappa B (NF-κB), regulates a number of genes related to inflammation and cell cycle control, which are involved in the pathology of diabetes, atherosclerosis, and cancer (20). Physiologically relevant concentrations of LA added to cultured cells have been found to inhibit NF-κB nuclear translocation (44). Another redox-sensitive transcription factor known as Nrf2 enhances the transcription of genes that contain specific DNA sequences known as antioxidant response elements (AREs). LA has been found to enhance the nuclear translocation of Nrf2 and the transcription of genes containing AREs in vivo, including genes for GCL, the rate-limiting enzyme in glutathione synthesis (34).

Deficiency

LA deficiency has not been described, suggesting that humans are able to synthesize enough to meet their needs for enzyme cofactors (45).

Disease Treatment

Diabetes mellitus

Chronically elevated blood glucose levels are the hallmark of diabetes mellitus (DM). In type 1 DM, insulin production is insufficient due to autoimmune destruction of the insulin-producing β-cells of the pancreas. Type 1 DM is also known as insulin-dependent DM because exogenous insulin is required to maintain normal blood glucose levels. In contrast, impaired cellular glucose uptake in response to insulin (insulin resistance) plays a key role in the development of type 2 DM (46). Although individuals with type 2 DM may eventually require insulin, type 2 DM is also known as noninsulin-dependent DM because interventions that enhance insulin sensitivity may be used to maintain normal blood glucose levels.

Glucose utilization

There is limited evidence that high doses of LA can improve glucose utilization in individuals with type 2 DM. A small clinical trial in 13 patients with type 2 DM found that a single intravenous infusion of 1,000 mg of LA improved insulin-stimulated glucose disposal (insulin sensitivity) by 50% compared to a placebo infusion (47). In an uncontrolled pilot study of 20 patients with type 2 DM, intravenous infusion of 500 mg/day of LA for 10 days also improved insulin sensitivity when measured 24 hours after the last infusion (48). A placebo-controlled study of 72 patients with type 2 DM found that oral administration of LA at doses of 600 mg/day, 1,200 mg/day or 1,800 mg/day improved insulin sensitivity by 25% after four weeks of treatment (49). There were no significant differences among the three doses of LA, suggesting that 600 mg/day may be the maximum effective dose (46). Data from animal studies suggest that the R-isomer of LA may be more effective in improving insulin sensitivity than the S-isomer (39, 50), but this possibility has not been tested in any published human trials.

The effect of LA supplementation on long-term blood glucose (glycemic) control has not been well studied. In an uncontrolled pilot study of a controlled-release form of oral LA, 15 patients with type 2 DM took 900 mg/day for six weeks and 1,200 mg/day for another six weeks, in addition to their current medications (17). At the end of 12 weeks, plasma fructosamine concentrations decreased by about 10% from baseline, but glycated hemoglobin (HbA1c) levels did not change. Plasma fructosamine levels reflect blood glucose control over the past 2-3 weeks, while HbA1c values reflect blood glucose control over the past 2-4 months. At present, it is not clear whether oral or intravenous LA therapy improves long-term glycemic control in individuals with type 2 DM.

Vascular disease

The inner lining of blood vessels, known as the endothelium, plays an important role in vascular disease. Endothelial function is often impaired in diabetic patients, who are at high risk for vascular disease (51). Intra-arterial infusion of LA improved endothelium dependent vasodilation in 39 diabetic patients but not in 11 healthy controls (52). In addition, a randomized, double-blind, placebo-controlled study in 30 patients with type 2 diabetes found that intravenous infusion of 600 mg of LA improved the response to the endothelium-dependent vasodilator acetylcholine, but not to the endothelium-independent vasodilator, glycerol trinitrate (53). Endothelial function can be assessed noninvasively by using ultrasound to measure flow-mediated vasodilation, which is endothelium-dependent (54). Using ultrasound, intravenous LA has also been shown to improve endothelial function in patients with impaired fasting glucose (55) or impaired glucose tolerance (56), which are prediabetic conditions.

A few studies have investigated whether oral administration of LA might improve vascular function in patients with diabetes or metabolic syndrome. A randomized controlled trial assessed the effect of oral LA supplementation on flow-mediated vasodilation in 58 patients diagnosed with metabolic syndrome, a condition characterized by abnormal glucose and lipid (fat) metabolism (57). Oral supplementation with 300 mg/day of LA for four weeks improved flow-mediated vasodilation by 44% compared to placebo. Diabetic patients are also at high risk for microvascular disease, which may contribute to diabetic neuropathy (46). In an uncontrolled study, oral supplementation with 1,200 mg/day of LA for six weeks improved a measure of capillary perfusion in the fingers of eight diabetic patients with peripheral neuropathy (58). While these results are encouraging, long-term randomized controlled trials are needed to determine whether LA supplementation can reduce the risk of vascular complications in individuals with diabetes.

Diabetic neuropathy

More than 20% of diabetic patients develop peripheral neuropathy, a type of nerve damage that may result in pain, loss of sensation, and weakness, particularly in the lower extremities (46). Peripheral neuropathy is also a leading cause of lower limb amputation in diabetic patients (59). Chronic hyperglycemia has been linked to peripheral nerve damage; several mechanisms have been proposed to explain the glucose-induced nerve damage, such as intracellular accumulation of sorbitol, glycation reactions, and oxidative and nitrosative stress (reviewed in 60). The results of several large randomized controlled trials indicate that maintaining blood glucose at near normal levels is the most important step in decreasing the risk of diabetic neuropathy (61, 62). However, such intensive blood glucose control may not be achievable in all diabetic patients.

Intravenous and oral LA are approved for the treatment of diabetic neuropathy in Germany (4). A meta-analysis that combined the results of four randomized controlled trials, including 1,258 diabetic patients, found that treatment with 600 mg/day of intravenous LA for three weeks significantly reduced the symptoms of diabetic neuropathy to a clinically meaningful degree (63).

The efficacy of oral LA in the treatment of diabetic neuropathy is less clear. A short-term study of 24 patients with type 2 diabetes mellitus (DM) found that the symptoms of peripheral neuropathy were improved in those who took 1,800 mg/day of oral LA for three weeks compared to those who took a placebo (64). More recently, a randomized, double-blind, placebo-controlled trial in 181 patients with diabetic neuropathy found that oral supplementation with 600 mg/day, 1,200 mg/day, or 1,800 mg/day of LA for five weeks significantly improved neuropathic symptoms (65). In this study, the 600 mg/day dose was as effective as the higher doses. A much larger clinical trial randomly assigned more than 500 patients with type 2 DM and symptomatic peripheral neuropathy to one of the following treatments: (1) 600 mg/day of intravenous LA for 3 weeks followed by 1,800 mg/day of oral LA for six months, (2) 600 mg/day of intravenous LA for three weeks followed by oral placebo for six months, or (3) intravenous placebo for three weeks followed by oral placebo for six months (66). Although symptom scores did not differ significantly from baseline in any of the groups, assessments of sensory and motor deficits by physicians improved significantly after three weeks of intravenous LA therapy. Motor and sensory deficits were also somewhat improved at the end of six months of oral LA therapy, but the trend did not reach statistical significance. In another trial of oral LA therapy, 299 patients with diabetic peripheral neuropathy were randomly assigned to treatment with 1,200 mg/day of LA, 600 mg/day of LA, or a placebo (67). However, after two years of treatment, only 65 of the original participants were included in the final analysis. In that subgroup, those who took either 1,200 mg/day or 600 mg/day of LA showed significant improvement in electrophysiological tests of nerve conduction compared to those who took the placebo. In the longest clinical trial of oral LA therapy, 421 diabetic patients with distal symmetric sensorimotor polyneuropathy took either 600 mg/day of LA or a placebo for four years (68). No difference between the two groups was seen for the primary endpoint, a composite score that assessed neuropathic impairment of the lower limbs and nerve conduction; however, some measures of neuropathic impairment improved with LA supplementation.

Another neuropathic complication of diabetes is cardiovascular autonomic neuropathy (CAN), which occurs in as many as 25% of diabetic patients (46). CAN is characterized by reduced heart rate variability (HRV; variability in the time interval between heartbeats) and is associated with increased risk of mortality in diabetic patients. In a randomized controlled trial of 72 patients with type 2 DM and reduced HRV, oral supplementation with 800 mg/day of LA for four months resulted in significant improvement in 2 out of 4 measures of heart rate variability compared to placebo (69).

Overall, the available research suggests that treatment with 600 mg/day of intravenous LA for three weeks significantly reduces the symptoms of diabetic peripheral neuropathy. Although the benefit of long-term oral LA supplementation is less clear, there is some evidence to suggest that oral LA may be beneficial in the treatment of diabetic peripheral neuropathy (600-1,800 mg/day) and cardiovascular autonomic neuropathy (800 mg/day).

Multiple sclerosis

Feeding high doses of LA to mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), has been found to slow disease progression (70, 71). LA treatment through subcutaneous injection also reduced clinical signs of the disease in a rat model of MS (72). LA treatment has been shown to inhibit the migration of leukocytes (inflammatory T cells, monocytes, and macrophages) into the brain and spinal cord, possibly by decreasing endothelial expression of cell adhesion molecules, inhibiting enzymes called matrix metalloproteinases (MMP), and reducing the permeability of the blood-brain barrier (70, 72-74). More recently, LA has been found to reduce the production of proinflammatory cytokines (75) and stimulate the production of cyclic AMP and cell signaling in certain immune cells (75, 76), which may also modulate the effects of LA in MS.

Although results of animal studies are promising, human research is needed to determine whether oral LA supplementation might be efficacious in MS. A small pilot study designed to evaluate the safety of LA in 30 people with relapsing or progressive MS found that treatment with 1,200-2,400 mg/day of oral LA for two weeks was generally well tolerated (see Safety), and that higher peak serum levels of LA were associated with greater decreases in serum MMP-9 levels (77). A pharmacokinetic study showed that an oral dose of 1,200 mg of LA can result in similar serum levels in MS patients as those found to be therapeutic in mice (78). However, large-scale, long-term clinical trials are needed to assess the safety and efficacy of LA in the treatment of MS (79).

Cognitive decline and dementia

LA, alone or in combination with other antioxidants or L-carnitine, has been found to improve measures of memory in aged animals or in animal models of age-associated cognitive decline, including rats (80, 81), mice (82-85) and dogs (86). Memory assessments were done at the end of LA treatment period, and it is not known whether LA treatment might have lasting memory effects in these animal models. It is not clear whether oral LA supplementation can slow cognitive decline related to aging or pathological conditions in humans. An uncontrolled, open-label trial in nine patients with probable Alzheimer’s disease and related dementias, who were also taking acetylcholinesterase inhibitors, reported that oral supplementation with 600 mg/day of LA appeared to stabilize cognitive function over a one-year period (87). This study was subsequently extended to include 43 patients with probable Alzheimer’s disease, who were followed up to four years. Patients with mild dementia or moderate-early dementia who took 600 mg/day of LA, in addition to acetylcholinesterase inhibitors, experienced slower cognitive decline compared to the typical cognitive decline of Alzheimer’s patients as reported in the literature (88). However, the significance of these findings is difficult to assess without a control group for comparison. A randomized controlled trial found that oral supplementation with 1,200 mg/day of LA for 10 weeks was of no benefit in treating HIV-associated cognitive impairment (89). Although studies in animals suggest that LA may be helpful in slowing age-related cognitive decline, randomized controlled trials are needed to determine whether LA supplementation is effective in preventing or slowing cognitive decline associated with age or neurodegenerative diseases.

Sources

Endogenous biosynthesis

R-LA is synthesized endogenously by humans and bound to proteins (see Metabolism and Bioavailability).

Food sources

R-LA occurs naturally in foods covalently bound to lysine in proteins (lipoyllysine). Although LA is found in a wide variety of foods from plant and animal sources, quantitative information on the LA or lipoyllysine content of food is limited and published databases are lacking. Animal tissues that are rich in lipoyllysine (~1-3 μg/g dry wt) include kidney, heart, and liver, while vegetables that are rich in lipoyllysine include spinach and broccoli (90). Somewhat lower amounts of lipoyllysine (~0.5 μg/g dry wt) have been measured in tomatoes, peas, and Brussels sprouts.

Supplements

Unlike LA in foods, LA in supplements is free, meaning it is not bound to protein. Moreover, the amounts of LA available in dietary supplements (200-600 mg) are likely as much as 1,000 times greater than the amounts that could be obtained in the diet. In Germany, LA is approved for the treatment of diabetic neuropathies and is available by prescription (45). LA is available as a dietary supplement without a prescription in the US (91). Most LA supplements contain a (50/50) mixture of R-LA and S-LA (d,l-LA). Supplements that claim to contain only R-LA are usually more expensive, and information regarding their purity is not currently available (92). Since taking LA with a meal decreases its bioavailability, it is generally recommended that LA be taken on an empty stomach (one hour before or two hours after eating).

Racemic vs. R-LA supplements

R-LA is the isomer that is synthesized by plants and animals and functions as a cofactor for mitochondrial enzymes in its protein-bound form (see Biological Activities). Direct comparisons of the bioavailability of oral LA and R-LA supplements have not been published. After oral dosing with LA, peak plasma concentrations of R-LA were found to be 40%-50% higher than S-LA, suggesting R-LA is better absorbed than S-LA, but both isomers are rapidly metabolized and eliminated (12, 14, 16). In rats, R-LA was more effective than S-LA in enhancing insulin-stimulated glucose transport and metabolism in skeletal muscle (50), and R-LA was more effective than LA and S-LA in preventing cataracts (93). However, virtually all of the published studies of LA supplementation in humans have used racemic LA. At present, it is not clear whether R-LA supplements are more effective than LA supplements in humans.

Safety

Adverse effects

In general, LA supplementation at moderate doses has been found to have few serious side effects. When used to treat diabetic peripheral neuropathy, intravenous administration of LA at doses of 600 mg/day for three weeks (63) and oral LA at doses as high as 1,800 mg/day for six months (67) and 1,200 mg/day for two years (66) did not result in serious adverse effects when used to treat diabetic peripheral neuropathy. Two mild anaphylactoid reactions and one severe anaphylactic reaction, including laryngospasm, were reported after intravenous LA administration (46). The most frequently reported side effects of oral LA supplementation are allergic reactions affecting the skin, including rashes, hives, and itching. Abdominal pain, nausea, vomiting, diarrhea, and vertigo have also been reported, and one trial found that the incidence of nausea, vomiting, and vertigo was dose-dependent (65). Further, malodorous urine has been noted by people taking 1,200 mg/day of LA orally (77).

Pregnancy and lactation

The safety of LA supplements in pregnant and lactating women has not been established (94).

Drug interactions

Because there is some evidence that LA supplementation improves insulin-mediated glucose utilization (49), it is possible that LA supplementation could increase the risk of hypoglycemia in diabetic patients using insulin or oral antidiabetic agents. Consequently, blood glucose levels should be monitored closely when LA supplementation is added to diabetes treatment regimens. Co-administration of a single oral dose of LA (600 mg) and the oral antidiabetic agents, glyburide or acarbose, did not result in any significant drug interactions in one study in 24 healthy volunteers (95).

Nutrient interactions

Biotin

The chemical structure of biotin is similar to that of LA, and there is some evidence that high concentrations of LA can compete with biotin for transport across cell membranes (96, 97). The administration of high doses of LA by injection to rats decreased the activity of two biotin-dependent enzymes by about 30%-35% (98), but it is not known whether oral or intravenous LA supplementation substantially increases the requirement for biotin in humans (99).


Authors and Reviewers

Originally written in 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2006 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in April 2012 by:
Tory M. Hagen, Ph.D.
Principal Investigator, Linus Pauling Institute
Professor, Dept. of Biochemistry and Biophysics
Burgess and Elizabeth Jamieson Endowed Chair in Healthspan Research
Oregon State University

Copyright 2002-2017  Linus Pauling Institute


References

1.  Reed LJ. A trail of research from lipoic acid to alpha-keto acid dehydrogenase complexes. J Biol Chem. 2001;276(42):38329-38336.  (PubMed)

2.  Carreau JP. Biosynthesis of lipoic acid via unsaturated fatty acids. Methods Enzymol. 1979;62:152-158.  (PubMed)

3.  Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem. 2004;11(9):1135-1146.  (PubMed)

4.  Kramer K, Packer L. R-alpha-lipoic acid. In: Kramer K, Hoppe P, Packer L, eds. Nutraceuticals in Health and Disease Prevention. New York: Marcel Dekker, Inc.; 2001:129-164.

5.  Cicchillo RM, Iwig DF, Jones AD, et al. Lipoyl synthase requires two equivalents of S-adenosyl-L-methionine to synthesize one equivalent of lipoic acid. Biochemistry. 2004;43(21):6378-6386.  (PubMed)

6.  Zhao X, Miller JR, Jiang Y, Marletta MA, Cronan JE. Assembly of the covalent linkage between lipoic acid and its cognate enzymes. Chem Biol. 2003;10(12):1293-1302.  (PubMed)

7.  Cicchillo RM, Booker SJ. Mechanistic investigations of lipoic acid biosynthesis in Escherichia coli: both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide. J Am Chem Soc. 2005;127(9):2860-2861.  (PubMed)

8.  Miller JR, Busby RW, Jordan SW, et al. Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein. Biochemistry. 2000;39(49):15166-15178.  (PubMed)

9.  Hagen TM. Personal Communication; April 6, 2006.

10.  Fujiwara K, Suzuki M, Okumachi Y, et al. Molecular cloning, structural characterization and chromosomal localization of human lipoyltransferase gene. Eur J Biochem. 1999;260(3):761-767.  (PubMed)

11.  Fujiwara K, Takeuchi S, Okamura-Ikeda K, Motokawa Y. Purification, characterization, and cDNA cloning of lipoate-activating enzyme from bovine liver. J Biol Chem. 2001;276(31):28819-28823.  (PubMed)

12.  Hermann R, Niebch G, Borbe HO, et al. Enantioselective pharmacokinetics and bioavailability of different racemic alpha-lipoic acid formulations in healthy volunteers. Eur J Pharm Sci. 1996;4:167-174.

13.  Teichert J, Hermann R, Ruus P, Preiss R. Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers. J Clin Pharmacol. 2003;43(11):1257-1267.  (PubMed)

14.  Gleiter CH, Schug BS, Hermann R, Elze M, Blume HH, Gundert-Remy U. Influence of food intake on the bioavailability of thioctic acid enantiomers. Eur J Clin Pharmacol. 1996;50(6):513-514.  (PubMed)

15.  Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L. The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects. Altern Med Rev. 2007;12(4):343-351.  (PubMed)

16.  Breithaupt-Grogler K, Niebch G, Schneider E, et al. Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data. Eur J Pharm Sci. 1999;8(1):57-65.  (PubMed)

17.  Evans JL, Heymann CJ, Goldfine ID, Gavin LA. Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlled-release formulation of alpha-lipoic acid. Endocr Pract. 2002;8(1):29-35.  (PubMed)

18.  Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med. 1998;24(6):1023-1039.  (PubMed)

19.  Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr. 2005;135(6 Suppl):1527S-1530S.  (PubMed)

20.  Packer L. alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev. 1998;30(2):245-275.  (PubMed)

21.  Jones W, Li X, Qu ZC, Perriott L, Whitesell RR, May JM. Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med. 2002;33(1):83-93.  (PubMed)

22.  May JM, Qu ZC, Mendiratta S. Protection and recycling of alpha-tocopherol in human erythrocytes by intracellular ascorbic acid. Arch Biochem Biophys. 1998;349(2):281-289.  (PubMed)

23.  Kozlov AV, Gille L, Staniek K, Nohl H. Dihydrolipoic acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone. Arch Biochem Biophys. 1999;363(1):148-154.  (PubMed)

24.  Upston JM, Terentis AC, Stocker R. Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement. FASEB J. 1999;13(9):977-994.  (PubMed)

25.  Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem. 2005;12(10):1161-1208.  (PubMed)

26.  Doraiswamy PM, Finefrock AE. Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol. 2004;3(7):431-434.  (PubMed)

27.  Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol. 1995;50(1):123-126.  (PubMed)

28.  Suh JH, Zhu BZ, deSzoeke E, Frei B, Hagen TM. Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep. 2004;9(1):57-61.  (PubMed)

29.  Yamamoto H, Watanabe T, Mizuno H, et al. The antioxidant effect of DL-alpha-lipoic acid on copper-induced acute hepatitis in Long-Evans Cinnamon (LEC) rats. Free Radic Res. 2001;34(1):69-80.  (PubMed)

30.  Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep. 2005;10(1):52-60.  (PubMed)

31.  Hagen TM, Vinarsky V, Wehr CM, Ames BN. (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox Signal. 2000;2(3):473-483.  (PubMed)

32.  Busse E, Zimmer G, Schopohl B, Kornhuber B. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittelforschung. 1992;42(6):829-831.  (PubMed)

33.  Monette JS, Gomez LA, Moreau RF, et al. (R)-alpha-Lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria. Pharmacol Res. 2011;63(1):23-29.  (PubMed)

34.  Suh JH, Shenvi SV, Dixon BM, et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A. 2004;101(10):3381-3386.  (PubMed)

35.  Suh JH, Wang H, Liu RM, Liu J, Hagen TM. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys. 2004;423(1):126-135.  (PubMed)

36.  Konrad D. Utilization of the insulin-signaling network in the metabolic actions of alpha-lipoic acid-reduction or oxidation? Antioxid Redox Signal. 2005;7(7-8):1032-1039.  (PubMed)

37.  Diesel B, Kulhanek-Heinze S, Holtje M, et al. Alpha-lipoic acid as a directly binding activator of the insulin receptor: protection from hepatocyte apoptosis. Biochemistry. 2007;46(8):2146-2155.  (PubMed)

38.  Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia. 2000;43(3):294-303.  (PubMed)

39.  Estrada DE, Ewart HS, Tsakiridis T, et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes. 1996;45(12):1798-1804.  (PubMed)

40.  Zhang L, Xing GQ, Barker JL, et al. Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Neurosci Lett. 2001;312(3):125-128.  (PubMed)

41.  Shay KP, Hagen TM. Age-associated impairment of Akt phosphorylation in primary rat hepatocytes is remediated by alpha-lipoic acid through PI3 kinase, PTEN, and PP2A. Biogerontology. 2009;10(4):443-456.  (PubMed)

42.  Zhang WJ, Wei H, Hagen T, Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci U S A. 2007;104(10):4077-4082.  (PubMed)

43.  Smith AR, Hagen TM. Vascular endothelial dysfunction in aging: loss of Akt-dependent endothelial nitric oxide synthase phosphorylation and partial restoration by (R)-alpha-lipoic acid. Biochem Soc Trans. 2003;31(Pt 6):1447-1449.  (PubMed)

44.  Zhang WJ, Frei B. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J. 2001;15(13):2423-2432.  (PubMed)

45.  Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997;29(3):315-331.  (PubMed)

46.  Ziegler D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical review. Treat Endocrinol. 2004;3(3):173-189.  (PubMed)

47.  Jacob S, Henriksen EJ, Schiemann AL, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung. 1995;45(8):872-874.  (PubMed)

48.  Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes. 1996;104(3):284-288.  (PubMed)

49.  Jacob S, Rett K, Henriksen EJ, Haring HU. Thioctic acid--effects on insulin sensitivity and glucose-metabolism. Biofactors. 1999;10(2-3):169-174.  (PubMed)

50.  Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol. 1997;273(1 Pt 1):E185-191.  (PubMed)

51.  Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond). 2005;109(2):143-159.  (PubMed)

52.  Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic Biol Med. 2001;31(1):53-61.  (PubMed)

53.  Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial. Eur J Clin Invest. 2010;40(2):148-154.  (PubMed)

54.  Gokce N, Keaney JF, Jr., Hunter LM, Watkins MT, Menzoian JO, Vita JA. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002;105(13):1567-1572.  (PubMed)

55.  Xiang G, Pu J, Yue L, Hou J, Sun H. alpha-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose. Metabolism. 2011;60(4):480-485.  (PubMed)

56.  Xiang GD, Sun HL, Zhao LS, Hou J, Yue L, Xu L. The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance. Clin Endocrinol (Oxf). 2008;68(5):716-723.  (PubMed)

57.  Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005;111(3):343-348.  (PubMed)

58.  Haak E, Usadel KH, Kusterer K, et al. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2000;108(3):168-174.  (PubMed)

59.  Greene DA, Stevens MJ, Obrosova I, Feldman EL. Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur J Pharmacol. 1999;375(1-3):217-223.  (PubMed)

60.  Obrosova IG. Diabetes and the peripheral nerve. Biochim Biophys Acta. 2009;1792(10):931-940.  (PubMed)

61.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-986.  (PubMed)

62.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.  (PubMed)

63.  Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114-121.  (PubMed)

64.  Ruhnau KJ, Meissner HP, Finn JR, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med. 1999;16(12):1040-1043.  (PubMed)

65.  Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365-2370.  (PubMed)

66.  Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22(8):1296-1301.  (PubMed)

67.  Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999;31(3):171-179.  (PubMed)

68.  Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34(9):2054-2060.  (PubMed)

69.  Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997;20(3):369-373.  (PubMed)

70.  Marracci GH, Jones RE, McKeon GP, Bourdette DN. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002;131(1-2):104-114.  (PubMed)

71.  Morini M, Roccatagliata L, Dell'Eva R, et al. Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148(1-2):146-153.  (PubMed)

72.  Schreibelt G, Musters RJ, Reijerkerk A, et al. Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity. J Immunol. 2006;177(4):2630-2637.  (PubMed)

73.  Chaudhary P, Marracci GH, Bourdette DN. Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2006;175(1-2):87-96.  (PubMed)

74.  Marracci GH, McKeon GP, Marquardt WE, Winter RW, Riscoe MK, Bourdette DN. Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis. J Neurosci Res. 2004;78(3):362-370.  (PubMed)

75.  Salinthone S, Schillace RV, Tsang C, Regan JW, Bourdette DN, Carr DW. Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms. J Nutr Biochem. 2011;22(7):681-690.  (PubMed)

76.  Schillace RV, Pisenti N, Pattamanuch N, et al. Lipoic acid stimulates cAMP production in T lymphocytes and NK cells. Biochem Biophys Res Commun. 2007;354(1):259-264.  (PubMed)

77.  Yadav V, Marracci G, Lovera J, et al. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005;11(2):159-165.  (PubMed)

78.  Yadav V, Marracci GH, Munar MY, et al. Pharmacokinetic study of lipoic acid in multiple sclerosis: comparing mice and human pharmacokinetic parameters. Mult Scler. 2010;16(4):387-397.  (PubMed)

79.  National Multiple Sclerosis Society. Progress in Research: Research Highlights Winter/Spring 2005. http://www.nationalmssociety.org/Highlights-Antioxidants.asp. Accessed January 9, 2006.

80.  Liu J, Head E, Gharib AM, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A. 2002;99(4):2356-2361.  (PubMed)

81.  Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002;99(4):1870-1875.  (PubMed)

82.  Farr SA, Poon HF, Dogrukol-Ak D, et al. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem. 2003;84(5):1173-1183.  (PubMed)

83.  Quinn JF, Bussiere JR, Hammond RS, et al. Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging. 2007;28(2):213-225.  (PubMed)

84.  Shenk JC, Liu J, Fischbach K, et al. The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease. J Neurol Sci. 2009;283(1-2):199-206.  (PubMed)

85.  Stoll S, Hartmann H, Cohen SA, Muller WE. The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits. Pharmacol Biochem Behav. 1993;46(4):799-805.  (PubMed)

86.  Milgram NW, Head E, Zicker SC, et al. Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging. 2005;26(1):77-90.  (PubMed)

87.  Hager K, Marahrens A, Kenklies M, Riederer P, Munch G. Alpha-lipoic acid as a new treatment option for Azheimer type dementia. Arch Gerontol Geriatr. 2001;32(3):275-282.  (PubMed)

88.  Hager K, Kenklies M, McAfoose J, Engel J, Munch G. Alpha-lipoic acid as a new treatment option for Alzheimer's disease--a 48 months follow-up analysis. J Neural Transm Suppl. 2007;(72):189-193.  (PubMed)

89.  A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment. Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Neurology. 1998;50(3):645-651.  (PubMed)

90.  Lodge JK, Youn HD, Handelman GJ, et al. Natural sources of lipoic acid: determination of lipoyllysine released from protease-digested tissues by high performance liquid chromatography incorporating electrochemical detection. J Appl Nutr. 1997;49(1 & 2):3-11.

91.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

92.   Alpha-Lipoic Acid Supplements. ConsumerLab.com. October 2, 2009. Available at: https://www.consumerlab.com/reviews/Alpha-Lipoic_Acid_Supplements/alphalipoic/. Accessed 11/11/11.

93.  Maitra I, Serbinova E, Tritschler HJ, Packer L. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun. 1996;221(2):422-429.  (PubMed)

94.  Alpha-Lipoic Acid. In: Hendler SS, Rorvik DR,eds. PDR for Nutritional Supplements. 2nd ed. Montvale: Physicians' Desk Reference Inc.; 2008:25-29.

95.  Gleiter CH, Schreeb KH, Freudenthaler S, et al. Lack of interaction between thioctic acid, glibenclamide and acarbose. Br J Clin Pharmacol. 1999;48(6):819-825.  (PubMed)

96.  Prasad PD, Wang H, Huang W, et al. Molecular and functional characterization of the intestinal Na+-dependent multivitamin transporter. Arch Biochem Biophys. 1999;366(1):95-106.  (PubMed)

97.  Balamurugan K, Vaziri ND, Said HM. Biotin uptake by human proximal tubular epithelial cells: cellular and molecular aspects. Am J Physiol Renal Physiol. 2005;288(4):F823-831.  (PubMed)

98.  Zempleni J, Trusty TA, Mock DM. Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver. J Nutr. 1997;127(9):1776-1781.  (PubMed)

99.  Zempleni J, Mock DM. Biotin biochemistry and human requirements. J Nutr Biochem. 1999;10(3):128-138.  (PubMed)

Phytochemicals

Phytochemicals can be defined, in the strictest sense, as chemicals produced by plants. However, the term is generally used to describe chemicals from plants that may affect health, but are not essential nutrients. While there is ample evidence to support the health benefits of diets rich in fruit, vegetables, legumes, whole grains, and nuts, evidence that these effects are due to specific nutrients or phytochemicals is limited. Because plant-based foods are complex mixtures of bioactive compounds, information on the potential health effects of individual phytochemicals is linked to information on the health effects of foods that contain those phytochemicals.

Select a phytochemical from the list for more information.

The information on dietary phytochemicals from the Linus Pauling Institute's Micronutrient Information Center is now available in a book titled, An Evidence-based Approach to Phytochemicals and Other Dietary Factors. The book can be purchased from the Linus Pauling Institute or Thieme Medical Publishers.

Carotenoids

α-Carotene, β-Carotene, β-Cryptoxanthin, Lycopene, Lutein, and Zeaxanthin

Summary

  • Carotenoids are yellow, orange, and red pigments synthesized by plants. The most common carotenoids in North American diets are α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene. (More information)
  • Provitamin A carotenoids, α-carotene, β-carotene, and β-cryptoxanthin, can be converted by the body to retinol (vitamin A). In contrast, no vitamin A activity can be derived from lutein, zeaxanthin, and lycopene. (More information)
  • Dietary lutein and zeaxanthin are selectively taken up into the macula of the eye, where they absorb up to 90% of blue light and help maintain optimal visual function. (More information)
  • At present, it is unclear whether the biological effects of carotenoids in humans are related to their antioxidant activity and/or other non-antioxidant activities. (More information)
  • Although the results of observational studies suggest that diets high in carotenoid-rich fruit and vegetables are associated with reduced risks of cardiovascular disease and some cancers, high-dose β-carotene supplements did not reduce the risk of cardiovascular disease or cancer in large randomized controlled trials. (More information)
  • Two randomized controlled trials found that high-dose β-carotene supplements increased the risk of lung cancer in smokers and former asbestos workers. (More information)
  • Recent meta-analyses of observational studies reported an inverse association between blood lycopene concentration and risk of developing prostate cancer. To date, most small-scale intervention studies found little-to-no benefit of lycopene supplements in reducing incidence or severity of prostate cancer in high-risk patients. (More information)
  • Observational studies have suggested that diets rich in lutein and zeaxanthin may help slow the development of age-related macular degeneration (AMD). Randomized controlled trials found that lutein and zeaxanthin supplements could improve visual acuity and slow the progression to advanced AMD in subjects with AMD. (More information)
  • Evidence is lacking to suggest a role for lutein and zeaxanthin in the management of other eye conditions, including cataracts, diabetic retinopathy, and retinopathy of maturity. (More information)
  • Carotenoids are best absorbed with fat in a meal. Chopping, puréeing, and cooking carotenoid-containing vegetables in oil generally increase the bioavailability of the carotenoids they contain. (More information)

Introduction

Carotenoids are a class of more than 750 naturally occurring pigments synthesized by plants, algae, and photosynthetic bacteria (1). These richly colored molecules are the sources of the yellow, orange, and red colors of many plants. Fruit and vegetables provide most of the 40 to 50 carotenoids found in the human diet. α-Carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene are the most common dietary carotenoids (1). α-Carotene, β-carotene and β-cryptoxanthin are provitamin A carotenoids, meaning they can be converted by the body to retinol (Figure 1). Lutein, zeaxanthin, and lycopene are nonprovitamin A carotenoids because they cannot be converted to retinol (Figure 2).

 

Figure 1. All-trans Chemical Structures of Provitamin A Carotenoids


Figure 2. All-trans Chemical Structures of Nonprovitamin A Carotenoids 

Absorption, Metabolism, and Bioavailability

For dietary carotenoids to be absorbed intestinally, they must be released from the food matrix and incorporated into mixed micelles (mixtures of bile salts and several types of lipids). Food processing and cooking help release carotenoids embedded in their food matrix and increase intestinal absorption (1). Moreover, carotenoid absorption requires the presence of fat in a meal. As little as 3 to 5 g of fat in a meal appears sufficient to ensure carotenoid absorption (2, 3), although the minimum amount of dietary fat required may be different for each carotenoid. The type of fat (e.g., medium-chain vs. long-chain triglycerides), the presence of soluble fiber, and the type and amount of carotenoids (e.g., esterified vs. non-esterified) in the food also appear to influence the rate and extent of carotenoid absorption (reviewed in 4). Because they do not need to be released from the plant matrix, carotenoid supplements (in oil) are more efficiently absorbed than carotenoids in food (3). Although carotenoids were initially thought to be absorbed within the cells that line the intestine (enterocytes) only by passive diffusion, recent investigations identified the apical membrane transporters, Scavenger Receptor-class B type I (SR-BI) and Cluster Determinant 36 (CD36), suggesting active uptake of carotenoids as well (5).

Within the enterocytes, provitamin A carotenoids may be cleaved by either β-carotene 15,15’-oxygenase 1 (BCO1) or by β-carotene 9’,10’-oxygenase 2 (BCO2) (Figure 3). BCO1 catalyzes the cleavage of provitamin A carotenoids into retinal, which is further reduced to retinol (vitamin A) or oxidized to retinoic acid (the biologically active form of vitamin A). β-Apocarotenal derived from the cleavage of β-carotene by BCO2 can be cleaved further by BCO1 to produce retinal. Although provitamin A carotenoids can be converted into apocarotenals by BCO2, the activity of this enzyme is higher toward nonprovitamin A carotenoids. Conversely, BCO1 shows limited affinity toward nonprovitamin A carotenoids (1).

Within the enterocytes, uncleaved carotenoids and retinyl esters (derived from retinol) are incorporated into triglyceride-rich lipoproteins called chylomicrons, secreted into lymphatic vessels, and then released in the bloodstream (1). Triglycerides are depleted from circulating chylomicrons through the activity of an enzyme called lipoprotein lipase, resulting in the formation of chylomicron remnants. Chylomicron remnants are taken up by the liver, where carotenoids can be cleaved by BCO1/BCO2 or incorporated into lipoproteins and secreted back into the circulation for delivery to extrahepatic tissues. Of note, more hydrophilic molecules in the enterocytes like retinoic acid and apocarotenals can be transported directly to the liver through the portal blood system.

The conversion of provitamin A carotenoids to retinol is influenced by the vitamin A status of the individual (6). The regulatory mechanism involving the intestine-specific homeobox (ISX) transcription factor can block carotenoid uptake and vitamin A production by inhibiting the expression of SR-BI and BCO1. ISX is under the control of retinoid acid and retinoic acid receptor (RAR)-dependent mechanisms such that, when vitamin A stores are high, ISX is activated and both provitamin A carotenoid absorption and conversion to retinol are inhibited. Conversely, during vitamin A insufficiency, the expression of both SR-BI and BCO1 is no longer repressed by ISX, allowing for provitamin A carotenoid absorption and conversion to retinol (1).

Interindividual variations in blood and tissue concentrations of carotenoids have been attributed to genetic differences among individuals. Specifically, a number of single nucleotide polymorphisms (SNPs) — corresponding to changes of one nucleotide in the sequence of genes — have been identified in genes coding for proteins involved in intestinal uptake, transport, and metabolism of carotenoids (7). Specifically, SNPs within genes coding for SR-BI, CD36, and BCO1 are suspected to affect the expression and/or activity of these proteins and, in turn, individual carotenoid status (7).

Figure 3. Metabolic Pathways of Carotenoids

Biological Activities

Provitamin A function

Vitamin A is essential for normal growth and development, immune system function, and vision (see the article on Vitamin A). Currently, the only essential function of carotenoids recognized in humans is that of the provitamin A carotenoids, α-carotene, β-carotene, and β-cryptoxanthin, to serve as a source of vitamin A (8).

Retinol activity equivalents (RAEs)

Provitamin A carotenoids are less easily absorbed than preformed vitamin A and must be converted to retinol and other retinoids by the body (Figure 3). The efficiency of conversion of provitamin A carotenoids into retinol is highly variable, depending on factors like food matrix, food preparation, and one’s digestive and absorptive capacities (9).

The most recent international standard of measure for vitamin A is retinol activity equivalent (RAE), which represents vitamin A activity as retinol. It has been determined that 2 micrograms (µg) of β-carotene in oil provided as a supplement could be converted by the body to 1 µg of retinol, giving it an RAE ratio of 2:1. However, 12 µg of β-carotene from food are required to provide the body with 1 µg of retinol, giving dietary β-carotene an RAE ratio of 12:1. Other provitamin A carotenoids in food are less easily absorbed than β-carotene, resulting in RAE ratios of 24:1. RAE ratios are shown in Table 1.

Table 1. Retinol Activity Equivalent (RAE) Ratios for Preformed Vitamin A and Provitamin A Carotenoids
Quantity Consumed Quantity Bioconverted to Retinol RAE Ratio
1 µg of dietary or supplemental preformed vitamin A 1 µg of retinol 1:1
2 µg of supplemental β-carotene 1 µg of retinol 2:1
12 µg of dietary β-carotene 1 µg of retinol 12:1
24 µg of dietary α-carotene 1 µg of retinol 24:1
24 µg of dietary β-cryptoxanthin 1 µg of retinol 24:1

Antioxidant activity

In plants, carotenoids have the important antioxidant function of quenching (deactivating) singlet oxygen, an oxidant formed during photosynthesis (10). Test tube studies indicated that lycopene is one of the most effective quenchers of singlet oxygen among carotenoids (11). They also suggested that carotenoids could inhibit the oxidation of fats (i.e., lipid peroxidation) under certain conditions, but their actions in humans appear to be more complex (12). Although important for plants, the relevance of singlet oxygen quenching to human health is less clear (1).

Nrf2-dependent antioxidant pathway

Some evidence suggests that carotenoids and/or their metabolites may upregulate the expression of antioxidant and detoxifying enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (reviewed in 13). Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol. Keap1 responds to oxidative stress signals by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoter of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for numerous mediators of the antioxidant response, including glutamate-cysteine ligase (GCL), glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (14). A recent study showed an increase in the level of the major antioxidant glutathione and a protection against TNFα-induced oxidative stress in retinal pigment epithelial cells (RPE) following lycopene-mediated Nrf2 activation and GCL induction (15). Nrf2 activation by lycopene also protected RPE against TNFα-mediated proinflammatory signaling involving nuclear factor-κB (NF-κB) activation and intercellular adhesion molecule-1 (ICAM-1) expression (15). Lycopene was shown to trigger Nrf2-mediated antioxidant pathway in various cell types (16-18). At present, evidence from animal and human studies is very limited (13).

Blue light filtering

The long system of alternating double and single bonds common to all carotenoids allows them to absorb light in the visible range of the spectrum (10). This feature has particular relevance to the eye, where lutein, zeaxanthin, and meso-zeaxanthin (derived from lutein) efficiently absorb blue light. Depending on the carotenoid pigment density at the center of the eye’s retina (macula), up to 90% of blue light can be absorbed by these pigments. Reducing the amount of short-wavelength light that reaches the critical visual structures of the eye may protect them from light-induced oxidative damage (19). Because the only source of these plant pigments in the eye is diet, a number of observational and intervention studies have examined the potential of dietary and supplemental lutein and zeaxanthin to protect against age-related eye diseases (see Age-related macular degeneration and Cataracts). Supplemental lutein, alone or with zeaxanthin, was found to improve contrast sensitivity and protect against visual fatigue in young and/or healthy individuals (20-23). Lutein has also been suggested to improve visual function through stimulating neuronal signaling efficiency in the eye (24).

Intercellular communication

Carotenoids can facilitate communication between neighboring cells grown in culture by stimulating the synthesis of connexin proteins (25). Connexins form pores (gap junctions) in cell membranes, allowing cells to communicate through the exchange of small molecules. This type of intercellular communication is important for maintaining cells in a differentiated state and is often lost in cancer cells. Carotenoids facilitate intercellular communication by increasing the expression of the gene encoding a connexin protein, an effect that appears unrelated to the vitamin A or antioxidant activities of various carotenoids (26) and involving a retinoic acid receptor (RAR)-independent mechanism (27).

Immune function

Because vitamin A is essential for normal immune system function, it is difficult to determine whether the effects of provitamin A carotenoids are related to their vitamin A activity or other activities of carotenoids. Although some clinical trials have found that β-carotene supplementation improves several biomarkers of immune function (28-30), increasing intakes of lycopene and lutein — carotenoids without vitamin A activity — have not resulted in similar improvements in biomarkers of immune function (31-33).

 

Deficiency

Although consumption of provitamin A carotenoids (α-carotene, β-carotene, and β-cryptoxanthin) can prevent vitamin A deficiency (see the article on Vitamin A), no overt deficiency symptoms have been identified in people consuming low-carotenoid diets if they consume adequate vitamin A (8). After reviewing the published scientific research in 2000, the Food and Nutrition Board of the Institute of Medicine concluded that the existing evidence was insufficient to establish a recommended dietary allowance (RDA) or adequate intake (AI) for carotenoids. The Board has set an RDA for vitamin A (see the article on Vitamin A). Recommendations by the National Cancer Institute, American Cancer Society, and American Heart Association to consume a variety of fruit and vegetables daily are aimed, in part, at increasing intakes of carotenoids.

Disease Prevention

Cancer

Lung cancer

Dietary carotenoids: Several large prospective cohort studies, including the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), have examined potential associations between carotenoid intake and/or blood concentrations and lung cancer (36). In a meta-analysis of eight prospective cohort studies, including NHS and HPFS, the highest versus lowest quantile of total carotenoid intake was significantly associated with a 21% reduced risk of lung cancer. For the individual carotenoids, the risk of lung cancer was estimated to be 20% and 14% lower with the highest versus lowest intakes of β-cryptoxanthin and lycopene, respectively. In contrast, dietary intakes of β-carotene, α-carotene, and lutein/zeaxanthin were not found to be significantly linked to a reduced risk of developing lung cancer (36). In addition, an analysis of the pooled results of 11 nested case-control and four prospective cohort studies found no association between serum concentrations of total carotenoids, β-carotene, α-lycopene, β-cryptoxanthin, and lutein/zeaxanthin and lung cancer. Only high versus low serum lycopene concentrations could be linked to a 29% lower risk of lung cancer (36). Any protective effect of dietary carotenoids against the development of lung cancer is likely small and not statistically significant (36).

Supplemental β-carotene: The effect of β-carotene supplementation on the risk of developing lung cancer has been examined in three large randomized, placebo-controlled trials. In Finland, the Α-Tocopherol Βeta-Carotene (ATBC) cancer prevention trial evaluated the effects of 20 mg/day of β-carotene and/or 50 mg/day of α-tocopherol on more than 29,000 male smokers (37), and in the United States, the β-Carotene And Retinol Efficacy Trial (CARET) evaluated the effects of a combination of 30 mg/day of β-carotene and 25,000 IU/day of retinol (preformed vitamin A) in 18,314 men and women who were smokers, former smokers, or had a history of occupational asbestos exposure (38). Unexpectedly, the risk of lung cancer in the groups taking β-carotene supplements was increased by 16% after six years in the ATBC participants and by 28% after four years in the CARET participants. In contrast, the Physicians’ Health Study (PHS) examined the effect of β-carotene supplementation (50 mg every other day) on cancer risk in 22,071 male physicians in the United States, of whom only 11% were current smokers (39). In that lower risk population, β-carotene supplementation for more than 12 years was not associated with an increased risk of lung cancer. In addition, in the Linxian General Population trial conducted in about 29,000 Chinese participants, randomization to 15 mg/day of β-carotene, 30 mg/day of α-tocopherol, and 15 µg/day of selenium, was not found to be associated with lung cancer mortality 10 years after the intervention ended (40).

Although the reasons for the increase in lung cancer risk are not yet clear and several mechanisms have been proposed (41). The US Preventive Services Task Force estimated that the risks of high-dose β-carotene supplementation outweigh any potential benefits for cancer prevention and recommended against supplementation, especially in smokers or other high-risk populations (42).

Prostate cancer

Prostate cancer is the most common cancer affecting US men, more prevalent than lung and colorectal cancers (34).

Dietary lycopene: Several early prospective cohort studies have suggested that lycopene-rich diets were associated with significant reductions in the risk of prostate cancer, particularly more aggressive forms (43). However, pooled data analyses of observational studies that examined potential links between dietary intakes and/or circulating concentrations of lycopene and risk of prostate cancer have given mixed results. An early meta-analysis that combined the results of 10 case-control and four prospective studies found that men with the highest intakes of raw tomatoes, cooked tomatoes, or dietary lycopene had a 11 to 19% lower risk of prostate cancer (44). In addition, pooled data from two case-control and five nested case-control studies showed a 26% lower risk of prostate cancer in participants with the highest serum concentrations of lycopene (44). Most recently, a meta-analysis of observational studies found no association of prostate cancer risk with dietary lycopene intakes (10 case-cohort and two prospective cohort studies) but an inverse association with blood lycopene concentrations (two case-control, nine nested case-control, and one cohort studies) (45, 46). Additionally, a meta-analysis of 15 nested case-control studies conducted by the Endogenous Hormones, Nutritional Biomarkers, and Prostate Cancer Collaborative Group showed an inverse association between circulating lycopene concentrations and risk of advanced stage and/or aggressive prostate cancer, while no association was found with risk of non-aggressive or localized disease (47).

While there is considerable scientific interest in the potential for lycopene to help prevent prostate cancer, it is not yet clear whether the prostate cancer risk reduction observed in some observational studies is related to lycopene itself, other compounds in tomatoes, or other factors associated with lycopene-rich diets (48). Of note, the 2014 World Cancer Research Fund International report on Diet, Nutrition, Physical Activity, and Prostate Cancer suggested the need for better designed studies to establish whether consumption of lycopene-containing foods could be linked to a lower risk of prostate cancer (49).

Supplemental lycopene: To date, a few short-term, dietary intervention studies using lycopene in patients with precancerous prostate lesions (high grade prostatic intraepithelial neoplasia; HGPIN) or prostate cancer have been completed. Specifically, two small randomized controlled studies have recently examined the effect of lycopene supplementation for up to six months in men with HGPIN (50, 51). The consumption of 30 to 35 mg/day of supplemental lycopene in the form of tomato extract (50), or together with selenium (55 mg/day) and green tea catechins (600 mg/day) (51), showed no benefit on the rate of progression to prostate cancer at six-month (50, 51) and 37-month follow-ups (51). Earlier small trials in men with HGPIN led to similar conclusions (reviewed in 52). Additionally, a randomized controlled trial in men with localized prostate cancer found that supplementation with 15, 30, or 45 mg of lycopene (until prostatectomy) did not significantly increase plasma lycopene concentration, modify the ratio of steroid hormones in blood, or reduce the concentration of markers of proliferation (i.e., prostate-specific antigen [PSA] and Ki-67) compared to placebo (53). In another trial, 54 patients with metastatic prostate cancer were randomized to orchidectomy alone or orchidectomy plus 4 mg/day of lycopene (54). The proportion of complete clinical response to treatment — assessed by serum PSA and/or bone scan returning to normal — and patient survival rate were found to be significantly higher in patients supplemented with lycopene (54).

Large-scale, controlled clinical trials are needed to further examine the safety and efficacy of long-term use of lycopene supplements for prostate cancer prevention or treatment.

Other types of cancer

In a meta-analysis of 12 prospective cohort studies, no association was found between total and individual carotenoid intake and risk of breast cancer, except with β-carotene for which a 5% reduction in breast cancer risk was estimated for every 5 mg/day increment in consumption (55). In a pooled analysis of 14 nested case-control studies and one follow-up study of a clinical trial, reductions in breast cancer risk were found to be associated with blood concentrations of total carotenoids (-26%), α-carotene (-20%), and lutein (-30%) (55). Another study that recalibrated data for consistency across eight large prospective cohorts before pooled analysis found reduced breast cancer risk to be associated with the highest versus lowest quintile of blood concentrations of total carotenoids (-21%), β-carotene (-17%), and lycopene (-22%) (56). Further analyses found an inverse association between the blood concentrations of β-carotene and α-carotene and risk of estrogen receptor-negative (ER-), but not estrogen receptor-positive (ER+), breast tumors (56). A similar result was recently reported in a case-control study nested within the multicenter, large, European Prospective Investigation into Cancer and Nutrition (EPIC) study (57).

Another case-control study nested within the EPIC study found a 31% lower risk of colorectal cancer with the highest versus lowest quartile of β-carotene intake, while no associations were shown with blood concentrations of other carotenoids or total carotenoids (58). The nested case-control study was included in a recent meta-analysis of 22 observational studies that failed to find associations between carotenoid intakes and colorectal cancer (59).

Pooled data from mostly case-control studies also suggested that higher intakes of individual carotenoids, especially β-cryptoxanthin and lycopene, might be associated with a reduced risk of cancers of the mouth, pharynx, and larynx (60). However, the results of case-control studies are more likely to be distorted by bias than results of prospective studies.

Examining blood concentrations of each carotenoid in relation to cancer subsites may help overcome limitations associated with dietary data and differences in carotenoid absorption.

Eye diseases

Age-related macular degeneration

In Western countries, degeneration of the macula, the center of the eye’s retina, is a leading cause of blindness in older adults. Long-term blue light exposure and oxidative damage in the outer segments of photoreceptors may lead to drusen and/or pigment abnormalities in the macula, increasing the risk of age-related macular degeneration (AMD) and central blindness.

Dietary lutein and zeaxanthin: The carotenoids found in the retina are lutein and zeaxanthin, which are both of dietary origin, and meso-zeaxanthin, which is derived from lutein. These three carotenoids are present in high concentrations in the macula (known as macular pigment), where they are efficient absorbers of blue light. They may prevent a substantial amount of the blue light entering the eye from reaching the underlying structures involved in vision and protect against light-induced oxidative damage, which is thought to play a role in the pathology of age-related macular degeneration (reviewed in 19). It is also possible, though not proven, that lutein, zeaxanthin, and meso-zeaxanthin, act directly to neutralize oxidants formed in the retina.

Increasing dietary consumption of lutein and zeaxanthin was shown to raise their serum concentration and macular pigment density (61, 62). Some, but not all, observational studies have provided evidence that higher intakes of lutein and zeaxanthin are associated with lower risk of age-related macular degeneration (AMD) (63). While cross-sectional and retrospective case-control studies found that higher levels of lutein and zeaxanthin in the diet (64-66), blood (67, 68), and retina (69, 70) were associated with a lower incidence of AMD, several prospective cohort studies found no relationship between baseline dietary intakes or serum concentrations of lutein and zeaxanthin and the risk of developing AMD over time (71-74). A recent report examined the association between the incidence of AMD and calculated dietary intakes and predicted plasma concentrations of lutein and zeaxanthin in older adults (≥50 years) from two large prospective cohorts, the Nurses’ Health Study (NHS; 63,443 women) and the Health Professionals Follow-up Study (HPFS; 38,603 men), followed for 26 years and 24 years, respectively (75). The highest versus lowest quintile of predicted plasma lutein and zeaxanthin scores was associated with a 41% lower risk of advanced AMD, yet no association was found with intermediate AMD. The evidence also suggested that the consumption of about 6 mg/day of lutein and zeaxanthin from fruit and vegetables (compared with less than 2 mg/day) may decrease the risk of advanced AMD (75).

Supplemental lutein and zeaxanthin: The first randomized controlled trial in patients with atrophic AMD found that supplementation with 10 mg/day of lutein slightly improved visual acuity after one year compared to a placebo (76). The effects of long-term lutein supplementation on atrophic AMD were further investigated in combination with antioxidant vitamins and minerals in the Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-blind, placebo-controlled trial. In AREDS, oral supplementation with β-carotene (15 mg/day), vitamin C (500 mg/day), vitamin E (400 IU/day), zinc (80 mg/day as zinc oxide), and copper (2 mg/day as cupric oxide) for five years was shown to reduce the risk of developing advanced AMD by 25% (77). In the AREDS2 study conducted in 4,203 participants at risk for developing late AMD, supplemental lutein (10 mg/day) and zeaxanthin (2 mg/day), in combination with β-carotene, vitamin C, vitamin E, zinc, and copper (the ‘AREDS’ formulation), did not slow the progression to advanced AMD, although subgroup analyses revealed a benefit in those with the lowest dietary intakes of lutein + zeaxanthin (77). A total of 3,036 subjects were further randomized to various combinations of carotenoids; supplementation with lutein and zeaxanthin significantly reduced the risk of progression to late AMD and to neovascular AMD compared to supplementation with β-carotene (78)

Several smaller (n=30-433) randomized controlled trials also suggested that supplementation with xanthophyll carotenoids would be beneficial in the management of AMD (reviewed in 79). A meta-analysis of eight trials that examined the effect of supplemental lutein (6 to 20 mg/day) or/and zeaxanthin (0 to 10 mg/day) in 1,176 AMD subjects for up to 36 months found improvements in visual acuity and contrast sensitivity with increased levels of xanthophyll carotenoids (80). Finally, a recent randomized, placebo-controlled trial found daily consumption of a buttermilk drink with egg yolks enriched with lutein (1.4 mg), zeaxanthin (0.2 mg), and an omega-3 polyunsaturated fatty acid (DHA; 160 mg) for one year improved visual acuity and macular pigment optical density in subjects with drusen and/or retinal pigment abnormalities (about half of them being classified as having early AMD) (81).

Supplemental β-carotene: The first randomized controlled trial designed to examine the effect of a carotenoid supplement on AMD used β-carotene in combination with vitamin C, vitamin E, and zinc because lutein and zeaxanthin were not commercially available as supplements at the time the trial began (82). Although the combination of antioxidants and zinc lowered the risk of developing advanced macular degeneration in individuals with signs of moderate-to-severe macular degeneration in at least one eye, it is unlikely that the benefit was related to β-carotene since it is not present in the retina. Supplementation of male smokers in Finland with 20 mg/day of β-carotene for six years did not decrease the risk of AMD compared to placebo (83). A placebo-controlled trial in a cohort of 22,071 healthy US men found that β-carotene supplementation (50 mg every other day) had no effect on the incidence of age-related maculopathy — an early stage of AMD (84). Recent systematic reviews of randomized controlled trials have concluded that there is no evidence that β-carotene supplementation prevents or delays the onset of AMD (85, 86).

Other retinopathies

Retinopathy of prematurity

Preterm infants have an immature retinal vascular system that places them at risk of developing retinopathy of prematurity (ROP). Basically, preterm birth halts the normal development of retinal vascular system, which results in a retina that is poorly vascularized and highly susceptible to hyperoxia. In order to meet metabolic demand, the hypoxic retina induces the production of proangiogenic factors like VEGF (vascular endothelial growth factor). These factors stimulate the development of new blood vessels (angiogenesis), causing aberrant vessels sprouting from the retina into the vitreous. It is thought that an imbalance between the production of reactive oxygen species (ROS) and the reduced levels of antioxidants in preterm infants contributes to ROP pathogenesis and causes additional damage to the retina (reviewed in 87).

Supplemental lutein and zeaxanthin: A randomized controlled trial in 62 preterm infants (≤32 weeks of gestational age) failed to observe any benefits regarding ROP incidence and severity with lutein (0.5 mg/kg/day) and zeaxanthin (0.02 mg/kg/day) supplemented from the seventh day post birth until about 10 weeks of age (88). In two other multicenter, placebo-controlled trials in a total of 343 preterm infants, a daily oral dose of 0.14 mg of lutein and 0.006 mg of zeaxanthin administered from the first week after birth did not significantly reduce ROP incidence or the rate of progression from early to more advanced stages of ROP occurrence (89, 90). A fourth multicenter, randomized controlled trial in 203 preterm infants found that administration of a formula containing carotenoids (lutein/zeaxanthin, lycopene, and β-carotene) had no effect on ROP incidence but limited the progression to severe ROP stages in infants with mild ROP compared to a carotenoid-free formula (91). Compared with the control formula, preterm infants free of ROP fed the carotenoid-containing formula had significantly increased plasma carotenoid concentrations, which were correlated with greater rod photoreceptor sensitivity (91). More research is needed to examine whether carotenoid supplementation might promote normal photoreceptor development and prevent ROP in preterm infants.

Diabetic retinopathy

Supplementation with lutein and zeaxanthin has been shown to help preserve retina integrity in diabetic rodents by reducing oxidative stress and inflammatory mediators (87). A higher ratio of plasma nonprovitamin A carotenoids (lutein, zeaxanthin, and lycopene) to vitamin A carotenoids (β-carotene, β-carotene, β-cryptoxanthin) was associated with a reduced risk of diabetic retinopathy in a cross-sectional analysis in 111 individuals with type 2 diabetes mellitus (92). Recent data from 1,430 individuals participating in the Atherosclerosis Risk In Communities (ARIC) study found no association between lutein intake and diabetic retinopathy after adjustment for confounding variables (93). To date, the role of carotenoids in the prevention of diabetic retinopathy has not been examined in clinical studies.

Cataracts

The primary function of the eye’s lens is to collect and focus light on the retina. Ultraviolet light and oxidants can damage proteins in the lens, causing structural changes that result in the formation of opacities known as cataracts. As people age, cumulative damage to lens proteins often results in cataracts that are large enough to interfere with vision (10). Risk factors other than aging and sunlight exposure include smoking, diabetes mellitus, higher body mass index, and use of estrogen replacement therapy. An estimated 50 million US adults are projected to be affected by age-related cataracts by 2050 (94).

Dietary lutein and zeaxanthin: The observation that lutein and zeaxanthin are the only carotenoids in the human lens has stimulated interest in the potential for increased intakes of lutein and zeaxanthin to prevent or slow the progression of cataracts (reviewed in 79). Large prospective cohort studies have found that men and women with the highest intakes of foods rich in lutein and zeaxanthin, particularly spinach, kale, and broccoli, were 18%-50% less likely to require cataract extraction (95, 96) or develop cataracts (97-99). Moreover, plasma concentrations of lutein and zeaxanthin have been found to be inversely associated to the progression of nuclear cataract. Additional research is required to determine whether these findings are related specifically to lutein and zeaxanthin intake or to other factors associated with diets high in carotenoid-rich foods (63).

Supplemental lutein and zeaxanthin: The Age-related Eye Disease Study 2 (AREDS2) failed to show an effect of supplemental lutein (10 mg/day) and zeaxanthin (2 mg/day; supplementation for a median of 4.7 years) on the risk of developing cataract, on the progression to severe cataract or to cataract surgery, and on visual acuity (100). However, the results might have been confounded by the fact that most participants were better nourished than the general population and/or used multivitamins that have been found to decrease the risk of developing cataract (101). Additional limitations to consider in interpreting the results have been reviewed elsewhere (100). Additional interventions are required to study whether supplemental lutein and zeaxanthin might be helpful in the prevention of cataract.

Supplemental β-carotene: Evidence from observational studies that cataracts were less prevalent in people with high dietary intakes and blood concentrations of carotenoids led to the inclusion of β-carotene supplements in several large randomized controlled trials of antioxidants. The results of those trials have been somewhat conflicting. β-Carotene supplementation (20 mg/day) for more than six years did not affect the prevalence of cataracts or the frequency of cataract surgery in male smokers living in Finland (83). In contrast, a 12-year study of male physicians in the US found that β-carotene supplementation (50 mg every other day) decreased the risk of cataracts in smokers but not in nonsmokers (102). Note that use of β-carotene supplements have been shown to increase the risk of lung cancer in smokers (see Supplemental β-carotene in lung cancer). Three randomized controlled trials examined the effect of an antioxidant combination that included β-carotene, vitamin C, and vitamin E on the progression of cataracts. Two trials found no benefit after supplementation for five years (103) or more than six years (104), but one trial found a small decrease in the progression of cataracts after three years of supplementation (105). Overall, the results of randomized controlled trials suggest that the benefit of β-carotene supplementation in slowing the progression of age-related cataracts does not outweigh the potential risks.

Cardiovascular disease

Dietary carotenoids: Because carotenoids are very soluble in fat and very insoluble in water, they circulate in lipoproteins, along with cholesterol and other fats. Evidence that low-density lipoprotein (LDL) oxidation plays a role in the development of atherosclerosis led scientists to investigate the role of antioxidant compounds like carotenoids in the prevention of cardiovascular disease (106). The thickness of the inner layers of the carotid arteries can be measured noninvasively using ultrasound technology. This measurement of carotid intima-media thickness is considered a reliable marker of atherosclerosis (107). A number of case-control and cross-sectional studies have found higher blood concentrations of carotenoids to be associated with significantly lower measures of carotid artery intima-media thickness (108-113). Additionally, higher plasma carotenoids at baseline have been associated with significant reductions in risk of cardiovascular disease in some prospective cohort studies (114-118) but not in others (119-122).

More recently, an analysis of data from the 2003-2006 US National Health And Nutrition Examination Survey (NHANES) in a sample of 2,856 adults found that serum total carotenoid concentration was inversely associated to blood concentrations of two cardiovascular risk factors, C-reactive protein (CRP) and total homocysteine (123). HDL-cholesterol concentration was found to be positively associated with α-carotene, β-cryptoxanthin, and lutein/zeaxanthin concentrations, but only the latter was inversely associated with LDL-cholesterol (123). Finally, a recent meta-analysis of observational studies reported lower risks of coronary heart disease (-12%) and stroke (-18%) in individuals in the highest versus lowest tertile of blood lutein concentration (124).

While the results of several prospective studies indicate that people with higher intakes of carotenoid-rich fruit and vegetables are at lower risk of cardiovascular disease (122, 125-127), it is not yet clear whether this effect is a result of carotenoids or other factors associated with diets high in carotenoid-rich fruit and vegetables.

Supplemental β-carotene: In contrast to the results of observational studies suggesting that high dietary intakes of carotenoid-rich fruit and vegetables may decrease cardiovascular disease risk, four randomized controlled trials found no evidence that β-carotene supplements in doses ranging from 20 to 50 mg/day were effective in preventing cardiovascular disease (39, 128-130). Based on the results of these randomized controlled trials, the US Preventive Health Services Task Force found good evidence to suggest that β-carotene supplements provided no benefit in the prevention of cardiovascular disease in healthy adults (42). Thus, although diets rich in β-carotene have generally been associated with reduced cardiovascular disease risk in observational studies, there is no evidence that β-carotene supplementation reduces cardiovascular disease risk (131).

Osteoporosis

A recent experimental study found that the administration of β-cryptoxanthin to ovariectomized mice limited bone resorption by inhibiting osteoclast differentiation but had no effect on osteoblast-driven bone formation (132). Yet, evidence of a protective role of β-cryptoxanthin — and other individual carotenoids — against bone loss in humans is scarce. In the prospective Framingham Osteoporosis Study, data analysis of 603 participants found no association between β-cryptoxanthin intake and changes in bone mineral density (BMD) over a four-year period (133). In contrast, intakes of total and individual carotenoids (β-carotene, lycopene, and lutein/zeaxanthin) were positively associated with proximal femur BMD in men over a four-year period, while lycopene intake was positively linked to lumbar spine BMD in women (133). The 17-year follow-up of participants in the Framingham Osteoporosis Study (946 participants) showed those in the highest tertile of total carotenoid intake (median intake: 23.7 mg/day) had a 51% lower risk of hip fracture compared to those in the lowest tertile (median intake: 7.3 mg/day) (134). In a much larger prospective study — the Singapore Chinese Health Study — in 63,257 men and women followed for 10 years, the highest versus lowest quartile of total carotenoid intake was associated with a 37% lower risk of hip fracture in men but not in women (135). Dietary intakes of α- and β-carotene — but not of β-cryptoxanthin, lycopene, and lutein/zeaxanthin — were inversely associated with hip fracture risk in men (135). Nevertheless, in a small, four-year, Japanese prospective cohort study in 457 adults, the risk of osteoporosis was 93% lower in postmenopausal women in the highest versus lowest tertile of serum β-cryptoxanthin concentration (136). No such association was reported with serum concentrations of other individual carotenoids. Whether carotenoid supplementation may help prevent bone loss and reduce the risk of osteoporosis in older individuals is currently unknown.

Cognitive function

Observational studies have suggested that dietary lutein may be of benefit in maintaining cognitive health (137, 138). As stated above, among the carotenoids, lutein and its isomer zeaxanthin are the only two that cross the blood-retina barrier to form macular pigment in the eye. Lutein also preferentially accumulates in the brain (139, 140). Recent studies suggested that lutein and zeaxanthin concentrations in the macula were correlated with brain lutein and zeaxanthin status and might be used as a biomarker to assess cognitive health (140-142). Additionally, in the Georgia Centenarian Study, the analysis of cross-sectional data from 47 centenarian decedents showed a positive association between post-mortem measures of brain lutein concentrations and pre-mortem measures of cognitive function (139). Brain lutein concentrations were found to be significantly lower in individuals with mild cognitive impairment compared to those with normal cognitive function (139). In a small, four-month, double-blind, placebo-controlled study in older women (ages, 60 to 80 years) without cognitive impairment, supplementation with lutein (12 mg/day) and zeaxanthin (~0.5 mg/day) significantly improved cognitive test performance (143). Nevertheless, the Age-related Eye Disease Study 2 (AREDS2) failed to show an effect of supplemental lutein (10 mg/day) and zeaxanthin (2 mg/day; supplementation for a median of 4.7 years) on the cognitive test scores of 3,741 participants (mean age, 72.7 years) (144).

Sources

Food sources

The most prevalent carotenoids in the human diet are α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin (8). Most carotenoids in foods are found in the all-trans form (see Figure 1 and Figure 2 above), although cooking may result in the formation of other isomers. The relatively low bioavailability of carotenoids from most foods compared to supplements is partly due to the fact that they are associated with proteins in the plant matrix (145). Chopping, homogenizing, and cooking disrupt the plant matrix, increasing the bioavailability of carotenoids (3). For example, the bioavailability of lycopene from tomatoes is substantially improved by heating tomatoes in oil (146, 147).

α-Carotene and β-carotene

α-Carotene and β-carotene are provitamin A carotenoids, meaning they can be converted in the body to vitamin A. The vitamin A activity of β-carotene in food is 112 that of retinol (preformed vitamin A). Thus, it would take 12 µg of β-carotene from food to provide the equivalent of 1 µg (0.001 mg) of retinol. The vitamin A activity of α-carotene from foods is 124 that of retinol, so it would take 24 µg of α-carotene from food to provide the equivalent of 1 µg of retinol. Orange and yellow vegetables like carrots and winter squash are rich sources of α- and β-carotene. Spinach is also a rich source of β-carotene, although the chlorophyll in spinach leaves hides the yellow-orange pigment. Some foods that are good sources of α-carotene and β-carotene are listed in Table 2 and Table 3 (148).

Table 2. α-Carotene Content of Selected Foods
Food Serving α-Carotene (mg)
Pumpkin, canned 1 cup 11.7
Carrot juice, canned 1 cup (8 fl oz) 10.2
Carrots, cooked 1 cup 5.9
Carrots, raw 1 medium 2.1
Mixed vegetables, frozen, cooked 1 cup 1.8
Winter squash, baked 1 cup 1.4
Plantains, raw 1 medium 0.8
Collards, frozen, cooked 1 cup 0.2
Tomatoes, raw 1 medium 0.1
Tangerines, raw 1 medium 0.09
Peas, edible-podded, frozen, cooked 1 cup 0.09

 

Table 3. β-Carotene Content of Selected Foods
Food Serving β-Carotene (mg)
Carrot juice, canned 1 cup (8 fl oz) 22.0
Pumpkin, canned 1 cup 17.0
Spinach, frozen, cooked 1 cup 13.8
Sweet potato, baked 1 medium 13.1
Carrots, cooked 1 cup 13.0
Collards, frozen, cooked 1 cup 11.6
Kale, frozen, cooked 1 cup 11.5
Turnip greens, frozen, cooked 1 cup 10.6
Pumpkin pie 1 piece 7.4
Winter squash, cooked 1 cup 5.7
Carrots, raw 1 medium 5.1
Dandelion greens, cooked 1 cup 4.1
Cantaloupe, raw 1 cup 3.2
β-Cryptoxanthin

Like α- and β-carotene, β-cryptoxanthin is a provitamin A carotenoid. The vitamin A activity of β-cryptoxanthin from food was estimated to be 124 that of retinol, so it would take 24 µg of β-cryptoxanthin from food to provide the equivalent of 1 µg of retinol. Orange and red fruit and vegetables like sweet red peppers and oranges are particularly rich sources of β-cryptoxanthin. Some foods that are good sources of β-cryptoxanthin are listed in Table 4 (148).

Table 4. β-Cryptoxanthin Content of Selected Foods
Food Serving β-Cryptoxanthin (mg)
Pumpkin, cooked 1 cup 3.6
Papayas, raw 1 medium 2.3
Sweet red peppers, cooked 1 cup 0.6
Sweet red peppers, raw 1 medium 0.6
Orange juice, fresh 1 cup (8 fl oz) 0.4
Tangerines, raw 1 medium 0.4
Carrots, frozen, cooked 1 cup 0.3
Yellow corn, frozen, cooked 1 cup 0.2
Watermelon, raw 1 wedge (116 of a melon that is 15 inches long x 7.5 inches in diameter) 0.2
Paprika, dried 1 teaspoon 0.2
Oranges, raw 1 medium 0.2
Nectarines, raw 1 medium 0.1
Lycopene

Lycopene gives tomatoes, pink grapefruit, watermelon, and guava their red color. It has been estimated that 80% of the lycopene in the US diet comes from tomatoes and tomato products like tomato sauce, tomato paste, and ketchup (catsup) (149). Lycopene is not a provitamin A carotenoid because it cannot be converted to retinol. Some foods that are good sources of lycopene are listed in Table 5 (148).

Table 5. Lycopene Content of Selected Foods
Food Serving Lycopene (mg)
Tomato paste, canned 1 cup 75.4
Tomato purée, canned 1 cup 54.4
Tomato soup, canned, condensed 1 cup 26.4
Vegetable juice cocktail, canned 1 cup 23.3
Tomato juice, canned 1 cup 22.0
Watermelon, raw 1 wedge (116 of a melon that is 15 inches long x 7.5 inches in diameter) 13.0
Tomatoes, raw 1 cup 4.6
Ketchup (catsup) 1 tablespoon 2.5
Pink grapefruit, raw ½ grapefruit 1.7
Baked beans, canned 1 cup 1.3
Lutein and zeaxanthin

Although lutein and zeaxanthin are different compounds, they are both classified as xanthophylls and nonprovitamin A carotenoids (see Figure 2 above). Some methods used to quantify lutein and zeaxanthin in food do not separate the two compounds, so they are typically reported as lutein and zeaxanthin or lutein + zeaxanthin. Both pigments are present in a variety of fruit and vegetables. Dark green leafy vegetables like spinach and kale are particularly rich sources of lutein but poor sources of zeaxanthin (150). Although relatively low in lutein, egg yolks and avocados are highly bioavailable sources of lutein. Good sources of dietary zeaxanthin include yellow corn, orange pepper, orange juice, honeydew (melon), and mango (150). Some foods containing lutein and zeaxanthin are listed in Table 6 (148).

Table 6. Lutein + Zeaxanthin Content of Selected Foods
Food Serving Lutein + Zeaxanthin (mg)
Spinach, frozen, cooked 1 cup 29.8
Kale, frozen, cooked 1 cup 25.6
Turnip greens, frozen, cooked 1 cup 19.5
Collards, frozen, cooked 1 cup 18.5
Dandelion greens, cooked 1 cup 9.6
Mustard greens, cooked 1 cup 8.3
Summer squash, cooked 1 cup 4.0
Peas, frozen, cooked 1 cup 3.8
Winter squash, baked 1 cup 2.9
Pumpkin, cooked 1 cup 2.5
Brussel sprouts, frozen, cooked 1 cup 2.4
Broccoli, frozen, cooked 1 cup 2.0
Sweet yellow corn, boiled 1 cup 1.5
Avocado, raw 1 medium 0.4
Egg yolk, raw 1 large 0.2

For more information on the carotenoid content of certain foods, search the USDA National Nutrient Database.

Supplements

Dietary supplements providing purified carotenoids and combinations of carotenoids are commercially available in the US without a prescription. Carotenoids are best absorbed when taken with a meal containing fat.

α-Carotene

Supplements containing a mixture of carotenoids may include α-carotene. As a provitamin A carotenoid, supplemental α-carotene can contribute to fulfill vitamin A requirements. It is not known whether the relative bioavailability of supplemental α-carotene is greater than that of dietary α-carotene.

α-Cryptoxanthin

Supplements containing a mixture of carotenoids may include α-cryptoxanthin. As a provitamin A carotenoid, supplemental α-cryptoxanthin can contribute to fulfill vitamin A requirements. It is not known whether the relative bioavailability of supplemental α-cryptoxanthin is greater than that of dietary α-cryptoxanthin.

β-Carotene

β-Carotene is sold as individual supplements and also found in supplements marketed to promote visual health (151). Commercially available β-carotene supplements usually contain between 1.5 mg and 15 mg of either synthetic β-carotene or natural β-carotene (mainly from the algae Dunaliella salina) per softgel capsule (150). As a provitamin A carotenoid, β-carotene may be used to provide all or part of the vitamin A in multivitamin supplements. The provitamin A activity of β-carotene from supplements is much higher than that of β-carotene from food: it takes only 2 micrograms [µg] (0.002 mg) of β-carotene from supplements to provide 1 µg of retinol (preformed vitamin A) compared to 12 µg of dietary β-carotene.

Of note, the β-carotene content of supplements is often listed in international units (IU) rather than µg: 3,000 µg (3 mg) of supplemental β-carotene provides 5,000 IU of vitamin A.

Lycopene

Lycopene has no provitamin A activity. Synthetic lycopene and lycopene from natural sources, mainly tomatoes, are available as nutritional supplements containing up to 15 mg of lycopene per softgel capsule (150).

Lutein and zeaxanthin

Lutein and zeaxanthin are not provitamin A carotenoids. Lutein and zeaxanthin supplements are available as free carotenoids (non-esterified) or as esters (esterified to fatty acids). Both forms appear to have comparable bioavailability (152). Many commercially available lutein and zeaxanthin supplements have much higher amounts of lutein than zeaxanthin (150). Supplements containing only lutein or zeaxanthin are also available.

Safety

Toxicity

β-Carotene

Although β-carotene can be converted to vitamin A, the conversion of β-carotene to vitamin A decreases when body stores of vitamin A are high (see Absorption, Metabolism, and Bioavailability). This may explain why high doses of β-carotene have never been found to cause vitamin A toxicity. High doses of β-carotene (up to 180 mg/day) have been used to treat erythropoietic protoporphyria, a photosensitivity disorder, without toxic side effects (8).

Lycopene, lutein, and zeaxanthin

No toxicities have been reported (153).

Adverse effects

β-Carotene

Increased lung cancer risk: Two randomized controlled trials in smokers and former asbestos workers found that supplementation with 20 to 30 mg/day of β-carotene for 4 to 6 years was associated with significant 16%-28% increases in the risk of lung cancer compared to placebo (see Supplemental β-carotene in lung cancer). Although the reasons for these findings are not yet clear, the potential risk of lung cancer in smokers and other high-risk groups supplemented with high-dose β-carotene outweigh any possible benefits for chronic disease prevention (42). It should be noted that there is no evidence that β-carotene supplementation may harm nonsmokers.

Carotenodermia: High doses of β-carotene supplements (≥30 mg/day) and the consumption of large amounts of carotene-rich food have resulted in a yellow discoloration of the skin (xanthoderma) known as carotenodermia. Carotenodermia is not associated with any underlying health problems and resolves when supplementation with β-carotene is discontinued or dietary carotene intake is reduced.

Lycopene

Lycopenodermia: High intakes of lycopene-rich food or supplements may result in a deep orange discoloration of the skin known as lycopenodermia. Because lycopene is more intensely colored than the carotenes, lycopenodermia may occur at lower doses than carotenodermia (8).

Lutein and zeaxanthin

Adverse effects of lutein and zeaxanthin have not been reported (150).

Safety in pregnancy and lactation

β-Carotene

Unlike vitamin A, high doses of β-carotene taken by pregnant women have not been associated with increased risk of birth defects (8). However, the safety of high-dose β-carotene supplements in pregnancy and lactation has not been well studied. Although there is no reason to limit dietary β-carotene intake, pregnant and breast-feeding women should avoid consuming more than 3 mg/day (1,500 µg RAE/day; 5,000 IU/day) of β-carotene from supplements unless they prescribed under medical supervision.

Other carotenoids

The safety of carotenoid supplements other than β-carotene in pregnancy and lactation has not been established, so pregnant and breast-feeding women should obtain carotenoids from food rather than supplements. There is no reason to limit the consumption of carotenoid-rich fruit and vegetables during pregnancy (150).

Drug interactions

The cholesterol-lowering agents, cholestyramine (Questran) and colestipol (Colestid), can reduce absorption of fat-soluble vitamins and carotenoids, as can mineral oil and Orlistat (Xenical), a drug used to treat obesity (150). Colchicine, a drug used to treat gout, can cause intestinal malabsorption. However, long-term use of 1 to 2 mg/day of colchicine did not affect serum β-carotene concentrations in one study (154). Increasing gastric pH through the use of proton-pump inhibitors (Omeprazole, Lansoprazole) may decrease the absorption of a single dose of a β-carotene supplement, but the effect is unlikely to be clinically significant (155).

Antioxidant supplements and statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors)

A three-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low serum high density lipoprotein (HDL) concentrations found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis, and decreased the frequency of cardiovascular events, including myocardial infarction and stroke (156). Surprisingly, when an antioxidant combination of 1,000 mg of vitamin C, 536 mg of RRR-α-tocopherol (vitamin E), 100 µg of selenium, and 25 mg of β-carotene daily was taken with the simvastatin-niacin combination, the protective effects were diminished. Since the antioxidants were taken together in this trial, the individual contribution of β-carotene cannot be determined. In contrast, a much larger randomized controlled trial of simvastatin and an antioxidant combination of 297 mg of RRR-α-tocopherol, 250 mg of vitamin C, and 20 mg of β-carotene daily in more than 20,000 men and women with CHD or diabetes mellitus found that the antioxidant combination did not diminish the cardioprotective effects of simvastatin therapy over a five-year period (157). These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplements and cholesterol-lowering agents, such as niacin and statins.

Interactions with food

Fat substitute Olestra

In a controlled feeding study, consumption of 18 g/day of the fat substitute Olestra (sucrose polyester; Olean) resulted in a 27% decrease in serum carotenoid concentrations after three weeks (158). Studies in people before and after the introduction of Olestra-containing snacks to the marketplace found that total serum carotenoid concentrations decreased by 15% in those who reported consuming at least 2 g/day of Olestra (159). One study in adults found that those who consumed more than 4.4 g of Olestra weekly experienced a 9.7% decline in total serum carotenoids compared to those not consuming Olestra (160).

Plant sterol- or stanol-containing foods

Some studies found that the regular use of plant sterol-containing spreads resulted in modest, 10%-20% decreases in the plasma concentrations of some carotenoids, particularly α-carotene, β-carotene, and lycopene (see the article on Phytosterols) (161, 162). However, advising people who use plant sterol- or stanol-containing margarines to consume an extra serving of carotenoid-rich fruit or vegetables daily prevented decreases in plasma carotenoid concentrations (163, 164).

Alcohol

The relationships between alcohol consumption and carotenoid metabolism are not well understood. There is some evidence that regular alcohol consumption inhibits the conversion of β-carotene to retinol (165). Increases in lung cancer risk associated with high-dose β-carotene supplementation in two randomized controlled trials were enhanced in those with higher alcohol intakes (38, 166).

Interactions among carotenoids

The results of metabolic studies suggested that high doses of β-carotene competed with lutein and lycopene for absorption when consumed at the same time (167-169). However, the consumption of high-dose β-carotene supplements did not adversely affect serum carotenoid concentrations in long-term clinical trials (170-173).


Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2016 by:
Elizabeth J. Johnson, Ph.D., Research Scientist
Antioxidants Research Laboratory
Jean Mayer USDA Human Nutrition Research Center on Aging
Assistant Professor, Friedman School of Nutrition Science
Tufts University

Copyright 2004-2017  Linus Pauling Institute


References

1.  Wang XD. Carotenoids. In: Ross CA, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed: Lippincott Williams & Wilkins; 2014:427-439.

2.  Jalal F, Nesheim MC, Agus Z, Sanjur D, Habicht JP. Serum retinol concentrations in children are affected by food sources of β-carotene, fat intake, and anthelmintic drug treatment. Am J Clin Nutr. 1998;68(3):623-629.  (PubMed)

3.  van Het Hof KH, West CE, Weststrate JA, Hautvast JG. Dietary factors that affect the bioavailability of carotenoids. J Nutr. 2000;130(3):503-506.  (PubMed)

4.  Priyadarshani AM. A review on factors influencing bioaccessibility and bioefficacy of carotenoids. Crit Rev Food Sci Nutr. 2015. [Epub ahead of print].  (PubMed)

5.  Reboul E. Absorption of vitamin A and carotenoids by the enterocyte: focus on transport proteins. Nutrients. 2013;5(9):3563-3581.  (PubMed)

6.  Tanumihardjo SA, Palacios N, Pixley KV. Provitamin a carotenoid bioavailability:what really matters? Int J Vitam Nutr Res. 2010;80(4-5):336-350.  (PubMed)

7.  Borel P. Genetic variations involved in interindividual variability in carotenoid status. Mol Nutr Food Res. 2012;56(2):228-240.  (PubMed)

8.  Food and Nutrition Board, Institute of Medicine. β-Carotene and other carotenoids. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, D.C.: National Academy Press; 2000:325-400.  (National Academy Press)

9.  Weber D, Grune T. The contribution of β-carotene to vitamin A supply of humans. Mol Nutr Food Res. 2012;56(2):251-258.  (PubMed)

10.  Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 3rd ed. New York, NY: Oxford University Press; 1999.

11.  Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys. 1989;274(2):532-538.  (PubMed)

12.  Young AJ, Lowe GM. Antioxidant and prooxidant properties of carotenoids. Arch Biochem Biophys. 2001;385(1):20-27.  (PubMed)

13.  Kaulmann A, Bohn T. Carotenoids, inflammation, and oxidative stress--implications of cellular signaling pathways and relation to chronic disease prevention. Nutr Res. 2014;34(11):907-929.  (PubMed)

14.  Ben-Dor A, Steiner M, Gheber L, et al. Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther. 2005;4(1):177-186.  (PubMed)

15.  Yang PM, Wu ZZ, Zhang YQ, Wung BS. Lycopene inhibits ICAM-1 expression and NF-kappaB activation by Nrf2-regulated cell redox state in human retinal pigment epithelial cells. Life Sci. 2016;155:94-101.  (PubMed)

16.  Lian F, Wang XD. Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. Int J Cancer. 2008;123(6):1262-1268.  (PubMed)

17.  Sung LC, Chao HH, Chen CH, et al. Lycopene inhibits cyclic strain-induced endothelin-1 expression through the suppression of reactive oxygen species generation and induction of heme oxygenase-1 in human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol. 2015;42(6):632-639.  (PubMed)

18.  Yang CM, Huang SM, Liu CL, Hu ML. Apo-8'-lycopenal induces expression of HO-1 and NQO-1 via the ERK/p38-Nrf2-ARE pathway in human HepG2 cells. J Agric Food Chem. 2012;60(6):1576-1585.  (PubMed)

19.  Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr. 2003;23:171-201.  (PubMed)

20.  Kvansakul J, Rodriguez-Carmona M, Edgar DF, et al. Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance. Ophthalmic Physiol Opt. 2006;26(4):362-371.  (PubMed)

21.  Ma L, Lin XM, Zou ZY, Xu XR, Li Y, Xu R. A 12-week lutein supplementation improves visual function in Chinese people with long-term computer display light exposure. Br J Nutr. 2009;102(2):186-190.  (PubMed)

22.  Stringham JM, Hammond BR. Macular pigment and visual performance under glare conditions. Optom Vis Sci. 2008;85(2):82-88.  (PubMed)

23.  Yagi A, Fujimoto K, Michihiro K, Goh B, Tsi D, Nagai H. The effect of lutein supplementation on visual fatigue: a psychophysiological analysis. Appl Ergon. 2009;40(6):1047-1054.  (PubMed)

24.  Stringham JM, Hammond BR, Jr. Dietary lutein and zeaxanthin: possible effects on visual function. Nutr Rev. 2005;63(2):59-64.  (PubMed)

25.  Bertram JS. Carotenoids and gene regulation. Nutr Rev. 1999;57(6):182-191.  (PubMed)

26.  Stahl W, Nicolai S, Briviba K, et al. Biological activities of natural and synthetic carotenoids: induction of gap junctional communication and singlet oxygen quenching. Carcinogenesis. 1997;18(1):89-92.  (PubMed)

27.  Vine AL, Leung YM, Bertram JS. Transcriptional regulation of connexin 43 expression by retinoids and carotenoids: similarities and differences. Mol Carcinog. 2005;43(2):75-85.  (PubMed)

28.  van Poppel G, Spanhaak S, Ockhuizen T. Effect of β-carotene on immunological indexes in healthy male smokers. Am J Clin Nutr. 1993;57(3):402-407.  (PubMed)

29.  Hughes DA, Wright AJ, Finglas PM, et al. The effect of β-carotene supplementation on the immune function of blood monocytes from healthy male nonsmokers. J Lab Clin Med. 1997;129(3):309-317.  (PubMed)

30.  Santos MS, Gaziano JM, Leka LS, Beharka AA, Hennekens CH, Meydani SN. β-Carotene-induced enhancement of natural killer cell activity in elderly men: an investigation of the role of cytokines. Am J Clin Nutr. 1998;68(1):164-170.  (PubMed)

31.  Hughes DA, Wright AJ, Finglas PM, et al. Effects of lycopene and lutein supplementation on the expression of functionally associated surface molecules on blood monocytes from healthy male nonsmokers. J Infect Dis. 2000;182 Suppl 1:S11-15.  (PubMed)

32.  Watzl B, Bub A, Blockhaus M, et al. Prolonged tomato juice consumption has no effect on cell-mediated immunity of well-nourished elderly men and women. J Nutr. 2000;130(7):1719-1723.  (PubMed)

33.  Corridan BM, O'Donoghue M, Hughes DA, Morrissey PA. Low-dose supplementation with lycopene or β-carotene does not enhance cell-mediated immunity in healthy free-living elderly humans. Eur J Clin Nutr. 2001;55(8):627-635.  (PubMed)

34.  Centers for Disease Control and Prevention. Cancer among men. August 20, 2015. Available at: https://www.cdc.gov/cancer/dcpc/data/men.htm. Accessed 6/13/16.

35.  Centers for Disease Control and Prevention. Cancer among women. August 20, 2015. Available at: https://www.cdc.gov/cancer/dcpc/data/women.htm. Accessed 6/13/16.

36.  Gallicchio L, Boyd K, Matanoski G, et al. Carotenoids and the risk of developing lung cancer: a systematic review. Am J Clin Nutr. 2008;88(2):372-383.  (PubMed)

37.  The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and β-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-1035.  (PubMed)

38.  Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996;88(21):1550-1559.  (PubMed)

39.  Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with β-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334(18):1145-1149.  (PubMed)

40.  Kamangar F, Qiao YL, Yu B, et al. Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1562-1564.  (PubMed)

41.  Veeramachaneni S, Wang XD. Carotenoids and lung cancer prevention. Front Biosci (Schol Ed). 2009;1:258-274.  (PubMed)

42.  Moyer, V. A. U S Preventive Services Task Force. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive services Task Force recommendation statement. Ann Intern Med. 2014;160(8):558-564.  (PubMed)

43.  Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer. Exp Biol Med (Maywood). 2002;227(10):852-859.  (PubMed)

44.  Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev. 2004;13(3):340-345.  (PubMed)

45.  Wang Y, Cui R, Xiao Y, Fang J, Xu Q. Effect of carotene and lycopene on the risk of prostate cancer: a systematic review and dose-response meta-analysis of observational studies. PLoS One. 2015;10(9):e0137427.  (PubMed)

46.  Wang Y, Cui R, Xiao Y, Fang J, Xu Q. Correction: effect of carotene and lycopene on the risk of prostate cancer: a systematic review and dose-response meta-analysis of observational studies. PLoS One. 2015;10(10):e0140415.  (PubMed)

47.  Key TJ, Appleby PN, Travis RC, et al. Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies. Am J Clin Nutr. 2015;102(5):1142-1157.  (PubMed)

48.  Melendez-Martinez AJ, Mapelli-Brahm P, Benitez-Gonzalez A, Stinco CM. A comprehensive review on the colorless carotenoids phytoene and phytofluene. Arch Biochem Biophys. 2015;572:188-200.  (PubMed)

49.  World Cancer Research Fund International/American Institute for Cancer Research Continuous Update Project Report. Diet, nutrition, physical activity, and prostate cancer. 2014.

50.  Gann PH, Deaton RJ, Rueter EE, et al. A phase II randomized trial of lycopene-rich tomato extract among men with high-grade prostatic intraepithelial neoplasia. Nutr Cancer. 2015;67(7):1104-1112.  (PubMed)

51.  Gontero P, Marra G, Soria F, et al. A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"? Prostate. 2015;75(11):1177-1186.  (PubMed)

52.  Holzapfel NP, Holzapfel BM, Champ S, Feldthusen J, Clements J, Hutmacher DW. The potential role of lycopene for the prevention and therapy of prostate cancer: from molecular mechanisms to clinical evidence. Int J Mol Sci. 2013;14(7):14620-14646.  (PubMed)

53.  Kumar NB, Besterman-Dahan K, Kang L, et al. Results of a randomized clinical trial of the action of several doses of lycopene in localized prostate cancer: administration prior to radical prostatectomy. Clin Med Urol. 2008;1:1-14.  (PubMed)

54.  Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. 2003;92(4):375-378; discussion 378.  (PubMed)

55.  Aune D, Chan DS, Vieira AR, et al. Dietary compared with blood concentrations of carotenoids and breast cancer risk: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2012;96(2):356-373.  (PubMed)

56.  Eliassen AH, Hendrickson SJ, Brinton LA, et al. Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies. J Natl Cancer Inst. 2012;104(24):1905-1916.  (PubMed)

57.  Bakker MF, Peeters PH, Klaasen VM, et al. Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Am J Clin Nutr. 2016;103(2):454-464.  (PubMed)

58.  Leenders M, Leufkens AM, Siersema PD, et al. Plasma and dietary carotenoids and vitamins A, C and E and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2014;135(12):2930-2939.  (PubMed)

59.  Panic N, Nedovic D, Pastorino R, Boccia S, Leoncini E. Carotenoid intake from natural sources and colorectal cancer: a systematic review and meta-analysis of epidemiological studies. Eur J Cancer Prev. 2016. [Epub ahead of print]  (PubMed)

60.  Leoncini E, Nedovic D, Panic N, Pastorino R, Edefonti V, Boccia S. Carotenoid intake from natural sources and head and neck cancer: a systematic review and meta-analysis of epidemiological studies. Cancer Epidemiol Biomarkers Prev. 2015;24(7):1003-1011.  (PubMed)

61.  Hammond BR, Jr., Johnson EJ, Russell RM, et al. Dietary modification of human macular pigment density. Invest Ophthalmol Vis Sci. 1997;38(9):1795-1801.  (PubMed)

62.  Mares JA, LaRowe TL, Snodderly DM, et al. Predictors of optical density of lutein and zeaxanthin in retinas of older women in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative. Am J Clin Nutr. 2006;84(5):1107-1122.  (PubMed)

63.  Mares-Perlman JA, Millen AE, Ficek TL, Hankinson SE. The body of evidence to support a protective role for lutein and zeaxanthin in delaying chronic disease. Overview. J Nutr. 2002;132(3):518S-524S.  (PubMed)

64.  Snellen EL, Verbeek AL, Van Den Hoogen GW, Cruysberg JR, Hoyng CB. Neovascular age-related macular degeneration and its relationship to antioxidant intake. Acta Ophthalmol Scand. 2002;80(4):368-371.  (PubMed)

65.  Mares-Perlman JA, Fisher AI, Klein R, et al. Lutein and zeaxanthin in the diet and serum and their relation to age-related maculopathy in the third national health and nutrition examination survey. Am J Epidemiol. 2001;153(5):424-432.  (PubMed)

66.  Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994;272(18):1413-1420.  (PubMed)

67.  Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Control Study Group. Arch Ophthalmol. 1993;111(1):104-109.  (PubMed)

68.  Gale CR, Hall NF, Phillips DI, Martyn CN. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2003;44(6):2461-2465.  (PubMed)

69.  Bone RA, Landrum JT, Mayne ST, Gomez CM, Tibor SE, Twaroska EE. Macular pigment in donor eyes with and without AMD: a case-control study. Invest Ophthalmol Vis Sci. 2001;42(1):235-240.  (PubMed)

70.  Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci. 2001;42(2):439-446.  (PubMed)

71.  Cho E, Seddon JM, Rosner B, Willett WC, Hankinson SE. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol. 2004;122(6):883-892.  (PubMed)

72.  Flood V, Smith W, Wang JJ, Manzi F, Webb K, Mitchell P. Dietary antioxidant intake and incidence of early age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology. 2002;109(12):2272-2278.  (PubMed)

73.  Mares-Perlman JA, Klein R, Klein BE, et al. Association of zinc and antioxidant nutrients with age-related maculopathy. Arch Ophthalmol. 1996;114(8):991-997.  (PubMed)

74.  Mares-Perlman JA, Brady WE, Klein R, et al. Serum antioxidants and age-related macular degeneration in a population-based case-control study. Arch Ophthalmol. 1995;113(12):1518-1523.  (PubMed)

75.  Wu J, Cho E, Willett WC, Sastry SM, Schaumberg DA. Intakes of lutein, zeaxanthin, and other carotenoids and age-related macular degeneration during 2 decades of prospective follow-up. JAMA Ophthalmol. 2015;133(12):1415-1424.  (PubMed)

76.  Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75(4):216-230.  (PubMed)

77.  Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015.  (PubMed)

78.  Age-Related Eye Disease Study 2 Research Group, Chew EY, Clemons TE, et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol. 2014;132(2):142-149.  (PubMed)

79.  Scripsema NK, Hu DN, Rosen RB. Lutein, zeaxanthin, and meso-zeaxanthin in the clinical management of eye disease. J Ophthalmol. 2015;2015:865179.  (PubMed)

80.  Liu R, Wang T, Zhang B, et al. Lutein and zeaxanthin supplementation and association with visual function in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2015;56(1):252-258.  (PubMed)

81.  van der Made SM, Kelly ER, Kijlstra A, Plat J, Berendschot TT. Increased macular pigment optical density and visual acuity following consumption of a buttermilk drink containing lutein-enriched egg yolks: a randomized, double-blind, placebo-controlled trial. J Ophthalmol. 2016;2016:9035745.  (PubMed)

82.  Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, β-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.  (PubMed)

83.  Teikari JM, Laatikainen L, Virtamo J, et al. Six-year supplementation with alpha-tocopherol and β-carotene and age-related maculopathy. Acta Ophthalmol Scand. 1998;76(2):224-229.  (PubMed)

84.  Christen WG, Manson JE, Glynn RJ, et al. β-Carotene supplementation and age-related maculopathy in a randomized trial of US physicians. Arch Ophthalmol. 2007;125(3):333-339.  (PubMed)

85.  Evans JR, Henshaw K. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev. 2008(1):CD000253.  (PubMed)

86.  Evans J. Antioxidant supplements to prevent or slow down the progression of AMD: a systematic review and meta-analysis. Eye. 2008;22(6):751-760.  (PubMed)

87.  Gong X, Rubin LP. Role of macular xanthophylls in prevention of common neovascular retinopathies: retinopathy of prematurity and diabetic retinopathy. Arch Biochem Biophys. 2015;572:40-48.  (PubMed)

88.  Romagnoli C, Giannantonio C, Cota F, et al. A prospective, randomized, double blind study comparing lutein to placebo for reducing occurrence and severity of retinopathy of prematurity. J Matern Fetal Neonatal Med. 2011;24 Suppl 1:147-150.  (PubMed)

89.  Dani C, Lori I, Favelli F, et al. Lutein and zeaxanthin supplementation in preterm infants to prevent retinopathy of prematurity: a randomized controlled study. J Matern Fetal Neonatal Med. 2012;25(5):523-527.  (PubMed)

90.  Manzoni P, Guardione R, Bonetti P, et al. Lutein and zeaxanthin supplementation in preterm very low-birth-weight neonates in neonatal intensive care units: a multicenter randomized controlled trial. Am J Perinatol. 2013;30(1):25-32.  (PubMed)

91.  Rubin LP, Chan GM, Barrett-Reis BM, et al. Effect of carotenoid supplementation on plasma carotenoids, inflammation and visual development in preterm infants. J Perinatol. 2012;32(6):418-424.  (PubMed)

92.  Brazionis L, Rowley K, Itsiopoulos C, O'Dea K. Plasma carotenoids and diabetic retinopathy. Br J Nutr. 2009;101(2):270-277.  (PubMed)

93.  Sahli MW, Mares JA, Meyers KJ, et al. Dietary intake of lutein and diabetic retinopathy in the Atherosclerosis Risk in Communities Study (ARIC). Ophthalmic Epidemiol. 2016;23(2):99-108.  (PubMed)

94.  The National Institutes of Heath/National Eye Institute. Cataracts. Available at: https://nei.nih.gov/eyedata/cataract. Accessed 6/9/16.

95.  Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and risk of cataract extraction in US men. Am J Clin Nutr. 1999;70(4):517-524.  (PubMed)

96.  Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of carotenoid and vitamin A intakes and risk of cataract extraction in US women. Am J Clin Nutr. 1999;70(4):509-516.  (PubMed)

97.  Lyle BJ, Mares-Perlman JA, Klein BE, Klein R, Greger JL. Antioxidant intake and risk of incident age-related nuclear cataracts in the Beaver Dam Eye Study. Am J Epidemiol. 1999;149(9):801-809.  (PubMed)

98.  Christen WG, Liu S, Glynn RJ, Gaziano JM, Buring JE. Dietary carotenoids, vitamins C and E, and risk of cataract in women: a prospective study. Arch Ophthalmol. 2008;126(1):102-109.  (PubMed)

99.  Moeller SM, Voland R, Tinker L, et al. Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the Carotenoids in the Age-Related Eye Disease Study, an Ancillary Study of the Women's Health Initiative. Arch Ophthalmol. 2008;126(3):354-364.  (PubMed)

100.  Age-Related Eye Disease Study 2 Research Group, Chew EY, SanGiovanni JP, et al. Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4. JAMA Ophthalmol. 2013;131(7):843-850.  (PubMed)

101.  Glaser TS, Doss LE, Shih G, et al. The Association of Dietary Lutein plus Zeaxanthin and B Vitamins with Cataracts in the Age-Related Eye Disease Study: AREDS Report No. 37. Ophthalmology. 2015;122(7):1471-1479.  (PubMed)

102.  Christen WG, Manson JE, Glynn RJ, et al. A randomized trial of β-carotene and age-related cataract in US physicians. Arch Ophthalmol. 2003;121(3):372-378.  (PubMed)

103.  Gritz DC, Srinivasan M, Smith SD, et al. The Antioxidants in Prevention of Cataracts Study: effects of antioxidant supplements on cataract progression in South India. Br J Ophthalmol. 2006;90(7):847-851.  (PubMed)

104.  Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and β-carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119(10):1439-1452.  (PubMed)

105.  Chylack LT, Jr., Brown NP, Bron A, et al. The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiol. 2002;9(1):49-80.  (PubMed)

106.  Kritchevsky SB. β-Carotene, carotenoids and the prevention of coronary heart disease. J Nutr. 1999;129(1):5-8.  (PubMed)

107.  Bots ML, Grobbee DE. Intima media thickness as a surrogate marker for generalised atherosclerosis. Cardiovasc Drugs Ther. 2002;16(4):341-351.  (PubMed)

108.  Rissanen TH, Voutilainen S, Nyyssonen K, Salonen R, Kaplan GA, Salonen JT. Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2003;77(1):133-138.  (PubMed)

109.  Dwyer JH, Paul-Labrador MJ, Fan J, Shircore AM, Merz CN, Dwyer KM. Progression of carotid intima-media thickness and plasma antioxidants: The Los Angeles Atherosclerosis Study. Arterioscler Thromb Vasc Biol. 2004;24(2):313-9.  (PubMed)

110.  McQuillan BM, Hung J, Beilby JP, Nidorf M, Thompson PL. Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS). J Am Coll Cardiol. 2001;38(7):1788-1794.  (PubMed)

111.  Rissanen T, Voutilainen S, Nyyssonen K, Salonen R, Salonen JT. Low plasma lycopene concentration is associated with increased intima-media thickness of the carotid artery wall. Arterioscler Thromb Vasc Biol. 2000;20(12):2677-2681.  (PubMed)

112.  D'Odorico A, Martines D, Kiechl S, et al. High plasma levels of alpha- and β-carotene are associated with a lower risk of atherosclerosis: results from the Bruneck study. Atherosclerosis. 2000;153(1):231-239.  (PubMed)

113.  Iribarren C, Folsom AR, Jacobs DR, Jr., Gross MD, Belcher JD, Eckfeldt JH. Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis. A case-control study. The ARIC Study Investigators. Atherosclerosis Risk in Communities. Arterioscler Thromb Vasc Biol. 1997;17(6):1171-1177.  (PubMed)

114.  Sesso HD, Buring JE, Norkus EP, Gaziano JM. Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in women. Am J Clin Nutr. 2004;79(1):47-53.  (PubMed)

115.  Rissanen TH, Voutilainen S, Nyyssonen K, et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr. 2001;85(6):749-754.  (PubMed)

116.  Street DA, Comstock GW, Salkeld RM, Schuep W, Klag MJ. Serum antioxidants and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk factors for myocardial infarction? Circulation. 1994;90(3):1154-1161.  (PubMed)

117.  Ito Y, Kurata M, Suzuki K, Hamajima N, Hishida H, Aoki K. Cardiovascular disease mortality and serum carotenoid levels: a Japanese population-based follow-up study. J Epidemiol. 2006;16(4):154-160.  (PubMed)

118.  Buijsse B, Feskens EJ, Kwape L, Kok FJ, Kromhout D. Both alpha- and β-carotene, but not tocopherols and vitamin C, are inversely related to 15-year cardiovascular mortality in Dutch elderly men. J Nutr. 2008;138(2):344-350.  (PubMed)

119.  Sesso HD, Buring JE, Norkus EP, Gaziano JM. Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in men. Am J Clin Nutr. 2005;81(5):990-997.  (PubMed)

120.  Hak AE, Stampfer MJ, Campos H, et al. Plasma carotenoids and tocopherols and risk of myocardial infarction in a low-risk population of US male physicians. Circulation. 2003;108(7):802-807.  (PubMed)

121.  Evans RW, Shaten BJ, Day BW, Kuller LH. Prospective association between lipid soluble antioxidants and coronary heart disease in men. The Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1998;147(2):180-186.  (PubMed)

122.  Sahyoun NR, Jacques PF, Russell RM. Carotenoids, vitamins C and E, and mortality in an elderly population. Am J Epidemiol. 1996;144(5):501-511.  (PubMed)

123.  Wang Y, Chung SJ, McCullough ML, et al. Dietary carotenoids are associated with cardiovascular disease risk biomarkers mediated by serum carotenoid concentrations. J Nutr. 2014;144(7):1067-1074.  (PubMed)

124.  Leermakers ET, Darweesh SK, Baena CP, et al. The effects of lutein on cardiometabolic health across the life course: a systematic review and meta-analysis. Am J Clin Nutr. 2016;103(2):481-494.  (PubMed)

125.  Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328(20):1450-1456.  (PubMed)

126.  Gaziano JM, Manson JE, Branch LG, Colditz GA, Willett WC, Buring JE. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann Epidemiol. 1995;5(4):255-260.  (PubMed)

127.  Osganian SK, Stampfer MJ, Rimm E, Spiegelman D, Manson JE, Willett WC. Dietary carotenoids and risk of coronary artery disease in women. Am J Clin Nutr. 2003;77(6):1390-1399.  (PubMed)

128.  Greenberg ER, Baron JA, Karagas MR, et al. Mortality associated with low plasma concentration of β-carotene and the effect of oral supplementation. JAMA. 1996;275(9):699-703.  (PubMed)

129.  Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of β-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155.  (PubMed)

130.  The effect of vitamin E and β-carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330(15):1029-1035.  (PubMed)

131.  Voutilainen S, Nurmi T, Mursu J, Rissanen TH. Carotenoids and cardiovascular health. Am J Clin Nutr. 2006;83(6):1265-1271.  (PubMed)

132.  Ozaki K, Okamoto M, Fukasawa K, et al. Daily intake of β-cryptoxanthin prevents bone loss by preferential disturbance of osteoclastic activation in ovariectomized mice. J Pharmacol Sci. 2015;129(1):72-77.  (PubMed)

133.  Sahni S, Hannan MT, Blumberg J, Cupples LA, Kiel DP, Tucker KL. Inverse association of carotenoid intakes with 4-y change in bone mineral density in elderly men and women: the Framingham Osteoporosis Study. Am J Clin Nutr. 2009;89(1):416-424.  (PubMed)

134.  Sahni S, Hannan MT, Blumberg J, Cupples LA, Kiel DP, Tucker KL. Protective effect of total carotenoid and lycopene intake on the risk of hip fracture: a 17-year follow-up from the Framingham Osteoporosis Study. J Bone Miner Res. 2009;24(6):1086-1094.  (PubMed)

135.  Dai Z, Wang R, Ang LW, Low YL, Yuan JM, Koh WP. Protective effects of dietary carotenoids on risk of hip fracture in men: the Singapore Chinese Health Study. J Bone Miner Res. 2014;29(2):408-417.  (PubMed)

136.  Sugiura M, Nakamura M, Ogawa K, Ikoma Y, Yano M. High serum carotenoids associated with lower risk for bone loss and osteoporosis in post-menopausal Japanese female subjects: prospective cohort study. PLoS One. 2012;7(12):e52643.  (PubMed)

137.  Kang JH, Ascherio A, Grodstein F. Fruit and vegetable consumption and cognitive decline in aging women. Ann Neurol. 2005;57(5):713-720.  (PubMed)

138.  Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology. 2006;67(8):1370-1376.  (PubMed)

139.  Johnson EJ, Vishwanathan R, Johnson MA, et al. Relationship between Serum and Brain Carotenoids, alpha-Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study. J Aging Res. 2013;2013:951786.  (PubMed)

140.  Vishwanathan R, Kuchan MJ, Sen S, Johnson EJ. Lutein and preterm infants with decreased concentrations of brain carotenoids. J Pediatr Gastroenterol Nutr. 2014;59(5):659-665.  (PubMed)

141.  Feeney J, Finucane C, Savva GM, et al. Low macular pigment optical density is associated with lower cognitive performance in a large, population-based sample of older adults. Neurobiol Aging. 2013;34(11):2449-2456.  (PubMed)

142.  Renzi LM, Dengler MJ, Puente A, Miller LS, Hammond BR, Jr. Relationships between macular pigment optical density and cognitive function in unimpaired and mildly cognitively impaired older adults. Neurobiol Aging. 2014;35(7):1695-1699.  (PubMed)

143.  Johnson EJ, McDonald K, Caldarella SM, Chung HY, Troen AM, Snodderly DM. Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women. Nutr Neurosci. 2008;11(2):75-83.  (PubMed)

144.  Chew EY, Clemons TE, Agron E, et al. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015;314(8):791-801.  (PubMed)

145.  Yeum KJ, Russell RM. Carotenoid bioavailability and bioconversion. Annu Rev Nutr. 2002;22:483-504.  (PubMed)

146.  Gärtner C, Stahl W, Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr. 1997;66(1):116-122.  (PubMed)

147.  Stahl W, Sies H. Uptake of lycopene and its geometrical isomers is greater from heat-processed than from unprocessed tomato juice in humans. J Nutr. 1992;122(11):2161-2166.  (PubMed)

148.  US Department of Agriculture, Agricultural Research Service. USDA Nutrient Database for Standard Reference; Release 28. 2015.

149.  Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev. 1998;56(2 Pt 1):35-51.  (PubMed)

150.  Hendler SS, Rorvik DM, eds. PDR for Nutritional Supplements. 2nd ed. Thomson Reuters; 2008.

151.  Tanvetyanon T, Bepler G. β-Carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer. 2008;113(1):150-157.  (PubMed)

152.  Bowen PE, Herbst-Espinosa SM, Hussain EA, Stacewicz-Sapuntzakis M. Esterification does not impair lutein bioavailability in humans. J Nutr. 2002;132(12):3668-3673.  (PubMed)

153.  Solomons NW. Vitamin A and carotenoids. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition. 8th ed. Washington, D.C.: ILSI Press; 2001:127-145. 

154.  Ehrenfeld M, Levy M, Sharon P, Rachmilewitz D, Eliakim M. Gastrointestinal effects of long-term colchicine therapy in patients with recurrent polyserositis (familial mediterranean fever). Dig Dis Sci. 1982;27(8):723-727.  (PubMed)

155.  Natural Medicines. β-carotene/Drug interactions - Professional monograph; 2016.

156.  Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592.  (PubMed)

157.  Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56(1):53-56.  (PubMed)

158.  Koonsvitsky BP, Berry DA, Jones MB, et al. Olestra affects serum concentrations of alpha-tocopherol and carotenoids but not vitamin D or vitamin K status in free-living subjects. J Nutr. 1997;127(8 Suppl):1636S-1645S.  (PubMed)

159.  Thornquist MD, Kristal AR, Patterson RE, et al. Olestra consumption does not predict serum concentrations of carotenoids and fat-soluble vitamins in free-living humans: early results from the sentinel site of the olestra post-marketing surveillance study. J Nutr. 2000;130(7):1711-1718.  (PubMed)

160.  Neuhouser ML, Rock CL, Kristal AR, et al. Olestra is associated with slight reductions in serum carotenoids but does not markedly influence serum fat-soluble vitamin concentrations. Am J Clin Nutr. 2006;83(3):624-631.  (PubMed)

161.  Katan MB, Grundy SM, Jones P, Law M, Miettinen T, Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc. 2003;78(8):965-978.  (PubMed)

162.  Weststrate JA, Meijer GW. Plant sterol-enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1998;52(5):334-343.  (PubMed)

163.  Ntanios FY, Duchateau GS. A healthy diet rich in carotenoids is effective in maintaining normal blood carotenoid levels during the daily use of plant sterol-enriched spreads. Int J Vitam Nutr Res. 2002;72(1):32-39.  (PubMed)

164.  Noakes M, Clifton P, Ntanios F, Shrapnel W, Record I, McInerney J. An increase in dietary carotenoids when consuming plant sterols or stanols is effective in maintaining plasma carotenoid concentrations. Am J Clin Nutr. 2002;75(1):79-86.  (PubMed)

165.  Leo MA, Lieber CS. Alcohol, vitamin A, and β-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69(6):1071-1085.  (PubMed)

166.  Albanes D, Heinonen OP, Taylor PR, et al. Alpha-Tocopherol and β-carotene supplements and lung cancer incidence in the alpha-tocopherol, β-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst. 1996;88(21):1560-1570.  (PubMed)

167.  van den Berg H. Carotenoid interactions. Nutr Rev. 1999;57(1):1-10.  (PubMed)

168.  Micozzi MS, Brown ED, Edwards BK, et al. Plasma carotenoid response to chronic intake of selected foods and β-carotene supplements in men. Am J Clin Nutr. 1992;55(6):1120-1125.  (PubMed)

169.  Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance, and interactions between lutein and β-carotene when administered to human adults in separate or combined oral doses. Am J Clin Nutr. 1995;62(3):604-610.  (PubMed)

170.  Albanes D, Virtamo J, Taylor PR, Rautalahti M, Pietinen P, Heinonen OP. Effects of supplemental β-carotene, cigarette smoking, and alcohol consumption on serum carotenoids in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 1997;66(2):366-372.  (PubMed)

171.  Nierenberg DW, Dain BJ, Mott LA, Baron JA, Greenberg ER. Effects of 4 y of oral supplementation with β-carotene on serum concentrations of retinol, tocopherol, and five carotenoids. Am J Clin Nutr. 1997;66(2):315-319.  (PubMed)

172.  Wahlqvist ML, Wattanapenpaiboon N, Macrae FA, Lambert JR, MacLennan R, Hsu-Hage BH. Changes in serum carotenoids in subjects with colorectal adenomas after 24 mo of β-carotene supplementation. Australian Polyp Prevention Project Investigators. Am J Clin Nutr. 1994;60(6):936-943.  (PubMed)

173.  Mayne ST, Cartmel B, Silva F, et al. Effect of supplemental β-carotene on plasma concentrations of carotenoids, retinol, and alpha-tocopherol in humans. Am J Clin Nutr. 1998;68(3):642-647.  (PubMed)

Chlorophyll and Chlorophyllin

Summary

  • Chlorophyll a and chlorophyll b are natural, fat-soluble chlorophylls found in plants. (More information)
  • Chlorophyllin is a semi-synthetic mixture of water-soluble sodium copper salts derived from chlorophyll. (More information)
  • Chlorophyllin has been used orally as an internal deodorant and topically in the treatment of slow-healing wounds for more than 50 years without any serious side effects. (More information)
  • Chlorophylls and chlorophyllin form molecular complexes with some chemicals known or suspected to cause cancer, and in doing so, may block carcinogenic effects. Carefully controlled studies have not been undertaken to determine whether a similar mechanism might limit uptake of required nutrients. (More information)
  • Supplementation with chlorophyllin before meals substantially decreased a urinary biomarker of aflatoxin-induced DNA damage in a Chinese population at high risk of liver cancer due to unavoidable, dietary aflatoxin exposure from moldy grains and legumes. (More information)
  • Scientists are hopeful that chlorophyllin supplementation will be helpful in decreasing the risk of liver cancer in high-risk populations with unavoidable, dietary aflatoxin exposure. However, it is not yet known whether chlorophyllin or natural chlorophylls will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary aflatoxin. (More information)

Introduction

Chlorophyll is the pigment that gives plants and algae their green color. Plants use chlorophyll to trap light needed for photosynthesis (1). The basic structure of chlorophyll is a porphyrin ring similar to that of heme in hemoglobin, although the central atom in chlorophyll is magnesium instead of iron. The long hydrocarbon (phytol) tail attached to the porphyrin ring makes chlorophyll fat-soluble and insoluble in water. Two different types of chlorophyll (chlorophyll a and chlorophyll b) are found in plants (Figure 1). The small difference in one of the side chains allows each type of chlorophyll to absorb light at slightly different wavelengths. Chlorophyllin is a semi-synthetic mixture of sodium copper salts derived from chlorophyll (2, 3). During the synthesis of chlorophyllin, the magnesium atom at the center of the ring is replaced with copper and the phytol tail is lost. Unlike natural chlorophyll, chlorophyllin is water-soluble. Although the content of different chlorophyllin mixtures may vary, two compounds commonly found in commercial chlorophyllin mixtures are trisodium copper chlorin e6 and disodium copper chlorin e4 (Figure 2).

Figure 1. Chemical structures of natural chlorophylls: chlorophyll a and chlorophyll b.

Figure 2. Chemcical structures of two compounds found in commercial sodium copper chlorophyllin: trisodium copper chlorin e6 and disodium copper chlorin e4.

Metabolism and Bioavailability

Little is known about the bioavailability and metabolism of chlorophyll or chlorophyllin. The lack of toxicity attributed to chlorophyllin led to the belief that it was poorly absorbed (4). However, significant amounts of copper chlorin e4 were measured in the plasma of humans taking chlorophyllin tablets in a controlled clinical trial, indicating that it is absorbed. More research is needed to understand the bioavailability and metabolism of natural chlorophylls and chlorin compounds in synthetic chlorophyllin.

Biological Activities

Complex formation with other molecules

Chlorophyll and chlorophyllin are able to form tight molecular complexes with certain chemicals known or suspected to cause cancer, including polycyclic aromatic hydrocarbons found in tobacco smoke (5), some heterocyclic amines found in cooked meat (6), and aflatoxin-B1 (7). The binding of chlorophyll or chlorophyllin to these potential carcinogens may interfere with gastrointestinal absorption of potential carcinogens, reducing the amount that reaches susceptible tissues (8). A recently completed study by Linus Pauling Institute investigator Professor George S. Bailey showed that chlorophyllin and chlorophyll were equally effective at blocking uptake of aflatoxin-B1 in humans, using accelerator mass spectrometry to track an ultra-low dose of the carcinogen (C Jubert et al., manuscript submitted).

Antioxidant effects

Chlorophyllin can neutralize several physically relevant oxidants in vitro (9, 10), and limited data from animal studies suggest that chlorophyllin supplementation may decrease oxidative damage induced by chemical carcinogens and radiation (11, 12).

Modification of the metabolism and detoxification of carcinogens

To initiate the development of cancer, some chemicals (procarcinogens) must first be metabolized to active carcinogens that are capable of damaging DNA or other critical molecules in susceptible tissues. Since enzymes in the cytochrome P450 family are required for the activation of some procarcinogens, inhibition of cytochrome P450 enzymes may decrease the risk of some types of chemically induced cancers. In vitro studies indicate that chlorophyllin may decrease the activity of cytochrome P450 enzymes (5, 13). Phase II biotransformation enzymes promote the elimination of potentially harmful toxins and carcinogens from the body. Limited data from animal studies indicate that chlorophyllin may increase the activity of the phase II enzyme, quinone reductase (14).

Therapeutic effects

A recent study showed that human colon cancer cells undergo cell cycle arrest after treatment with chlorophyllin (15). The mechanism involved inhibition of ribonucleotide reductase activity. Ribonucleotide reductase plays a pivotal role in DNA synthesis and repair, and is a target of currently used cancer therapeutic agents, such as hydroxyurea (15). This provides a potential new avenue for chlorophyllin in the clinical setting, sensitizing cancer cells to DNA damaging agents.

Disease Prevention

Aflatoxin-associated liver cancer

Aflatoxin-B1 (AFB1) a liver carcinogen produced by certain species of fungus, is found in moldy grains and legumes, such as corn, peanuts, and soybeans (2, 8). In hot, humid regions of Africa and Asia with improper grain storage facilities, high levels of dietary AFB1 are associated with increased risk of hepatocellular carcinoma. Moreover, the combination of hepatitis B infection and high dietary AFB1 exposure increases the risk of hepatocellular carcinoma still further. In the liver, AFB1 is metabolized to a carcinogen capable of binding DNA and causing mutations. In animal models of AFB1-induced liver cancer, administration of chlorophyllin at the same time as dietary AFB1 exposure significantly reduces AFB1-induced DNA damage in the livers of rainbow trout and rats (16-18), and dose-dependently inhibits the development of liver cancer in trout (19). One rat study found that chlorophyllin did not protect against aflatoxin-induced liver damage when given after tumor initiation (20). In addition, a recent study reported that natural chlorophyll inhibited AFB1-induced liver cancer in the rat (18).

Because of the long time period between AFB1 exposure and the development of cancer in humans, an intervention trial might require as long as 20 years to determine whether chlorophyllin supplementation can reduce the incidence of hepatocellular carcinoma in people exposed to high levels of dietary AFB1. However, a biomarker of AFB1-induced DNA damage (AFB1-N7-guanine) can be measured in the urine, and high urinary levels of AFB1-N7-guanine have been associated with significantly increased risk of developing hepatocellular carcinoma (21). In order to determine whether chlorophyllin could decrease AFB1-induced DNA damage in humans, a randomized, placebo-controlled intervention trial was conducted in 180 adults residing in a region in China where the risk of hepatocellular carcinoma is very high due to unavoidable dietary AFB1 exposure and a high prevalence of chronic hepatitis B infection (22). Participants took either 100 mg of chlorophyllin or a placebo before meals three times daily. After 16 weeks of treatment, urinary levels of AFB1-N7-guanine were 55% lower in those taking chlorophyllin than in those taking the placebo, suggesting that chlorophyllin supplementation before meals can substantially decrease AFB1-induced DNA damage. Although a reduction in hepatocellular carcinoma has not yet been demonstrated in humans taking chlorophyllin, scientists are hopeful that chlorophyllin supplementation will provide some protection to high-risk populations with unavoidable, dietary AFB1 exposure (8).

It is not known whether chlorophyllin will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary AFB1, as is the case for most people living in the US. Many questions remain to be answered regarding the exact mechanisms of cancer prevention by chlorophyllin, the implications for the prevention of other types of cancer, and the potential for natural chlorophylls in the diet to provide cancer protection. Scientists from the Linus Pauling Institute’s Cancer Chemoprotection Program (CCP) are actively pursuing these research questions. 

Therapeutic Uses of Chlorophyllin

Internal deodorant

Observations in the 1940s and 1950s that topical chlorophyllin had deodorizing effects on foul-smelling wounds led clinicians to administer chlorophyllin orally to patients with colostomies and ileostomies in order to control fecal odor (23). While early case reports indicated that chlorophyllin doses of 100-200 mg/day were effective in reducing fecal odor in ostomy patients (24, 25), at least one placebo-controlled trial found that 75 mg of oral chlorophyllin three times daily was no more effective than placebo in decreasing fecal odor assessed by colostomy patients (26). Several case reports have been published indicating that oral chlorophyllin (100-300 mg/day) decreased subjective assessments of urinary and fecal odor in incontinent patients (23, 27). Trimethylaminuria is a hereditary disorder characterized by the excretion of trimethylamine, a compound with a “fishy” or foul odor. A recent study in a small number of Japanese patients with trimethylaminuria found that oral chlorophyllin (60 mg three times daily) for three weeks significantly decreased urinary trimethylamine concentrations (28).

Wound healing

Research in the 1940s indicating that chlorophyllin slowed the growth of certain anaerobic bacteria in the test tube and accelerated the healing of experimental wounds in animals led to the use of topical chlorophyllin solutions and ointments in the treatment of persistent open wounds in humans (29). During the late 1940s and 1950s, a series of largely uncontrolled studies in patients with slow-healing wounds, such as vascular ulcers and pressure (decubitus) ulcers, reported that the application of topical chlorophyllin promoted healing more effectively than other commonly used treatments (30, 31). In the late 1950s, chlorophyllin was added to papain and urea-containing ointments used for the chemical debridement of wounds in order to reduce local inflammation, promote healing, and control odor (23). Chlorophyllin-containing papain/urea ointments are still available in the US by prescription (32). Several studies have reported that such ointments are effective in wound healing (33). Recently, a spray formulation of the papain/urea/chlorophyllin therapy has become available (34).

Sources

Chlorophylls

Chlorophylls are the most abundant pigments in plants. Dark green, leafy vegetables like spinach are rich sources of natural chlorophylls. The chlorophyll contents of selected vegetables are presented in Table 1 (35).

Table 1. Chlorophyll Content of Selected Raw Vegetables
Food Serving Chlorophyll (mg)
Spinach 1 cup 23.7
Parsley ½ cup 19.0
Cress, garden 1 cup 15.6
Green beans 1 cup 8.3
Arugula 1 cup 8.2
Leeks 1 cup 7.7
Endive 1 cup 5.2
Sugar peas 1 cup 4.8
Chinese cabbage 1 cup 4.1

Supplements

Chlorophyll

Green algae like chlorella are often marketed as supplemental sources of chlorophyll. Because natural chlorophyll is not as stable as chlorophyllin and is much more expensive, most over-the-counter chlorophyll supplements actually contain chlorophyllin.

Chlorophyllin

Oral preparations of sodium copper chlorophyllin (also called chlorophyllin copper complex) are available in supplements and as an over-the-counter drug (Derifil) used to reduce odor from colostomies or ileostomies or to reduce fecal odor due to incontinence (36). Sodium copper chlorophyllin may also be used as a color additive in foods, drugs, and cosmetics (37). Oral doses of 100-300 mg/day in three divided doses have been used to control fecal and urinary odor (see Therapeutic Uses of Chlorophyllin).

Safety

Natural chlorophylls are not known to be toxic, and no toxic effects have been attributed to chlorophyllin despite more than 50 years of clinical use in humans (8, 23, 29). When taken orally, chlorophyllin may cause green discoloration of urine or feces, or yellow or black discoloration of the tongue (38). There have also been occasional reports of diarrhea related to oral chlorophyllin use. When applied topically to wounds, chlorophyllin has been reported to cause mild burning or itching in some cases (39). Oral chlorophyllin may result in false positive results on guaiac card tests for occult blood (40). Since the safety of chlorophyll or chlorophyllin supplements has not been tested in pregnant or lactating women, they should be avoided during pregnancy and lactation.


Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in June 2009 by:
Roderick H. Dashwood, Ph.D.
Director, Cancer Chemoprotection Program, Linus Pauling Institute
Professor of Environmental & Molecular Toxicology
Leader, Environmental Mutagenesis & Carcinogenesis Core, Environmental Health Sciences Center
Oregon State University

Copyright 2004-2017  Linus Pauling Institute


References

1.  Matthews CK, van Holde KE. Biochemistry. 2nd ed. Menlo Park: The Benjamin/Cummings Publishing Company; 1996.

2.  Sudakin DL. Dietary aflatoxin exposure and chemoprevention of cancer: a clinical review. J Toxicol Clin Toxicol. 2003;41(2):195-204.  (PubMed)

3.  Dashwood RH. The importance of using pure chemicals in (anti) mutagenicity studies: chlorophyllin as a case in point. Mutat Res. 1997;381(2):283-286.  (PubMed)

4.  Egner PA, Stansbury KH, Snyder EP, Rogers ME, Hintz PA, Kensler TW. Identification and characterization of chlorin e(4) ethyl ester in sera of individuals participating in the chlorophyllin chemoprevention trial. Chem Res Toxicol. 2000;13(9):900-906.  (PubMed)

5.  Tachino N, Guo D, Dashwood WM, Yamane S, Larsen R, Dashwood R. Mechanisms of the in vitro antimutagenic action of chlorophyllin against benzo[a]pyrene: studies of enzyme inhibition, molecular complex formation and degradation of the ultimate carcinogen. Mutat Res. 1994;308(2):191-203.  (PubMed)

6.  Dashwood R, Yamane S, Larsen R. Study of the forces of stabilizing complexes between chlorophylls and heterocyclic amine mutagens. Environ Mol Mutagen. 1996;27(3):211-218.  (PubMed)

7.  Breinholt V, Schimerlik M, Dashwood R, Bailey G. Mechanisms of chlorophyllin anticarcinogenesis against aflatoxin B1: complex formation with the carcinogen. Chem Res Toxicol. 1995;8(4):506-514.  (PubMed)

8.  Egner PA, Munoz A, Kensler TW. Chemoprevention with chlorophyllin in individuals exposed to dietary aflatoxin. Mutat Res. 2003;523-524:209-216.  (PubMed)

9.  Kumar SS, Devasagayam TP, Bhushan B, Verma NC. Scavenging of reactive oxygen species by chlorophyllin: an ESR study. Free Radic Res. 2001;35(5):563-574.  (PubMed)

10.  Kamat JP, Boloor KK, Devasagayam TP. Chlorophyllin as an effective antioxidant against membrane damage in vitro and ex vivo. Biochim Biophys Acta. 2000;1487(2-3):113-127.  (PubMed)

11.  Park KK, Park JH, Jung YJ, Chung WY. Inhibitory effects of chlorophyllin, hemin and tetrakis(4-benzoic acid)porphyrin on oxidative DNA damage and mouse skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate as a possible anti-tumor promoting mechanism. Mutat Res. 2003;542(1-2):89-97.  (PubMed)

12.  Kumar SS, Shankar B, Sainis KB. Effect of chlorophyllin against oxidative stress in splenic lymphocytes in vitro and in vivo. Biochim Biophys Acta. 2004;1672(2):100-111.  (PubMed)

13.  Yun CH, Jeong HG, Jhoun JW, Guengerich FP. Non-specific inhibition of cytochrome P450 activities by chlorophyllin in human and rat liver microsomes. Carcinogenesis. 1995;16(6):1437-1440.  (PubMed)

14.  Dingley KH, Ubick EA, Chiarappa-Zucca ML, et al. Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes. Nutr Cancer. 2003;46(2):212-221.  (PubMed)

15.  Chimploy K, Diaz GD, Li Q, et al. E2F4 and ribonucleotide reductase mediate S-phase arrest in colon cancer cells treated with chlorophyllin. Int J Cancer. 2009;125(9):2086-94.  (PubMed)

16.  Dashwood RH, Breinholt V, Bailey GS. Chemopreventive properties of chlorophyllin: inhibition of aflatoxin B1 (AFB1)-DNA binding in vivo and anti-mutagenic activity against AFB1 and two heterocyclic amines in the Salmonella mutagenicity assay. Carcinogenesis. 1991;12(5):939-942.  (PubMed)

17.  Kensler TW, Groopman JD, Roebuck BD. Use of aflatoxin adducts as intermediate endpoints to assess the efficacy of chemopreventive interventions in animals and man. Mutat Res. 1998;402(1-2):165-172.  (PubMed)

18.  Simonich MT, Egner PA, Roebuck BD, et al. Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat. Carcinogenesis. 2007;28(6):1294-1302.  (PubMed)

19.  Breinholt V, Hendricks J, Pereira C, Arbogast D, Bailey G. Dietary chlorophyllin is a potent inhibitor of aflatoxin B1 hepatocarcinogenesis in rainbow trout. Cancer Res. 1995;55(1):57-62.  (PubMed)

20.  Orner GA, Roebuck BD, Dashwood RH, Bailey GS. Post-initiation chlorophyllin exposure does not modulate aflatoxin-induced foci in the liver and colon of rats. J Carcinog. 2006;5:6.  (PubMed)

21.  Qian GS, Ross RK, Yu MC, et al. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol Biomarkers Prev. 1994;3(1):3-10.  (PubMed)

22.  Egner PA, Wang JB, Zhu YR, et al. Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer. Proc Natl Acad Sci U S A. 2001;98(25):14601-14606.  (PubMed)

23.  Chernomorsky SA, Segelman AB. Biological activities of chlorophyll derivatives. N J Med. 1988;85(8):669-673.  (PubMed)

24.  Siegel LH. The control of ileostomy and colostomy odors. Gastroenterology. 1960;38:634-636.  (PubMed)

25.  Weingarten M, Payson B. Deodorization of colostomies with chlorophyll. Rev Gastroenterol. 1951;18(8):602-604.

26.  Christiansen SB, Byel SR, Stromsted H, Stenderup JK, Eickhoff JH. [Can chlorophyll reduce fecal odor in colostomy patients?]. Ugeskr Laeger. 1989;151(27):1753-1754.  

27.  Young RW, Beregi JS, Jr. Use of chlorophyllin in the care of geriatric patients. J Am Geriatr Soc. 1980;28(1):46-47.  (PubMed)

28.  Yamazaki H, Fujieda M, Togashi M, et al. Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patients. Life Sci. 2004;74(22):2739-2747.  (PubMed)

29.  Kephart JC. Chlorophyll derivatives - their chemistry, commercial preparation and uses. Econ Bot. 1955;9:3-38.

30.  Bowers WF. Chlorophyll in wound healing and suppurative disease. Am J Surg. 1947;73:37-50.

31.  Carpenter EB. Clinical experiences with chlorophyll preparations. Am J Surg. 1949;77:167-171.

32.  2004 Physicians' Desk Reference. 58th ed. Stamford: Thomson Health Care, Inc.; 2003.

33.  Smith RG. Enzymatic debriding agents: an evaluation of the medical literature. Ostomy Wound Manage. 2008;54(8):16-34.  (PubMed)

34.  Weir D, Farley KL. Relative delivery efficiency and convenience of spray and ointment formulations of papain/urea/chlorophyllin enzymatic wound therapies. J Wound Ostomy Continence Nurs. 2006;33(5):482-490.  (PubMed)

35.  Bohn T, Walczyk S, Leisibach S, Hurrell RF. Chlorophyll-bound magnesium in commonly consumed vegetables and fruits: relevance to magnesium nutrition. J Food Sci. 2004;69(9):S347-S350.

36.  GPO Access. Electronic Code of Federal Regulations: Miscellaneous Internal Drug Products for Over the Counter Use. [Web page]. Available at http://www.ecfr.gov/cgi-bin/text-idx?SID=fca8520c1cf723314cd462d3596b8682&node=pt21.5.357&rgn=div5. Accessed 2/26/15.

37.  GPO Access. Electronic Code of Federal Regulations: Listing of Color Additives Exempt from Certification [Web page]. http://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=3463c48f55ae08efd099682901bb9500&r=PART&n=pt21.1.73. Accessed 2/26/15.

38.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. 2nd ed. Montvale: Physicians' Desk Reference, Inc; 2008.

39.  Smith LW. The present status of topical chlorophyll therapy. N Y State J Med. 1955;55(14):2041-2050.  (PubMed)

40.  Gogel HK, Tandberg D, Strickland RG. Substances that interfere with guaiac card tests: implications for gastric aspirate testing. Am J Emerg Med. 1989;7(5):474-480.  (PubMed) 

Curcumin

Summary

    • Curcumin is a biologically active polyphenolic compound found in turmeric, a spice derived from the rhizomes of the plant Curcuma longa Linn. Commonly consumed in Asian countries, turmeric has been used for medicinal purposes for centuries. (More information)
  • Mounting evidence from preclinical studies shows that curcumin modulates numerous molecular targets and exerts antioxidant, anti-inflammatory, anticancer, and neuroprotective activities. (More information)
  • In humans, curcumin taken orally is poorly absorbed and rapidly metabolized and eliminated. Therefore, the potential of curcumin as a therapeutic agent is limited by its poor bioavailability. (More information)
  • Current evidence suggesting that curcumin may help prevent and/or treat colorectal cancer and type 2 diabetes mellitus is very limited. Yet, several clinical trials designed to assess the safety and efficacy of curcumin alone or with first-line treatment in patients with breast, prostate, pancreatic, lung, or colorectal cancer are under way. (More information)
  • While a few preliminary trials suggested that curcumin may have anti-inflammatory activities in humans, larger randomized controlled trials are still needed to establish the efficacy of curcumin as an anti-inflammatory agent against rheumatoid arthritis, ulcerative colitis, and radiotherapy-induced dermatitis. (More information)
  • There is currently no substantial evidence showing that curcumin may improve cognitive performance in older adults with or without cognitive impairments. Yet, some preclinical studies have found curcumin prevented or reversed certain pathological features of Alzheimer’s disease (AD). A number of clinical trials designed to assess whether curcumin might help prevent or treat AD are under way. (More information)
  • Long-term clinical trials are required to confirm whether curcumin could exhibit long-lasting antidepressant effects in patients suffering from major depressive disorder. (More information)
  • Oral supplementation with curcumin is generally regarded as safe, especially because of its low bioavailability. However, use of curcumin supplements may affect the efficacy or increase the toxicity of a wide range of drugs when taken concurrently. (More information)

Introduction

Turmeric is a spice derived from the rhizomes of the tropical plant Curcuma longa Linn, which is a member of the ginger family (Zingiberaceae). Rhizomes are horizontal underground stems that send out shoots, as well as roots. The bright yellow-orange color of turmeric comes mainly from fat-soluble, polyphenolic pigments known as curcuminoids. Curcumin, the principal curcuminoid found in turmeric, is generally considered its most active constituent (1). Other curcuminoids found in turmeric include demethoxycurcumin and bisdemethoxycurcumin (Figure 1). In addition to its use as a spice and pigment, turmeric has been used in India for medicinal purposes for centuries (2). More recently, evidence that curcumin may have anti-inflammatory and anticancer activities has renewed scientific interest in its potential to prevent and treat disease.

Figure 1. Major Turmeric-derived Curcuminoids. Curcuminoids in turmeric roots are a mixture of three main compounds: curcumin (~77%), demethoxycurcumin (~17%), and bisdemethoxycurcumin (~3%). Curcumin exists in two molecular configurations (known as tautomers): the bis-keto form is predominatly found in neutral and acidic conditions and in a solid phase, while the enolate form is predominately found in alkaline conditions. 

Metabolism and Bioavailability

Clinical trials in humans indicate that the systemic bioavailability of orally administered curcumin is relatively low (3-5) and that mostly metabolites of curcumin, instead of curcumin itself, are detected in plasma or serum following oral consumption (6, 7). In the intestine and liver, curcumin is readily conjugated to form curcumin glucuronide and curcumin sulfate or, alternately, reduced to tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin (Figure 2) (4). An early clinical trial conducted in Taiwan indicated that serum curcumin concentrations peaked at 0.41 to 1.75 micromoles/liter (μM) one hour after oral doses of 4 to 8 g of curcumin (8). Another clinical trial conducted in the UK found that plasma concentrations of curcumin, curcumin sulfate, and curcumin glucuronide were in the range of 0.01 μM one hour after a 3.6 g oral dose of curcumin (9). Curcumin and its metabolites could not be detected in plasma at doses lower than 3.6 g/day. There is some evidence that orally administered curcumin accumulates in gastrointestinal tissues. For instance, when colorectal cancer patients took 3.6 g/day of curcumin orally for seven days prior to surgery, curcumin was detected in both malignant and normal colorectal tissue (10). In contrast, curcumin was not detected in the liver tissue of patients with liver metastases of colorectal cancer after the same oral dose of curcumin (11), suggesting that oral curcumin administration may not effectively deliver curcumin to tissues outside the gastrointestinal tract.

The safety and efficacy of several curcumin formulations are currently being explored in (pre)clinical settings with the aim of increasing the absorption, bioavailability, and tissue-targeted delivery of curcumin (12-16). Examples of approaches include conjugation to peptide carriers (e.g., to polylactic-co-glycolic acid [PLGA]); complexation with essential oils; coadministration with piperine; and encapsulation into nanoparticles, liposomes, phytosomes, polymeric micelles, and cyclodextrins (reviewed in 17).

Figure 2. Curcumin Metabolites. Chemical structures of the curcumin metabolites: curcumin sulfate, curcumin glucuronide, dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin (hexahydrocurcuminol).

Biological Activities

Antioxidant activity

Curcumin is an effective scavenger of reactive oxygen species (ROS) and reactive nitrogen species in the test tube (18, 19). However, it is not clear whether curcumin acts as a direct antioxidant in vivo. Due to its limited oral bioavailability in humans (see Metabolism and Bioavailability), plasma and tissue curcumin concentrations are likely to be much lower than those of other fat-soluble antioxidants like α-tocopherol (vitamin E). Yet, curcumin taken orally may reach sufficient concentrations in the gastrointestinal tract and protect the intestinal mucosa against oxidative DNA damage (11). In addition to a potentially direct antioxidant activity, curcumin can induce the expression of phase II antioxidant enzymes, including glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Glutathione (GSH) is an important intracellular antioxidant that plays a critical role in cellular adaptation to stress (20). Curcumin was found to upregulate the expression of GCL through the activation of different signaling pathways (21). In particular, curcumin increases the expression of GCL and other detoxifying enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway.

Nrf2-dependent antioxidant pathway

Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol. Keap1 responds to oxidative stress signals by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoter of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for numerous mediators of the antioxidant response, including GCL, glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (22). Nrf2-dependent upregulation of HO-1 in curcumin-treated renal tubular epithelial cells challenged with high glucose concentrations was shown to prevent phenotype changes resembling fibrosis and known to occur at an early stage of diabetic renal injury (23). Curcumin also inhibited the progression of fibrosis in liver and lung in animal models of chronic inflammatory diseases (24, 25). Curcumin mitigated the effect of chronic ethanol intake on mouse liver, partly by upregulating Nrf2 target genes coding for NQO-1, HO-1, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) (26). Curcumin treatment also counteracted oxidative damage induced by heavy ion irradiation by upregulating Nrf2 downstream genes for GCL, HO-1, NQO-1, and SOD in the brain of rats (27). Additional studies have demonstrated the ability of curcumin to reduce oxidative stress in different experimental settings via the induction of Nrf2/ARE pathway (reviewed in 22).

Anti-inflammatory activity

Curcumin has been shown to inhibit mediators of the inflammatory response, including cytokines, chemokines, adhesion molecules, growth factors, and enzymes like cyclooxygenase (COX), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). Nuclear factor-kappa B (NF-κB) is a transcription factor that binds DNA and induces the transcription of the COX-2 gene, other pro-inflammatory genes, and genes involved in cell proliferation, adhesion, survival, and differentiation. The anti-inflammatory effects of curcumin result from its ability to inhibit the NF-κB pathway, as well as other pro-inflammatory pathways like the mitogen-activated protein kinase (MAPK)- and the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT)-dependent signaling pathways (28). Inhibition of dextran sulfate sodium (DSS)-induced colitis by curcumin in mice has been associated with a downregulation of the expression of p38-MAPK and pro-inflammatory cytokine TNF-α and a reduction of myeloperoxidase (MPO) activity, a marker of neutrophil infiltration in intestinal mucosa (29). Curcumin has also been shown to improve colitis by preventing STAT3 activation and STAT3-dependent induction of cell proliferation in mouse colon (30). Moreover, curcumin was shown to attenuate the immune response triggered by collagen injections in a mouse model of rheumatoid arthritis, partly by blocking the proliferation of T lymphocytes in mouse splenocytes (31). In addition, curcumin has been found to reduce the secretion of TNF-α and IL-1β and the production of COX-2-induced prostaglandin G2. In one study, curcumin inhibited the secretion of matrix metalloproteins (MMPs) — responsible for the degradation of the synovial joints — in human fibroblast-like synoviocytes (31) and in human articular chondrocytes (32). Curcumin has also been found to alleviate neuro-inflammation in a mouse model of traumatic brain injury, reducing macrophage and microglial activation and increasing neuronal survival (33).

Anticancer activity

Effects on biotransformation enzymes

Some compounds are not carcinogenic until they are metabolized in the body by phase I biotransformation enzymes, such as enzymes of the cytochrome P450 (CYP) family (34). Primarily based on evidence from rodent studies, it is thought that curcumin may inhibit procarcinogen bioactivation and help prevent cancer by inhibiting the activity of multiple CYP enzymes in humans (35-37). Curcumin may also increase the activity of phase II detoxification enzymes, such as GSTs and quinone reductase (QR) (see also Nrf2-dependent antioxidant pathway) (35, 38, 39). However, it is important to note that the effect of curcumin on biotransformation enzymes may vary depending on the route of administration, the dose, and the animal model. In addition, curcumin intakes ranging from 0.45 to 3.6 g/day for up to four months did not increase leukocyte GST activity in humans (9).

Inhibition of proliferation and induction of apoptosis

Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or for activation of pathways leading to programmed cell death (apoptosis) if the damage is irreparable (40). Defective cell-cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Unlike normal cells, cancer cells proliferate rapidly and are unable to respond to cell death signals that initiate apoptosis. Curcumin has been found to induce cell-cycle arrest and apoptosis by regulating a variety of cell-signaling pathways (3, 41-45). For example, the inhibition of cell proliferation by curcumin has been associated with the Nrf2-dependent downregulation of DNA repair-specific flap endonuclease 1 (Fen1) in breast cancer cells in culture (46). Curcumin has been shown to induce p53-dependent or -independent apoptosis depending on the cancer cell type (47). In a panel of cancer cell lines, p53-independent apoptosis induced by curcumin was mediated by the rapid increase of ROS and the activation of MAPK and c-jun kinase (JNK) signaling cascades (48). Inhibition of NF-κB signaling by curcumin also suppresses proliferation and induces apoptosis in cancer cells (47).

Inhibition of tumor invasion and angiogenesis

Malignant and aggressive forms of cancer can invade surrounding tissues and spread to distant tissues once cancer cells have acquired the ability to leave the primary site (reduced cell-to-cell adhesion and loss of polarity), migrate, and disseminate. Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells acquire the ability to migrate and invade through downregulating proteins like E-cadherin and γ-catenin and expressing mesenchymal markers like MMPs, N-cadherin, and vimentin. In breast cancer cells, curcumin prevented EMT-associated morphological changes induced by lipopolysaccharide (LPS) while upregulating E-cadherin and downregulating vimentin. It was further shown that curcumin inhibited NF-κB/Snail signaling involved in LPS-induced EMT (49). In another study, curcumin increased the expression of the small non-coding RNA miR181b, which then downregulated proinflammatory cytokines, CXCL1 and CXCL2, as well as MMPs, thereby reducing the metastatic potential of breast cancer cells. Curcumin inhibited IL-6-induced proliferation, migration, and invasiveness of human small cell lung cancer (SCLC) cells by reducing JAK/STAT3 phosphorylation (i.e., activation) and downstream genes coding for cyclin B1, survivin, Bcl-XL, MMPs, intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor (VEGF) (30).

Curcumin was found to exert its anticancer activities in many different types of cancer cells by regulating a variety of signaling pathways (reviewed in 2, 47).

Neuroprotective activity

In Alzheimer’s disease (AD), a peptide called β-amyloid (Aβ peptide) aggregates into oligomers and fibrils and forms deposits known as amyloid (or senile) plaques outside neurons in the hippocampus and cerebral cortex of patients. Another feature of AD is the accumulation of intracellular neurofibrillary tangles formed by phosphorylated Tau protein (50). Abnormal microglial activation, oxidative stress, and neuronal death are also associated with the progression of the disease. Curcumin has been found to inhibit Aβ fibril formation and extension and to destabilize preformed fibrils in vitro (51-53). Metal chelation by curcumin might interfere with metal ion (Cu2+/Zn2+)-induced Aβ aggregation. Curcumin might also affect the trafficking of Aβ peptide precursor (APP) and the generation of Aβ peptides from APP (54, 55). Abnormally activated microglia and hypertrophic astrocytes around amyloid plaques in AD brains release cytotoxic molecules, such as proinflammatory cytokines and ROS, which enhance Aβ formation and deposition and further damage neurons. Curcumin was found to reduce the inflammatory response triggered by Aβ peptide-induced microglial activation and increase neuronal cell survival (56). When injected into the carotid artery of a transgenic mouse model of AD, curcumin was found to cross the blood-brain barrier, bind to amyloid plaques, and block the formation of Aβ oligomers and fibrils (53). In other animal models of AD, dietary curcumin decreased biomarkers of inflammation and oxidative damage, increased Aβ peptide clearance by macrophages, dismantled amyloid plaques in the brain, stimulated neuronal cell growth in the hippocampus, and improved Aβ-induced memory deficits (reviewed in 57).

Note: It is important to keep in mind that some of the biological activities discussed above were observed in cultured cells and animal models exposed to curcumin at concentrations unlikely to be achieved in cells of humans consuming curcumin orally (see Metabolism and Bioavailability).

Disease Prevention

Cancer

Oral curcumin administration has been found to inhibit the development of chemically-induced cancer in animal models of oral (58, 59), stomach (60, 61), liver (62), and colon (63-65) cancer. ApcMin/+ mice have a mutation in the Apc (adenomatous polyposis coli) gene similar to that in humans with familial adenomatous polyposis, a genetic condition characterized by the development of numerous colorectal adenomas (polyps) and a high risk for colorectal cancer. Oral curcumin administration has been found to inhibit the development of intestinal adenomas in ApcMin/+ mice (66, 67). Despite promising results in animal studies, there is presently little evidence that high intakes of curcumin or turmeric are associated with decreased cancer risk in humans. A 30-day phase II clinical trial in 40 smokers with at least eight rectal aberrant crypt foci (ACF; precancerous lesions) found that the number of ACF was significantly lower with a daily supplementation with 4 g/day of curcumin compared to 2 g/day (68). Several controlled clinical trials in humans designed to evaluate the effect of oral curcumin supplementation on precancerous colorectal lesions, such as adenomas, are under way (69).

Type 2 diabetes mellitus

Oxidative stress and inflammation have been implicated in the pathogenesis of type 2 diabetes mellitus and related vascular complications. A large body of preclinical evidence suggests that the antioxidant, anti-inflammatory, and glucose-lowering activities of curcumin and its analogs may be useful in the prevention and/or treatment of type 2 diabetes (70). In a nine-month, randomized, double-blind, placebo-controlled study in 237 subjects with impaired glucose tolerance (pre-diabetes), no progression to overt diabetes was reported with a daily ingestion of a mixture of curcuminoids (0.5 g), while 16.4% of placebo-treated participants developed diabetes (71). In addition, curcumin supplementation was shown to reduce insulin resistance and improve measures of pancreatic β-cell function and glucose tolerance. In an eight-week, randomized, placebo-controlled study in 67 individuals with type 2 diabetes, oral curcumin (a mixture of all three major curcuminoids; 0.6 g/day) failed to significantly lower the level of glycated hemoglobin A1c (HbA1c; a measure of glycemic control), plasma fasting glucose, total serum cholesterol, LDL-cholesterol, and serum triglycerides (72). Yet, supplemental curcumin was found to be as effective as lipid-lowering drug atorvastatin (10 mg/day) in reducing circulating markers of oxidative stress (malondialdehyde) and inflammation (endothelin-1, TNFα, IL-6) and in improving endothelial function. Another randomized controlled trial also reported that oral curcumin supplementation (1.5 g/day) for six months improved endothelial function, insulin sensitivity, and metabolic markers associated with atherogenesis (plasma triglycerides, visceral fat, total body fat) in participants with type 2 diabetes (73). Finally, in a two-month randomized, double-blind, placebo-controlled study in 40 individuals with type 2 diabetic nephropathy (kidney disease), daily curcumin ingestion (66.3 mg) significantly reduced urinary concentrations of proteins and inflammation markers (TGF-β, IL-8), suggesting that curcumin might be helpful with slowing the progression of kidney damage and preventing kidney failure (74). Larger trials are needed to assess whether curcumin could be useful in the prevention or management of type 2 diabetes and vascular complications.

Disease Treatment

Cancer

The ability of curcumin to regulate a variety of signaling pathways involved in cell growth, apoptosis, invasion, metastasis, and angiogenesis in preclinical studies elicited scientific interest in its potential as an anticancer agent in tumor therapy (75). To date, most of the controlled clinical trials of curcumin supplementation in cancer patients have been phase I trials, which are aimed at determining feasibility, tolerability, safety, and providing early evidence of efficacy (76). A phase I clinical trial in patients with advanced colorectal cancer found that doses up to 3.6 g/day for four months were well tolerated, although the systemic bioavailability of oral curcumin was low (77). When colorectal cancer patients with liver metastases took 3.6 g/day of curcumin orally for seven days, trace levels of curcumin metabolites were measured in liver tissue, but curcumin itself was not detected (11). In contrast, curcumin was measurable in normal and malignant colorectal tissue after patients with advanced colorectal cancer took 3.6 g/day of curcumin orally for seven days (10). In a pilot trial in patients awaiting gastrointestinal endoscopy or colorectal cancer resection, the administration of a mixture of three major curcuminoids (2.35 g/day for 14 days) resulted in detectable amounts of curcumin in colonic mucosa (mean concentration, 48.4 μg/g of tissue), demethoxycurcumin (7.1 μg/g), and bisdemethoxycurcumin (0.7 μg/g) (78).

While these findings suggested that oral curcumin may likely be more effective as a therapeutic agent in cancers of the gastrointestinal tract than of other tissues, some phase I/II trials have also examined whether supplemental curcumin may confer additional benefits to conventional drugs against different types of cancer. Combining curcumin with anticancer drugs like gemcitabine in pancreatic cancer (79, 80), docetaxel in breast cancer (81), and imatinib in chronic myeloid leukemia (82) may be safe and well tolerated. A recent single-arm, phase II trial combining three cycles of docetaxel/prednisone and curcumin (6 g/day) was carried out in 26 patients with castration-resistant prostate cancer (83). The level of prostate-specific antigen (PSA) was decreased in most patients and was normalized in 36% of them, and the co-administration of curcumin with drugs showed no toxicity beyond adverse effects already related to docetaxel monotherapy. Many registered phase I/II clinical trials designed to investigate the effectiveness of curcumin alone or with first-line treatment in patients with breast, prostate, pancreatic, lung, or colorectal cancer are under way (69).

Inflammatory diseases

Although curcumin has been demonstrated to have anti-inflammatory and antioxidant activities in cell culture and animal studies, few randomized controlled trials have examined the efficacy of curcumin in the treatment of inflammatory conditions. A placebo-controlled trial in 40 men who had surgery to repair an inguinal hernia or hydrocele found that oral curcumin supplementation (1.2 g/day) for five days was more effective than placebo in reducing post-surgical edema, tenderness and pain, and was comparable to phenylbutazone therapy (300 mg/day) (84).

Rheumatoid arthritis

A preliminary intervention trial that compared curcumin with a nonsteroidal anti-inflammatory drug (NSAID) in 18 patients with rheumatoid arthritis (RA) found that improvements in morning stiffness, walking time, and joint swelling after two weeks of curcumin supplementation (1.2 g/day) were comparable to those experienced after two weeks of phenylbutazone (NSAID) therapy (300 mg/day) (85). In a more recent randomized, open-label study in 45 RA patients, supplementation with a mixture of all three major curcuminoids (0.5 g/day for eight weeks) was found to be as effective as diclofenac (NSAID; 50 mg/day) in reducing measures of disease activity, tenderness, and swelling joints (86). Larger randomized controlled trials are needed to determine whether oral curcumin supplementation is effective in the treatment of RA.

Radiation dermatitis

Radiation-induced skin inflammation occurs in most patients receiving radiation therapy for sarcoma, lung, breast, or head and neck cancer. One randomized, double-blind, placebo-controlled trial in 30 women prescribed radiation therapy for breast carcinoma in situ reported a reduction of radiation-induced dermatitis severity and moist desquamation with a supplemental curcuminoid mixture (6 g/day for four to seven weeks). Curcumin failed to reduce skin redness and radiation-induced pain at the site of treatment (87).

Ulcerative colitis

Ulcerative colitis (UC) is a long-term condition characterized by diffuse and superficial inflammation of the colonic mucosa. Disease activity may fluctuate between periods of remission and periods of relapse. Preliminary evidence suggests that curcumin might be useful as an add-on therapy to control disease activity. One multicenter, randomized, double-blind, placebo-controlled study has examined the efficacy of curcumin enema (2 g/day) in the prevention of relapse in 82 patients with quiescent UC (88). Six-month treatment with curcumin significantly reduced measures of disease activity and severity and resulted in a lower relapse rate than with placebo in subjects on standard-of-care medication (sulfasalazine or mesalamine); yet, there was no difference in the proportion of patients who experienced relapse six months after curcumin was discontinued (88). In another randomized controlled trial in active UC patients treated with mesalamine, the percentage of patients in clinical remission was significantly higher after a one-month treatment with oral curcumin (3 g/day) than with placebo (89). Larger trials are needed to ensure that curcumin can be safely used with conventional UC treatments and to further support its potential therapeutic benefits for relapsing-remitting UC.

Oral health

Emerging evidence suggests that curcumin has anti-inflammatory and antimicrobial properties that could be beneficial in the treatment of certain diseases of the oral cavity. For example, the topical application of a curcumin gel was found to reduce gingival bleeding and periodontal bacteria after conventional periodontal therapy (scaling and root planing) (90-92). A mouthwash containing curcumin was also found to be as effective as chlorhexidine in reducing inflammation in individuals who underwent periodontal therapy for gingivitis (93).

Oral submucous fibrosis

Any part of the oral cavity may be affected by oral submucous fibrosis (OSMF), a currently incurable condition especially prevalent in Southeast Asia and India. OSMF is characterized by the formation of excess fibrous tissue (fibrosis) that leads to stiffness of the mucosa and restricted mouth opening. A few recent intervention studies showed that curcumin could improve some symptoms, such as burning sensations and reduced mouth opening (reviewed in 94). In an open-label intervention study in 40 OSMF patients randomized to receive either the conventional treatment (weekly intra-lesional injections of steroids) or daily oral administration of a Curcuma longa Linn extract (600 mg/day) for three months, the burning sensation significantly improved in the curcumin-treated group, while tongue protrusion was reduced with conventional therapy. No differences between the two treatment groups were seen with respect to mouth opening (95). A six-month follow-up of the effect of oral curcumin (2 g/day) in OSMF patients treated for three months found that curcumin outperformed steroid ointment in its ability to increase maximum mouth opening and to reduce self-reported burning sensation (96). Further studies should assess the appropriate dose of curcumin to achieve the greatest benefits and determine whether curcumin can enhance the effect of standard-of-care treatment in limiting OSMF disease progression.

Cognitive decline and Alzheimer’s disease

Alzheimer’s disease (AD) is a form of dementia characterized by extracellular deposition of β-amyloid plaques, intracellular formation of neurofibrillary tangles, and neuronal loss, eventually leading to brain atrophy and cognitive impairment in affected individuals (57). When injected into the carotid artery, curcumin was found to cross the blood-brain barrier in an animal model of AD (53), though it is not known whether curcumin taken orally can reach the blood-brain barrier at sufficient concentrations and impede cognitive decline in humans. As a result of promising findings in animal models (see Neuroprotective activity), a few recent clinical trials have examined the effect of oral curcumin supplementation on cognition in healthy older adults and AD patients (57). A randomized, double-blind, placebo-controlled trial in 60 healthy older adults (mean age, 68.5 years) investigated whether acute (80 mg) or chronic (80 mg/day for 4 weeks) oral intake of curcumin could improve their ability to cope with the mental stress and change in mood usually associated with undergoing a battery of cognitive tests (97). A significant reduction in mental fatigue and higher levels of calmness and contentedness following cognitive test sessions were observed in individuals who consumed curcumin (either acutely or chronically) compared to the placebo group. Additionally, the results of cognitive ability tests suggested that curcumin treatment had limited benefits on cognitive function, as shown by better scores in measures of sustained attention and working memory compared to placebo (97).

The results of a six-month trial in 27 patients with AD found that oral supplementation with up to 4 g/day of curcumin — containing all three major curcuminoids — was safe (6). Yet, measures of cognitive performance (using the Mini Mental State Examination [MMSE] scoring scale) and levels of F2-isoprostanes (oxidative stress markers) and antioxidants in blood were not found to be significantly different between curcumin- and placebo-treated subjects at the end of the intervention period. In another six-month, randomized, double-blind, placebo-controlled study of subjects with mild-to-moderate AD, curcumin failed to improve cognitive test scores and to reduce blood and cerebrospinal fluid (CSF) concentrations of β-amyloid peptide, CSF concentrations of total and phosphorylated Tau protein, and CSF concentrations of F2-isoprostanes (98).

Despite the lack of encouraging results from completed trials, several randomized controlled studies are under way to determine whether supplemental curcumin has the ability to reverse or prevent cognitive deficits in both healthy and cognitively impaired individuals (57).

Major depressive disorder

Major depressive disorder (MDD) is a neuropsychiatric disorder associated with abnormal neurotransmission; it is primarily treated with drugs that improve the bioavailability of neurotransmitters like serotonin, noradrenaline, and dopamine in the brain (99). Characteristics of MDD also include alterations in the hypothalamus-pituitary-adrenal axis, increased neuroinflammation, defective neurogenesis, and neuronal death.

A few clinical studies have examined the effect of curcumin alone or with conventional antidepressant drugs in MDD patients. A recent meta-analysis of six randomized controlled trials found that supplementation with curcumin significantly reduced depression symptoms (100). However, in one of the studies included in this meta-analysis — a double-blind, controlled study in 56 adults diagnosed with MDD — curcumin treatment (~880 mg/day of curcuminoids) for eight weeks was no more effective than placebo in reducing self-reported depression- and anxiety-related symptoms (101). Significant improvements in the severity and frequency of specific depression-related symptoms only occurred after four weeks of treatment, suggesting that a longer treatment period might be needed to uncover the antidepressant effects of curcumin (100, 101). In another randomized, placebo-controlled trial, supplemental curcumin (330 mg/day) for five weeks failed to relieve depressive symptoms in patients treated with conventional antidepressants (102). In contrast, in a six-week, randomized, single-blinded, placebo-controlled study in 60 MDD patients, supplemental curcumin (~880 mg/day of curcuminoids) alone yielded a similar response rate to the antidepressant, fluoxetine (a serotonin reuptake inhibitor [Prozac]; 20 mg/day) in terms of depressive symptoms; no additional effect was observed when both curcumin and fluoxetine treatments were combined (103). Moreover, in a randomized controlled study in 100 participants taking escitalopram (a serotonin reuptake inhibitor [Lexapro]; 5 to 15 mg/week), supplemental curcumin (1,000 mg/day) for six weeks increased the antidepressant effect of the medication (104). Curcumin also induced a reduction in plasma concentrations of inflammatory markers and an increase in plasma concentrations of brain-derived neurotrophic factor compared to placebo (antidepressant drug alone) (104).

Larger clinical trials are needed to address the long-term effect of curcumin in subjects with major depression.

Premenstrual syndrome

Premenstrual syndrome (PMS) refers to a range of emotional (e.g., irritability, anxiety), behavioral (e.g., fatigue, insomnia), and physical symptoms (e.g., breast tenderness, headache) occurring prior to the monthly menstrual period in up to 90% of premenopausal women. In a recent randomized, double-blind, placebo-controlled trial in 70 women with PMS, the daily supplementation with 0.2 g of curcumin for 10 days during three consecutive menstrual cycles significantly reduced overall PMS severity, as assessed by a composite measure of all emotional, behavioral, and physical symptoms (105). Additional trials are necessary to evaluate the efficacy of curcumin in the management of PMS.

Sources

Food sources

Turmeric is the dried ground rhizome of Curcuma longa Linn (106). It is used as a spice in Indian, Southeast Asian, and Middle Eastern cuisines. Curcuminoids comprise about 2%-9% of turmeric (107). Curcumin is the most abundant curcuminoid in turmeric, providing about 75% of the total curcuminoids, while demethoxycurcumin and bisdemethoxycurcumin generally represent 10%-20% and less than 5% of the total curcuminoids, respectively (108). Curry powder contains turmeric along with other spices, but the amount of curcumin in curry powders is variable and often relatively low (109). Curcumin extracts are also used as food-coloring agents (110).

Supplements

Commercial curcumin is usually a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin (see Figure 1 above). Curcuminoid extracts are available as dietary supplements without a prescription in the US. The labels of a number of these extracts state that they are standardized to contain 95% curcuminoids, although such claims are not strictly regulated by the US Food and Drug Administration (FDA). Some curcumin preparations also contain piperine, which may increase the bioavailability of curcumin by inhibiting its metabolism (108). However, piperine may also affect the metabolism of drugs (see Drug interactions). Optimal doses of curcumin for cancer chemoprevention or therapeutic uses have not been established. It is unclear whether doses less than 3.6 g/day are biologically active in humans (see Metabolism and Bioavailability). Curcuminoid-containing supplements taken on an empty stomach may cause gastritis and peptic ulcer disease (108).

Safety

Adverse effects

In the United States, turmeric is generally recognized as safe (GRAS) by the FDA as a food additive (110). An increase in gallbladder contractions was observed in 12 healthy people supplemented with single doses of 20 to 40 mg of curcumin (111, 112). Yet, serious adverse effects have not been reported in humans taking high doses of curcumin. A dose escalation trial in 24 adults found that single oral dosages up to 12 g were safe, and adverse effects, including diarrhea, headache, rash, yellow stool, were not related to dose (7). In a phase I trial in Taiwan, curcumin supplementation up to 8 g/day for three months was reported to be well tolerated in patients with precancerous conditions or noninvasive cancer (8). Another clinical trial in the UK found that curcumin supplementation ranging from 0.45 to 3.6 g/day for four months was generally well tolerated by people with advanced colorectal cancer, although two participants experienced diarrhea and another reported nausea (9). Increases in serum alkaline phosphatase and lactate dehydrogenase were also observed in several participants, but it was not clear whether these increases were related to curcumin supplementation or cancer progression (3). In an open-label phase II trial, curcumin treatment (8 g/day) in combination with the anticancer drug gemcitabine was associated with severe abdominal pain in 7 out of 17 patients with advanced pancreatic cancer, leading to the treatment being discontinued in five patients while curcumin dosage was reduced to 4 g/day in two patients (79).

Pregnancy and lactation

Although there is no evidence that dietary consumption of turmeric as a spice adversely affects pregnancy or lactation, the safety of curcumin supplements in pregnancy and lactation has not been established.

Drug interactions

Curcumin has been found to inhibit platelet aggregation in vitro (113, 114), suggesting a potential for curcumin supplementation to increase the risk of bleeding in people taking anticoagulant or antiplatelet medications, such as aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), and warfarin (Coumadin). In cultured breast cancer cells, curcumin inhibited apoptosis induced by the chemotherapeutic agents, camptothecin, mechlorethamine, and doxorubicin at concentrations of 1 to 10 μM (115). In an animal model of breast cancer, dietary curcumin inhibited cyclophosphamide-induced tumor regression. Yet, it is not known whether oral curcumin administration will result in breast tissue concentrations that are high enough to inhibit cancer chemotherapeutic agents in humans (11). Curcuminoids may interfere with the activity of efflux drug transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein, multidrug resistance protein (MRP), and breast cancer-resistant protein (BCRP), which function as ATP-dependent efflux pumps that actively regulate the excretion of a number of drugs limiting their systemic bioavailability (116, 117). Curcumin was also found to affect the activity of phase I biotransformation enzymes like cytochrome P450 (CYP) 3A4 (CYP3A4) (118), which catalyzes the metabolism of about one-half of all marketed drugs in the US (119). In healthy Japanese volunteers, curcumin (2 g) was found to increase plasma sulfasalazine concentration following the administration of a therapeutic dose (2 g) of the anti-rheumatic drug sulfasalazine (Salazopyrin, Azulfidine) (120).

Some curcumin supplements also contain piperine to increase the bioavailability of curcumin. Piperine may also interfere with efflux drug transporters and phase I cytochrome P450 enzymes and increase the bioavailability and slow the elimination of a number of drugs, including phenytoin (Dilantin), propranolol (Inderal), theophylline, and carbamazepine (Tegretol) (121-123).


Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in February 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2016 by:
Lynne Howells, Ph.D.
Research Fellow
Experimental Cancer Medicine Centre Lab Quality Manager
University of Leicester

Copyright 2005-2017  Linus Pauling Institute 


References

1.  Gupta SC, Kismali G, Aggarwal BB. Curcumin, a component of turmeric: from farm to pharmacy. Biofactors. 2013;39(1):2-13.  (PubMed)

2.  Bandyopadhyay D. Farmer to pharmacist: curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer. Front Chem. 2014;2:113.  (PubMed)

3.  Sharma RA, Gescher AJ, Steward WP. Curcumin: The story so far. Eur J Cancer. 2005;41(13):1955-1968.  (PubMed)

4.  Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807-818.  (PubMed)

5.  Maheshwari RK, Singh AK, Gaddipati J, Srimal RC. Multiple biological activities of curcumin: a short review. Life Sci. 2006;78(18):2081-2087.  (PubMed)

6.  Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008;28(1):110-113.  (PubMed)

7.  Lao CD, Ruffin MTt, Normolle D, et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006;6:10.  (PubMed)

8.  Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895-2900.  (PubMed)

9.  Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res. 2004;10(20):6847-6854.  (PubMed)

10.  Garcea G, Berry DP, Jones DJ, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev. 2005;14(1):120-125.  (PubMed)

11.  Garcea G, Jones DJ, Singh R, et al. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer. 2004;90(5):1011-1015.  (PubMed)

12.  Aggarwal ML, Chacko KM, Kuruvilla BT. Systematic and comprehensive investigation of the toxicity of curcuminoidessential oil complex: A bioavailable turmeric formulation. Mol Med Rep. 2016;13(1):592-604.  (PubMed)

13.  Jager R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J. 2014;13:11.  (PubMed)

14.  Kanai M, Imaizumi A, Otsuka Y, et al. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol. 2012;69(1):65-70.  (PubMed)

15.  Mendonca LM, Machado Cda S, Teixeira CC, Freitas LA, Bianchi ML, Antunes LM. Comparative study of curcumin and curcumin formulated in a solid dispersion: Evaluation of their antigenotoxic effects. Genet Mol Biol. 2015;38(4):490-498.  (PubMed)

16.  Shakeri A, Sahebkar A. Optimized curcumin formulations for the treatment of Alzheimer's disease: A patent evaluation. J Neurosci Res. 2016;94(2):111-113.  (PubMed)

17.  Prasad S, Tyagi AK, Aggarwal BB. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Res Treat. 2014;46(1):2-18.  (PubMed)

18.  Sreejayan, Rao MN. Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol. 1997;49(1):105-107.  (PubMed)

19.  Sreejayan N, Rao MN. Free radical scavenging activity of curcuminoids. Arzneimittelforschung. 1996;46(2):169-171.  (PubMed)

20.  Dickinson DA, Levonen AL, Moellering DR, et al. Human glutamate cysteine ligase gene regulation through the electrophile response element. Free Radic Biol Med. 2004;37(8):1152-1159.  (PubMed)

21.  Dickinson DA, Iles KE, Zhang H, Blank V, Forman HJ. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J. 2003;17(3):473-475.  (PubMed)

22.  Scapagnini G, Vasto S, Abraham NG, Caruso C, Zella D, Fabio G. Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol. 2011;44(2):192-201.  (PubMed)

23.  Zhang X, Liang D, Guo L, et al. Curcumin protects renal tubular epithelial cells from high glucose-induced epithelial-to-mesenchymal transition through Nrf2-mediated upregulation of heme oxygenase-1. Mol Med Rep. 2015;12(1):1347-1355.  (PubMed)

24.  Suzuki M, Betsuyaku T, Ito Y, et al. Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol. 2009;296(4):L614-623.  (PubMed)

25.  Yao QY, Xu BL, Wang JY, Liu HC, Zhang SC, Tu CT. Inhibition by curcumin of multiple sites of the transforming growth factor-β1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats. BMC Complement Altern Med. 2012;12:156.  (PubMed)

26.  Xiong ZE, Dong WG, Wang BY, Tong QY, Li ZY. Curcumin attenuates chronic ethanol-induced liver injury by inhibition of oxidative stress via mitogen-activated protein kinase/nuclear factor E2-related factor 2 pathway in mice. Pharmacogn Mag. 2015;11(44):707-715.  (PubMed)

27.  Xie Y, Zhao QY, Li HY, Zhou X, Liu Y, Zhang H. Curcumin ameliorates cognitive deficits heavy ion irradiation-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Pharmacol Biochem Behav. 2014;126:181-186.  (PubMed)

28.  Ghosh S, Banerjee S, Sil PC. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem Toxicol. 2015;83:111-124.  (PubMed)

29.  Li CP, Li JH, He SY, Chen O, Shi L. Effect of curcumin on p38MAPK expression in DSS-induced murine ulcerative colitis. Genet Mol Res. 2015;14(2):3450-3458.  (PubMed)

30.  Yang JY, Zhong X, Yum HW, et al. Curcumin inhibits STAT3 signaling in the colon of dextran sulfate sodium-treated mice. J Cancer Prev. 2013;18(2):186-191.  (PubMed)

31.  Moon DO, Kim MO, Choi YH, Park YM, Kim GY. Curcumin attenuates inflammatory response in IL-1β-induced human synovial fibroblasts and collagen-induced arthritis in mouse model. Int Immunopharmacol. 2010;10(5):605-610.  (PubMed)

32.  Shakibaei M, John T, Schulze-Tanzil G, Lehmann I, Mobasheri A. Suppression of NF-κB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: Implications for the treatment of osteoarthritis. Biochem Pharmacol. 2007;73(9):1434-1445.  (PubMed)

33.  Zhu HT, Bian C, Yuan JC, et al. Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflammation. 2014;11:59.  (PubMed)

34.  Baird WM, Hooven LA, Mahadevan B. Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ Mol Mutagen. 2005;45(2-3):106-114.  (PubMed)

35.  Sehgal A, Kumar M, Jain M, Dhawan DK. Modulatory effects of curcumin in conjunction with piperine on benzo(a)pyrene-mediated DNA adducts and biotransformation enzymes. Nutr Cancer. 2013;65(6):885-890.  (PubMed)

36.  Thapliyal R, Maru GB. Inhibition of cytochrome P450 isozymes by curcumins in vitro and in vivo. Food Chem Toxicol. 2001;39(6):541-547.  (PubMed)

37.  Volak LP, Ghirmai S, Cashman JR, Court MH. Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos. 2008;36(8):1594-1605.  (PubMed)

38.  Das L, Vinayak M. Long term effect of curcumin in restoration of tumour suppressor p53 and phase-II antioxidant enzymes via activation of Nrf2 signalling and modulation of inflammation in prevention of cancer. PLoS One. 2015;10(4):e0124000.  (PubMed)

39.  Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol. 2003;92(1):33-38.  (PubMed)

40.  Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci. 2003;24(3):139-145.  (PubMed)

41.  Duvoix A, Blasius R, Delhalle S, et al. Chemopreventive and therapeutic effects of curcumin. Cancer Lett. 2005;223(2):181-190.  (PubMed)

42.  Surh YJ, Chun KS. Cancer chemopreventive effects of curcumin. Adv Exp Med Biol. 2007;595:149-172.  (PubMed)

43.  Singh S, Khar A. Biological effects of curcumin and its role in cancer chemoprevention and therapy. Anticancer Agents Med Chem. 2006;6(3):259-270.  (PubMed)

44.  Kuttan G, Kumar KB, Guruvayoorappan C, Kuttan R. Antitumor, anti-invasion, and antimetastatic effects of curcumin. Adv Exp Med Biol. 2007;595:173-184.  (PubMed)

45.  Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269(2):199-225.  (PubMed)

46.  Chen B, Zhang Y, Wang Y, Rao J, Jiang X, Xu Z. Curcumin inhibits proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression. J Steroid Biochem Mol Biol. 2014;143:11-18.  (PubMed)

47.  Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets. 2011;12(3):332-347.  (PubMed)

48.  Han X, Xu B, Beevers CS, et al. Curcumin inhibits protein phosphatases 2A and 5, leading to activation of mitogen-activated protein kinases and death in tumor cells. Carcinogenesis. 2012;33(4):868-875.  (PubMed)

49.  Huang T, Chen Z, Fang L. Curcumin inhibits LPS-induced EMT through downregulation of NF-κB-Snail signaling in breast cancer cells. Oncol Rep. 2013;29(1):117-124.  (PubMed)

50.  Prvulovic D, Hampel H. Amyloid beta (Aβ) and phospho-tau (p-τ) as diagnostic biomarkers in Alzheimer's disease. Clin Chem Lab Med. 2011;49(3):367-374.  (PubMed)

51.  Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro. J Neurosci Res. 2004;75(6):742-750.  (PubMed)

52.  Reinke AA, Gestwicki JE. Structure-activity relationships of amyloid β-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chem Biol Drug Des. 2007;70(3):206-215.  (PubMed)

53.  Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005;280(7):5892-5901.  (PubMed)

54.  Lin R, Chen X, Li W, Han Y, Liu P, Pi R. Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: blockage by curcumin. Neurosci Lett. 2008;440(3):344-347.  (PubMed)

55.  Zhang C, Browne A, Child D, Tanzi RE. Curcumin decreases amyloid-β peptide levels by attenuating the maturation of amyloid-β precursor protein. J Biol Chem. 2010;285(37):28472-28480.  (PubMed)

56.  Shi X, Zheng Z, Li J, et al. Curcumin inhibits Aβ-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways. Neurosci Lett. 2015;594:105-110.  (PubMed)

57.  Goozee KG, Shah TM, Sohrabi HR, et al. Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer's disease. Br J Nutr. 2015:1-17.  (PubMed)

58.  Krishnaswamy K, Goud VK, Sesikeran B, Mukundan MA, Krishna TP. Retardation of experimental tumorigenesis and reduction in DNA adducts by turmeric and curcumin. Nutr Cancer. 1998;30(2):163-166.  (PubMed)

59.  Li N, Chen X, Liao J, et al. Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin. Carcinogenesis. 2002;23(8):1307-1313.  (PubMed)

60.  Ikezaki S, Nishikawa A, Furukawa F, et al. Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine and sodium chloride in rats. Anticancer Res. 2001;21(5):3407-3411.  (PubMed)

61.  Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res. 1994;54(22):5841-5847.  (PubMed)

62.  Chuang SE, Kuo ML, Hsu CH, et al. Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis. 2000;21(2):331-335.  (PubMed)

63.  Pereira MA, Grubbs CJ, Barnes LH, et al. Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis. 1996;17(6):1305-1311.  (PubMed)

64.  Rao CV, Rivenson A, Simi B, Reddy BS. Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res. 1995;55(2):259-266.  (PubMed)

65.  Kawamori T, Lubet R, Steele VE, et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res. 1999;59(3):597-601.  (PubMed)

66.  Mahmoud NN, Carothers AM, Grunberger D, et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis. 2000;21(5):921-927.  (PubMed)

67.  Perkins S, Verschoyle RD, Hill K, et al. Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev. 2002;11(6):535-540.  (PubMed)

68.  Carroll RE, Benya RV, Turgeon DK, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 2011;4(3):354-364.  (PubMed)

69.  National Institutes of Health. Clinical Trials.gov [Website]. Available at: http://clinicaltrials.gov/. Accessed 1/27/16.

70.  Rivera-Mancia S, Lozada-Garcia MC, Pedraza-Chaverri J. Experimental evidence for curcumin and its analogs for management of diabetes mellitus and its associated complications. Eur J Pharmacol. 2015;756:30-37.  (PubMed)

71.  Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care. 2012;35(11):2121-2127.  (PubMed)

72.  Usharani P, Mateen AA, Naidu MU, Raju YS, Chandra N. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R D. 2008;9(4):243-250.  (PubMed)

73.  Chuengsamarn S, Rattanamongkolgul S, Phonrat B, Tungtrongchitr R, Jirawatnotai S. Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized controlled trial. J Nutr Biochem. 2014;25(2):144-150.  (PubMed)

74.  Khajehdehi P, Pakfetrat M, Javidnia K, et al. Oral supplementation of turmeric attenuates proteinuria, transforming growth factor-β and interleukin-8 levels in patients with overt type 2 diabetic nephropathy: a randomized, double-blind and placebo-controlled study. Scand J Urol Nephrol. 2011;45(5):365-370.  (PubMed)

75.  Schaffer M, Schaffer PM, Zidan J, Bar Sela G. Curcuma as a functional food in the control of cancer and inflammation. Curr Opin Clin Nutr Metab Care. 2011;14(6):588-597.  (PubMed)

76.  National Institutes of Health. An Introduction to Clinical Trials. Available at: https://clinicaltrials.gov/ct2/about-studies/learn. Accessed 2/8/16.

77.  Mall M, Kunzelmann K. Correction of the CF defect by curcumin: hypes and disappointments. Bioessays. 2005;27(1):9-13.  (PubMed)

78.  Irving GR, Howells LM, Sale S, et al. Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration — a clinical pilot study including assessment of patient acceptability. Cancer Prev Res (Phila). 2013;6(2):119-128.  (PubMed)

79.  Epelbaum R, Schaffer M, Vizel B, Badmaev V, Bar-Sela G. Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer. 2010;62(8):1137-1141.  (PubMed)

80.  Kanai M, Yoshimura K, Asada M, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol. 2011;68(1):157-164.  (PubMed)

81.  Bayet-Robert M, Kwiatkowski F, Leheurteur M, et al. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther. 2010;9(1):8-14.  (PubMed)

82.  Ghalaut VS, Sangwan L, Dahiya K, Ghalaut PS, Dhankhar R, Saharan R. Effect of imatinib therapy with and without turmeric powder on nitric oxide levels in chronic myeloid leukemia. J Oncol Pharm Pract. 2012;18(2):186-190.  (PubMed)

83.  Mahammedi H, Planchat E, Pouget M, et al. The new combination docetaxel, prednisone and curcumin in patients with castration-resistant prostate cancer: a pilot phase II study. Oncology. 2016;90(2):69-78.  (PubMed)

84.  Satoskar RR, Shah SJ, Shenoy SG. Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol. 1986;24(12):651-654.  (PubMed)

85.  Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res. 1980;71:632-634. 

86.  Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26(11):1719-1725.  (PubMed)

87.  Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res. 2013;180(1):34-43.  (PubMed)

88.  Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4(12):1502-1506.  (PubMed)

89.  Lang A, Salomon N, Wu JC, et al. Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in a randomized controlled trial. Clin Gastroenterol Hepatol. 2015;13(8):1444-1449 e1441.  (PubMed)

90.  Anuradha BR, Bai YD, Sailaja S, Sudhakar J, Priyanka M, Deepika V. Evaluation of anti-inflammatory effects of curcumin gel as an adjunct to scaling and root planing: A Clinical Study. J Int Oral Health. 2015;7(7):90-93.  (PubMed)

91.  Nagasri M, Madhulatha M, Musalaiah SV, Kumar PA, Krishna CH, Kumar PM. Efficacy of curcumin as an adjunct to scaling and root planning in chronic periodontitis patients: A clinical and microbiological study. J Pharm Bioallied Sci. 2015;7(Suppl 2):S554-558.  (PubMed)

92.  Sreedhar A, Sarkar I, Rajan P, et al. Comparative evaluation of the efficacy of curcumin gel with and without photo activation as an adjunct to scaling and root planing in the treatment of chronic periodontitis: A split mouth clinical and microbiological study. J Nat Sci Biol Med. 2015;6(Suppl 1):S102-109.  (PubMed)

93.  Muglikar S, Patil KC, Shivswami S, Hegde R. Efficacy of curcumin in the treatment of chronic gingivitis: a pilot study. Oral Health Prev Dent. 2013;11(1):81-86.  (PubMed)

94.  Alok A, Singh ID, Singh S, Kishore M, Jha PC. Curcumin — pharmacological actions and its role in oral submucous fibrosis: a review. J Clin Diagn Res. 2015;9(10):ZE01-03.  (PubMed)

95. Yadav M, Aravinda K, Saxena VS, et al. Comparison of curcumin with intralesional steroid injections in Oral Submucous Fibrosis - A randomized, open-label interventional study. J Oral Biol Craniofac Res.2014;4(3):169-173.  (PubMed)

96.  Hazarey VK, Sakrikar AR, Ganvir SM. Efficacy of curcumin in the treatment for oral submucous fibrosis — a randomized clinical trial. J Oral Maxillofac Pathol. 2015;19(2):145-152.  (PubMed)

97.  Cox KH, Pipingas A, Scholey AB. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol. 2015;29(5):642-651.  (PubMed)

98.  Ringman JM, Frautschy SA, Teng E, et al. Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther. 2012;4(5):43.  (PubMed)

99.  Davidson JR. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry. 2010;71 Suppl E1:e04.  (PubMed)

100.  Al-Karawi D, Al Mamoori DA, Tayyar Y. The role of curcumin administration in patients with major depressive disorder: mini meta-analysis of clinical trials. Phytother Res. 2016;30(2):175-183.  (PubMed)

101.  Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368-375.  (PubMed)

102.  Bergman J, Miodownik C, Bersudsky Y, et al. Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical study. Clin Neuropharmacol. 2013;36(3):73-77.  (PubMed)

103.  Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2014;28(4):579-585.  (PubMed)

104.  Yu JJ, Pei LB, Zhang Y, Wen ZY, Yang JL. Chronic supplementation of curcumin enhances the efficacy of antidepressants in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study. J Clin Psychopharmacol. 2015;35(4):406-410.  (PubMed)

105.  Fanaei H, Khayat S, Kasaeian A, Javadimehr M. Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: a randomized, double-blind, placebo-controlled trial. Neuropeptides. 2015. Nov 11. pii: S0143-4179(15)00118-3. doi: 10.1016/j.npep.2015.11.003. [Epub ahead of print].  (PubMed)

106.  Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol Adv. 2014;32(6):1053-1064.  (PubMed)

107.  Lechtenberg M, Quandt B, Nahrstedt A. Quantitative determination of curcuminoids in Curcuma rhizomes and rapid differentiation of Curcuma domestica Val. and Curcuma xanthorrhiza Roxb. by capillary electrophoresis. Phytochem Anal. 2004;15(3):152-158.  (PubMed)

108.  Hendler SS, Rorvik DM. PDR for Nutritional Supplements. 2nd ed: Thomson Reuters; 2008.

109.  Heath DD, Khwaja F, Rock CL. Curcumin content of turmeric and curry powders. FASEB J. 2004;18(4):A125-A125.  (PubMed)

110.  US Food and Drug Administration. Food Additive Status List: GRN number 460. Aug 23, 2013. Available at: http://www.accessdata.fda.gov/scripts/fdcc/?set=GRASNotices. Accessed 1/25/16.

111.  Rasyid A, Lelo A. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Aliment Pharmacol Ther. 1999;13(2):245-249.  (PubMed)

112.  Rasyid A, Rahman AR, Jaalam K, Lelo A. Effect of different curcumin dosages on human gall bladder. Asia Pac J Clin Nutr. 2002;11(4):314-318.  (PubMed)

113.  Shah BH, Nawaz Z, Pertani SA, et al. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol. 1999;58(7):1167-1172.  (PubMed)

114.  Srivastava KC, Bordia A, Verma SK. Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets. Prostaglandins Leukot Essent Fatty Acids. 1995;52(4):223-227.  (PubMed)

115.  Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res. 2002;62(13):3868-3875.  (PubMed)

116.  Chearwae W, Shukla S, Limtrakul P, Ambudkar SV. Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin. Mol Cancer Ther. 2006;5(8):1995-2006.  (PubMed)

117.  Chearwae W, Wu CP, Chu HY, Lee TR, Ambudkar SV, Limtrakul P. Curcuminoids purified from turmeric powder modulate the function of human multidrug resistance protein 1 (ABCC1). Cancer Chemother Pharmacol. 2006;57(3):376-388.  (PubMed)

118.  Hsieh YW, Huang CY, Yang SY, et al. Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies. Sci Rep. 2014;4:6587.  (PubMed)

119.  Koe XF, Tengku Muhammad TS, Chong AS, Wahab HA, Tan ML. Cytochrome P450 induction properties of food and herbal-derived compounds using a novel multiplex RT-qPCR in vitro assay, a drug-food interaction prediction tool. Food Sci Nutr. 2014;2(5):500-520.  (PubMed)

120.  Kusuhara H, Furuie H, Inano A, et al. Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol. 2012;166(6):1793-1803.  (PubMed)

121.  Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol. 1991;41(6):615-617.  (PubMed)

122.  Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P. Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients. Phytother Res. 2009;23(9):1281-1286.  (PubMed)

123.  Velpandian T, Jasuja R, Bhardwaj RK, Jaiswal J, Gupta SK. Piperine in food: interference in the pharmacokinetics of phenytoin. Eur J Drug Metab Pharmacokinet. 2001;26(4):241-247.  (PubMed)

Fiber

You should be automatically redirected to the current page, if not click here.

Flavonoids

Summary

  • Flavonoids are a large family of polyphenolic plant compounds. Six major subclasses of flavonoids, namely anthocyanidins, flavan-3-ols, flavonols, flavanones, flavones, and isoflavones, flavonols are the most widespread in the human diet. (More information)
  • Dietary flavonoids are naturally occurring in fruit, vegetables, chocolate, and beverages like wine and tea. There has been much interest in the potential health benefits of flavonoids associated with fruit- and vegetable-rich diets. (More information)
  • The physicochemical properties of flavonoids influence their metabolic fate, i.e., their digestion, absorption, and biotransformation. The bioavailability of these polyphenols in vivo is a major determinant in their ability to exert biological activities relevant to human health. (More information)
  • Many of the biological effects of flavonoids appear to be related to their ability to modulate a number of cell-signaling cascades. Flavonoids have been shown to exhibit antiinflammatory, antithrombogenic, antidiabetic, anticancer, and neuroprotective activities through different mechanisms of action in vitro and in animal models. (More information)
  • Accumulating evidence from randomized controlled trials suggests that consumption of flavan-3-ols and anthocyanidins can be beneficial for metabolic and cardiovascular health. (More information)
  • The results of small-scale randomized controlled trials suggest that consumption of flavonoid-rich food and beverages containing anthocyanins or flavan-3-ols may improve vascular endothelial function. As yet, it is not known whether these acute improvements result in long-term reductions in risk of cardiovascular disease. (More information)
  • Promising findings in randomized controlled studies indicate that supplementation with flavan-3-ols or anthocyanidins may improve glycemic control in subjects at-risk or diagnosed with type 2 diabetes mellitus. (More information)
  • Despite promising results in animal studies, only a limited number of observational studies have reported potential cancer preventive effects of flavonoids in humans. Higher intakes of soy isoflavones may be associated with reduced risks of breast cancer in postmenopausal women and prostate cancer in men. (More information)
  • Evidence suggesting that some flavonoids or flavonoid-rich foods may enhance cognitive function is currently limited, and it is not yet known whether their consumption could lower the risk of cognitive impairments and dementia in humans. (More information)
  • High intakes of dietary flavonoids are generally regarded as safe, especially because of their low bioavailability. However, flavonoid supplements may affect the action of anticoagulants and increase the toxicity of a wide range of drugs when taken concurrently. (More information)

Introduction

Flavonoids are a large family of over 5,000 hydroxylated polyphenolic compounds that carry out important functions in plants, including attracting pollinating insects; combating environmental stresses, such as microbial infection; and regulating cell growth (1). Their bioavailability and biological activities in humans appear to be strongly influenced by their chemical nature. Since the 1990s, there has been a growing interest in dietary flavonoids due to their likely contribution to the health benefits of fruit- and vegetable-rich diets. This article reviews some of the scientific evidence regarding the role of dietary flavonoids in health promotion and disease prevention in humans; it is not meant to be a comprehensive review on every health topic studied.

Flavonoid Subclasses

Flavonoids are classified into 12 major subclasses based on chemical structures, six of which, namely  anthocyanidins, flavan-3-ols, flavonols, flavones, flavanones, and isoflavones (Table 1 and Figures 1-9) are of dietary significance. Glycosylated flavonols (bound to at least one sugar molecule) are the most widely distributed flavonoids in the diet (2, 3).

Table 1. Common Dietary Flavonoids
(Select the highlighted text to see chemical structures.)
Flavonoid Subclass Dietary Flavonoids (aglycones) Some Common Food Sources (see also Sources)
Anthocyanidins* Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin Red, blue, and purple berries; red and purple grapes; red wine

Flavan-3-ols

  

Monomers (Catechins):
(+)-Catechin, (-)-Epicatechin, (-)-Epigallocatechin, (+)-Gallocatechin; and their gallate derivatives

Teas (particularly white, green, and oolong), cocoa-based products, grapes, berries, apples

Dimers and Polymers:
Proanthocyanidins#

Apples, berries, cocoa-based products, red grapes, red wine

Theaflavins, Thearubigins

Black tea

Flavonols Isorhamnetin, Kaempferol, Myricetin, Quercetin

Onions, scallions, kale, broccoli, apples, berries, teas

Flavones Apigenin, Luteolin, Baicalein, Chrysin

Parsley, thyme, celery, hot peppers

Flavanones Eriodictyol, Hesperetin, Naringenin

Citrus fruit and juices, e.g., oranges, grapefruits, lemons

Isoflavones

Daidzein, Genistein, Glycitein, Biochanin A, Formononetin

Soybeans, soy foods, legumes

*Anthocyanidins with one or more sugar moieties (anthocyanidin glycosides) are called anthocyanins.
#Proanthocyanidin oligomers formed from (+)-catechin and (-)-epicatechin subunits are called procyanidins.

For more detailed information on the health effects of isoflavones, a subclass of flavonoids with estrogenic activity, see the article on Soy Isoflavones.

For more information on the health benefits of foods that are rich in flavonoids, see the articles on Fruit and Vegetables, Legumes, and Tea.  

Figure 1. Basic Structures of Flavonoid Subclasses 

Figure 2. Chemical Structures of Some Flavan-3-ol Monomers (Catechins) 

Figure 3. Chemical Structures of Theaflavins 

Figure 4. Chemical Structures of Anthocyanidins

Figure 5. Chemical Structures of Flavonols 

Figure 6. Chemical Structures of Flavones

Figure 7. Chemical Structures of Flavanones 

Figure 8. Chemical Structures of Isoflavones

Figure 9. Chemical Structures of Proanthocyanidin Dimers

Metabolism and Bioavailability

The amount of flavonoids present in ingested food has little importance unless dietary flavonoids are absorbed and become available to target tissues within the body. During and after intestinal absorption, flavonoids are rapidly and extensively metabolized in intestinal and liver cells such that they are likely to appear as metabolites (e.g., phase II metabolites) in the bloodstream and urine (4). Additionally, the biological activities of flavonoid metabolites are likely to be different from those of their parent compounds (5). Some of the factors influencing the metabolic fate and bioavailability of dietary flavonoids are mentioned below.

Chemical structure of flavonoids

Most flavonoids occur in edible plants and foods as β-glycosides, i.e., bound to one or more sugar molecules (6). Exceptions include flavan-3-ols (catechins and proanthocyanidins) and fermented soy-based products that are exposed to microbial β-glucosidases, which catalyze the release of sugar molecules from glycosylated isoflavones (7). Even after food processing and cooking, most flavonoid glycosides reach the small intestine intact. Only flavonoid aglycones (not bound to a sugar molecule) and a few flavonoid glucosides (bound to glucose) are easily absorbed in the small intestine (8). Glycosylated flavonoids might be able to penetrate the mucus layer of the intestine and be deglycosylated on the cell surface before absorption. Those that cannot be deglycosylated in the small intestine may be hydrolyzed by bacterial enzymes in the colon (7). Nevertheless, colonic bacteria might remove sugar moieties and rapidly degrade aglycone flavonoids, thus limiting their absorption in the colon (9).

In contrast to monomeric flavan-3-ols (catechins), the polymeric nature of proanthocyanidins likely prevents their intestinal absorption. Flavan-3-ol monomers and procyanidins are transformed by the intestinal microbiota to 5-(hydroxyphenyl)-γ-valerolactones which appear in the circulatory system and are excreted in urine as sulfate and glucuronide metabolites (Figure 10). Valerolactones may be further degraded by the colonic microbiota to smaller phenolic acids and aromatic compounds. The colonic microbiota also metabolize the gallate esters of flavonoids, generating gallate, which is further catabolized to pyrogallol. Microbe-derived flavonoid metabolites are readily absorbed into the circulatory system and excreted in both free forms and as phase II metabolites in urine (9).

Figure 10. Chemical Structures of Some Flavan-3-ol Metabolites


Interactions with food matrix

The presence of macronutrients in food influences the bioavailability of co-ingested flavonoids (reviewed in 8, 10, 11). The binding affinity and potential (non-) covalent interactions of flavonoids with food proteins, carbohydrates, and fats are directly associated with the physicochemical properties of flavonoids (reviewed in 8). Proteins in milk might reduce the absorption of polyphenols from cocoa or black tea. The presence of milk proteins bound to flavonoids was shown to weaken the flavonoid antioxidant capacity in vitro (12), and milk consumption has been shown to blunt the vascular benefits of tea flavonoids in healthy volunteers (13). Some carbohydrate-rich foods may increase the deglycosylation and absorption of flavonoids by stimulating gastrointestinal motility, mucosal blood flow, and colonic fermentation. Conversely, dietary flavonoids have been shown to interfere with carbohydrate digestion and absorption (see Biological Activities).

Composition of gut microbiota

In the large intestine, gut microbial enzymes transform flavonoids through deglycosylation, ring fission, dehydroxylation, demethylation, etc. into metabolites that can then be absorbed or excreted (9, 14). The diversity and activity of colonic bacteria, which are partly dependent on a person’s dietary habits, will determine which metabolites can be produced from ingested flavonoids (15, 16). The composition of the colonic microbiota can therefore affect the metabolic fate and bioavailability of dietary flavonoids (17).

The detoxification pathway

Flavonoids are recognized as xenobiotics by the body such that they undergo extensive modifications first in the intestinal mucosa and then in the liver.

Phase II enzymes

Depending on their structural characteristics, flavonoids can be rapidly transformed by phase II detoxification enzymes to form methylated, glucuronidated, and/or sulfated metabolites (2). This metabolic pathway increases the solubility of phenolic aglycones and facilitates their excretion in the bile and urine (11). Free (unconjugated) aglycones are generally absent from the bloodstream, with the possible exception of trace levels of catechins (17). Catechol-O-methyltransferase (COMT) is the detoxifying enzyme responsible for the methylation of the hydroxyl groups of flavonoids, producing O-methylated flavonoids. A single nucleotide polymorphism (SNP) in the gene for COMT — known as SNP rs4680 G>A — causes a valine-to-methionine substitution in the sequence of the enzyme. Individuals with the A/A genotype have a form of the enzyme that is three- to four-fold less active than the wild-type variant in G/G genotype carriers (18). It has been suggested that subjects who are less efficient at eliminating green tea flavonoids may be more likely to benefit from their consumption (19).

Efflux transporters

Flavonoid conjugates are excreted via the action of efflux transporters from the ATP-binding cassette (ABC) family, including P-glycoprotein, MRPs (multidrug resistance proteins), or BCRPs (breast cancer-resistant proteins). Depending on their physicochemical properties, some flavonoids may interfere with the activity of ABC transporters (20). This implies that flavonoids can affect their own bioavailability, as well as that of other substrates of these transporters (e.g., pharmacological drugs) (see Drug interactions).

Binding to plasma proteins

Flavonoid bioavailability may be inversely related to their binding affinity to plasma proteins (21). Greater binding affinity to plasma proteins (and thus, possibly, lower flavonoid bioavailability) has been linked to structural characteristics, such as methylation and galloylation. On the contrary, glycosylation reduced binding affinity to plasma proteins, suggesting that aglycones might have a limited bioavailability compared to glycosylated flavonoids. While glucuronidation is thought to facilitate the excretion of flavonoids from the body, glucuronides show little affinity to plasma proteins and might thus be able to diffuse to target tissues where deglucuronidation can take place (8)

Summary

In general, the bioavailability of flavonoids is low due to limited absorption, extensive metabolism, and rapid excretion. Isoflavones are thought to be the most bioavailable of all flavonoid subclasses, while anthocyanins and galloylated catechins are very poorly absorbed (8, 22). Yet, given the wide variability in structures within subclasses, it is difficult to generalize the absorbability and bioavailability of flavonoids based only on their structural classification. In addition, when evaluating the data from flavonoid research in cultured cells, it is important to consider whether the flavonoid concentrations and metabolites used are physiologically relevant (23). In humans, peak plasma concentrations of soy isoflavones and citrus flavanones have not been found to exceed 10 micromoles/liter (μM) after oral consumption. Peak plasma concentrations measured after the consumption of anthocyanins, flavan-3-ols, and flavonols (including those from tea) are generally lower than 1 μM (2). A recent quantitative analysis of 88 polyphenolic metabolites (not limited to flavonoids) identified in human blood and urine found median peak concentrations of 0.9 μM and 3.2 μM after food intake and oral supplementation, respectively (4).

Biological Activities

Direct antioxidant activity

Flavonoids are effective scavengers of free radicals in the test tube (in vitro) (24, 25). However, even with very high flavonoid intakes, plasma and intracellular flavonoid concentrations in humans are likely to be 100 to 1,000 times lower than concentrations of other antioxidants, such as ascorbate (vitamin C), uric acid, and glutathione. Moreover, most circulating flavonoids are actually flavonoid metabolites, some of which have lower antioxidant activity than the parent flavonoid (5). For these reasons, the relative contribution of dietary flavonoids to plasma and tissue antioxidant function in vivo is likely to be very small or negligible (26-28).

Metal chelation

Metal ions, such as iron and copper, can catalyze the production of free radicals. The ability of flavonoids to chelate (bind) metal ions appears to contribute to their antioxidant activity in vitro (29, 30). In living organisms, most iron and copper are bound to proteins, limiting their participation in reactions that produce free radicals. Although the metal-chelating activities of flavonoids may be beneficial in pathological conditions of iron or copper excess, it is not known whether flavonoids or their metabolites function as effective metal chelators in vivo (26).

Effects on cell-signaling pathways

Cells are capable of responding to a variety of different stresses or signals by increasing or decreasing the availability of specific proteins. The complex cascades of events that lead to changes in the expression of specific genes are known as cell-signaling pathways or signal transduction pathways. These pathways regulate numerous cell processes, such as proliferation, differentiation, inflammatory responses, apoptosis (programmed cell death), and survival. Although it was initially hypothesized that the biological effects of flavonoids would be related to their antioxidant activity, available evidence from cell culture experiments suggests that many of the effects of flavonoids, including antiinflammatory, antidiabetic, anticancer, and neuroprotective activities, are related to their ability to modulate cell-signaling pathways (27). Intracellular concentrations of flavonoids required to affect cellular signaling are considerably lower than those required to affect cellular antioxidant capacity. Flavonoid metabolites may retain their ability to interact with cell-signaling proteins even if their antioxidant activity is diminished (31, 32).

Effective signal transduction requires proteins known as kinases that catalyze the phosphorylation of target proteins, which become either activated or inhibited. Cascades involving specific phosphorylations or dephosphorylations of signal transduction proteins ultimately affect the activity of transcription factors — proteins that bind to specific response elements on DNA and promote or prevent the transcription of target genes. Results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases (27, 33). Cell growth and proliferation are also regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors in cell membranes. Flavonoids may alter growth factor signaling by inhibiting receptor phosphorylation or blocking receptor binding by growth factors (34).

Each flavonoid subclass contains many types of chemicals with varying biological activities (and potential health benefits) such that the activity of a specific flavonoid cannot easily be generalized. Some examples of major biological activities of flavonoids are highlighted below.

Biological activities related to the prevention of cardiovascular disease

Flavonoids have been shown to (1) reduce inflammation by suppressing the expression of pro-inflammatory mediators (35-37); (2) down-regulate the expression of vascular cell adhesion molecules, which contribute to the recruitment of inflammatory white blood cells from the blood to the arterial wall (38, 39); (3) increase the production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS), thus improving vascular endothelial function (40); (4) inhibit angiotensin-converting enzyme, thus inducing vascular relaxation (41); (5) inhibit platelet aggregation (42); and (6) oppose smooth muscle cell proliferation and migration occurring during atherogenesis (43).

Biological activities related to the prevention of diabetes

Flavonoids have been found to interfere with the digestion, absorption, and metabolism of carbohydrates (reviewed in 44). Each subclass of flavonoids has also demonstrated anti-diabetic properties, including (1) improving insulin secretion and viability of pancreatic β-cells under glucotoxic or pro-inflammatory conditions, (2) increasing insulin-stimulated glucose uptake by target cells, (3) protecting muscle cells against fatty acid-induced insulin resistance, and (4) reducing hyperglycemia and improving glucose tolerance in animal models of obesity and/or type 2 diabetes mellitus (45).

Biological activities related to the prevention of cancer

Flavonoids have been found to (1) scavenge free radicals that can damage macromolecules, including DNA (46, 47); (2) interfere with biotransformation enzymes and efflux transporters, possibly preventing the activation of procarcinogenic chemicals and promoting their excretion from the body (48, 49); (3) regulate proliferation, DNA repair, or activation of pathways leading to apoptosis (programmed cell death) in case of irreversible DNA damage (50); and (4) inhibit tumor invasion and angiogenesis (51, 52).

Biological activities related to neuroprotection and cognitive function

Flavonoids are thought to (1) promote neurogenesis, synaptic growth, and neuron survival in the learning and memory-related brain regions (e.g., hippocampus) by stimulating the production of neurotrophins like BDNF; (2) protect hippocampal cells and striatal dopaminergic cells from cytotoxic molecules (pro-inflammatory mediators and ROS) released by abnormally activated microglia and hypertrophic astrocytes in neurodegenerative disorders; (3) reduce neuroinflammation by inhibiting the generation of pro-inflammatory cytokines, lipid mediators, and reactive oxygen species by astrocytes and microglial cells; (4) stimulate the production of nitric oxide (NO), which improves endothelial function, increases cerebral blood flow, and protects artery walls against the buildup of atherosclerotic plaques (reviewed in 53, 54).

Disease Prevention

Cardiovascular disease

Several prospective cohort studies conducted in the US and Europe have examined the relationship between some measure of dietary flavonoid intake and cardiovascular disease (CVD) or mortality. A recent meta-analysis of 14 prospective studies published between 1996 and 2012 reported that higher intakes in each flavonoid subclass were significantly associated with a reduced risk of cardiovascular events (55). Top versus bottom quantiles of intake for each of the flavonoid subclasses were associated with an approximate 10% reduction in the risk of CVD. Another meta-analysis of eight prospective studies found a 14% reduced risk of stroke with the highest versus lowest quintile of flavonol intakes (56). However, several serious limitations highlighted in a recent publication by Jacques et al. suggested caution when interpreting these results (57). In particular, most of the prospective studies in these meta-analyses did not include all flavonoid subclasses nor calculate intakes using the latest and more complete versions of the USDA databases for the flavonoid content of foods (58-60). Another major concern is the lack of adjustment regarding the overall quality of the diet. Consumers with higher flavonoid intakes are likely to have a greater consumption of fruit and vegetables and overall healthier diets than those with poor flavonoid intakes. Additionally, none of the studies excluded potential bias due to constituents of flavonoid-rich foods that are known to either lower (e.g., other phytochemicals, vitamins, dietary fiber) or increase (e.g., sodium, saturated fat) the risk of cardiovascular events (discussed in 57).

In the Framingham Offspring Cohort study that followed 2,880 adults for a mean of 14.9 years, consumption of all flavonoid subclasses except flavones and flavanones was inversely associated with CVD (57). Yet, adjusting for confounding factors, including fruit and vegetable intake and overall diet quality, attenuated these relationships such that they were no longer statistically significant. An analysis of a larger prospective study of the EPIC-Norfolk cohort (24,885 participants) that considered confounding by many dietary factors (vitamin C, dietary fiber, fat, saturated fat, potassium, sodium, and alcohol) found no significant association between flavan-3-ol intake and CVD-related or all-cause mortality (61).

A number of large prospective studies and small-scale, randomized controlled trials have investigated the effects of flavonoids on established biomarkers of CVD, including those involved in oxidative stress, inflammation, abnormal blood lipid profile, endothelial dysfunction, and hypertension; some of these studies are highlighted below.

Biochemical markers of cardiovascular disease

In a cross-sectional analysis of the Framingham Offspring Cohort study, the highest versus lowest intake of anthocyanins (≤3.5 mg/day versus ≥23.5 mg/day) was associated with lower concentrations of acute-phase reactant proteins (-100%), pro-inflammatory cytokines (-75%), and markers of oxidative stress (-52%), even after adjustment for confounding variables (62). Interestingly, a food-based analysis revealed that intakes of foods rich in anthocyanins, e.g., apples, red wine, and strawberries, were also inversely associated with an overall inflammation score based on 12 different biomarkers. Higher intakes of polymeric flavan-3-ols (i.e., theaflavins, thearubigins, and proanthocyanidins) were correlated with lower concentrations of pro-inflammatory cytokines and biomarkers of oxidative stress. Intake levels of total flavonoids and flavan-3-ol monomers (i.e., catechins) were inversely associated with concentrations of the biomarkers of oxidative stress. Although tea is a major source of flavan-3-ols, tea consumption was not correlated with the composite inflammation score or any components of this score in this study (62).

Cocoa is another source of flavan-3-ols, in particular (-)-epicatechin and procyanidins, that may provide cardiovascular benefits (63). Indeed, a recent randomized, double-blind, placebo-controlled study in 100 healthy adults (ages, 35-60 years) suggested that short-term benefits of cocoa flavan-3-ol consumption on cardiovascular health, including improvements in lipoprotein profile (i.e., higher HDL-cholesterol and lower total and LDL-cholesterol) and blood pressure, could be extrapolated to predict a 20%-30% reduced 10-year risk of CVD and CVD-related mortality (64).

An increasing number of trials in which participants were fed with berries (65-67) or juices (68) rich in anthocyanins or with purified anthocyanins (69) also reported reduced levels of inflammatory markers and/or improved antioxidant status, decreased LDL-cholesterol, improved insulin sensitivity, and lowered blood pressure (reviewed in 70). In a randomized, double-blind, placebo-controlled study in 150 individuals with hypercholesterolemia, supplementation with a purified anthocyanin mixture (320 mg/day) for 24 weeks reduced circulating markers of inflammation, including C-reactive protein (CRP), interleukin-1β (IL-1β), and soluble vascular adhesion molecule-1 (sVCAM-1) (71). Supplementation of dyslipidemic patients for 12 or 24 weeks with a mixture of 17 anthocyanins improved cholesterol clearance via the HDL-mediated reverse cholesterol transport from extra-hepatic tissues back to the liver and lowered LDL-cholesterol compared to a placebo in two randomized controlled trials (72, 73). However, a 12-week, randomized, double-blind, placebo-controlled study in 52 healthy postmenopausal women found that daily consumption of 500 mg of elderberry anthocyanins (as cyanidin-3-glucoside) had no effect on inflammation markers, markers of vascular health, lipid profile, and glycemia; all of these measures were in normal range of concentrations at baseline (74). Whether exposure to high-dose anthocyanins could lower the risk of CVD in subjects with established CVD risk factors and/or help maintain cardiovascular health in apparently healthy individuals remains to be confirmed.

Endothelial dysfunction

The vascular endothelial cells that line the inner surface of all blood vessels synthesize an enzyme, endothelial nitric oxide synthase (eNOS), whose function is essential to normal vascular physiology. Specifically, eNOS produces nitric oxide (NO), a compound that regulates vascular tone and blood flow by promoting the relaxation (vasodilation) of all types of blood vessels, including arteries (75). NO also regulates vascular homeostasis and protects the integrity of the endothelium by inhibiting vascular inflammation, leukocyte adhesion, platelet adhesion and aggregation, and proliferation of vascular smooth muscle cells (76). In the presence of cardiovascular risk factors (e.g., hypertension, hypercholesterolemia, hyperglycemia), early alterations in the structure and function of the vascular endothelium are associated with the loss of normal NO-mediated endothelium-dependent vasodilation. Endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities and is considered to be an early step in the development of atherosclerosis. Measures of brachial flow-mediated dilation (FMD), a surrogate marker of endothelial function, have been found to be inversely associated with risk of future cardiovascular events (77).

Preclinical studies have demonstrated the benefits of berry fruits, extracts, or purified anthocyanins on vascular function. Anthocyanin supplementation to diabetic mice was found to improve diabetes-induced vascular dysfunction by promoting NO-mediated endothelium-dependent vasodilation through the upregulation of adipocyte-derived adiponectin (78). Supplementation with purified anthocyanins (320 mg/day for 12 weeks) also increased serum adiponectin concentrations and improved FMD in 58 individuals with type 2 diabetes (78). In a randomized trial of 150 participants with hypercholesterolemia, supplemental anthocyanins increased FMD values by 28.4% compared to 2.2% in the placebo group (79).

Several small-scale, intervention studies have also examined the effect of flavan-3-ol-rich food and beverages, including tea, red wine, purple grape juice, cocoa, and chocolate, on endothelium-dependent vasodilation. A meta-analysis of nine intervention studies in a total of 213 participants estimated that the acute ingestion of 2 to 3 cups of tea (500 mL) — containing about 248 mg of flavonoids in green tea and 415 mg in black tea — significantly increased brachial FMD (see also the article on Tea) (80). Another meta-analysis of 18 randomized controlled studies found that acute (2 h post-ingestion) and chronic (≤18 months) consumption of flavan-3-ol-rich cocoa beverages and chocolate bars significantly increased FMD in participants (81). A small 15-day, cross-over intervention study in hypertensive individuals with endothelial dysfunction found that 100 g/day of flavan-3-ol-rich dark chocolate, but not 90 g/day of flavan-3-ol-free white chocolate, could restore FMD values almost to normal levels (82). Also, using a similar protocol, the authors showed that dark chocolate intake blunted acute endothelial dysfunction-induced by a glucose load challenge in 12 healthy volunteers (83). Other benefits of dark chocolate consumption included reductions in arterial stiffness (measured through pulse wave analysis) and serum concentrations of markers of oxidative stress and vasoconstriction (8-isoprostaglandin F2α and endothelin-1). A randomized controlled trial in overweight and obese participants also reported that the daily consumption of a high-flavan-3-ol cocoa drink (902 mg/day of flavan-3-ols), but not that of a cocoa drink low in flavan-3-ols (38 mg/day), resulted in a sustained increase in FMD during the 12-week study (84). A more recent four-week, randomized, double-blind, cross-over, controlled study in healthy overweight or obese adults found that the consumption of 22 g/day of natural cocoa (in the form of dark chocolate bar and cocoa drink; 814 mg/day of flavan-3-ols) increased arterial diameter and blood flow and lowered peripheral arterial stiffness, but there was no change in FMD (85). Another recent clinical trial found improvements in endothelium-dependent vasodilation in response to acute consumption of one bar (40 g) of dark chocolate (containing 10.8 mg of (+)-catechins and 36 mg of (-)-epicatechins) and daily consumption of two bars (80 g) for up to four weeks in 20 individuals with chronic heart failure (86). Oral administration of pure flavan-3-ol (-)-epicatechin to healthy volunteers showed NO-dependent vasodilatory effects similar to those observed following flavan-3-ol-rich cocoa ingestion (87). Administration of (-)-epicatechin also improved acetylcholine-induced endothelial-dependent vasodilation of thoracic aorta rings from rats with salt-induced hypertension (88).

Endothelial nitric oxide production also inhibits the adhesion and aggregation of platelets, one of the first steps in atherosclerosis and blood clot formation (76). A number of clinical trials that examined the potential for high flavonoid intakes to decrease various measures of platelet function outside of the body (ex vivo) have reported mixed results. A recent systematic review of these intervention studies suggested that consumption of flavan-3-ol-rich cocoa and grape seed extract was generally found to improve platelet function by inhibiting platelet adhesion, activation, and aggregation (89). Interestingly, in a cross-over, controlled study, the acute consumption of a flavan-3-ol-rich cocoa beverage (897 mg of total (-)-EC and procyanidins) exhibited additive anti-platelet effects to aspirin (81 mg) in healthy volunteers (90). In contrast, the results of interventions using apigenin-rich soup, quercetin-rich supplements or onion soups, isoflavone-rich soy protein isolates, black tea, wines, berries, or grape juices have given inconsistent results (reviewed in 89).

Hypertension

A meta-analysis of 20 short-term, randomized controlled trials, including a total of 856 mainly healthy participants, found that consumption of flavan-3-ol-rich dark chocolate and cocoa products significantly reduced systolic blood pressure by 2.77 mm Hg and diastolic blood pressure by 2.20 mm Hg. However, heterogeneity across studies was high, and risk of bias was significant (91). A greater blood pressure-reducing effect was observed in a subanalysis of studies using flavan-3-ol-free rather than flavan-3-ol-low control groups (91). Another meta-analysis of 22 trials (highly heterogeneous) found reductions in diastolic blood pressure (-1.60 mm Hg) and mean arterial pressure (-1.64 mm Hg) with chocolate or cocoa intake but no change in systolic blood pressure (81). Additionally, green tea flavan-3-ols have been shown to lower blood pressure especially in (pre-) hypertensive subjects. A pooled analysis of 13 randomized controlled trials in 1,040 subjects found a 2.05 mm Hg reduction in systolic blood pressure and a 1.71 mm Hg reduction in diastolic blood pressure with green tea consumption for at least three weeks (92). The inhibition of angiotensin-converting enzyme (ACE), a key regulator of arterial blood pressure, may partly explain how flavan-3-ol-rich food and beverages might exert blood pressure-lowering effects (93).

Some intervention trials have also examined the effect of the flavonol quercetin on blood pressure in human subjects. In a randomized, double-blind, cross-over, placebo-controlled trial in 96 participants diagnosed with metabolic disorders, supplementation with 150 mg/day of quercetin aglycone significantly reduced systolic blood pressure by 2.6 mm Hg without affecting diastolic blood pressure and other cardiometabolic markers (94). Similar results were found with 730 mg/day of quercetin in hypertensive individuals (95) and with 500 mg/day of quercetin in women with type 2 diabetes mellitus (96). In a recent six-week, cross-over, randomized, double-blind, placebo-controlled trial, daily ingestion of 162 mg of quercetin decreased 24 h-ambulatory blood pressure — but not systolic blood pressure in the resting state — in hypertensive but not in pre-hypertensive participants (97). There was no change in biomarkers of lipid metabolism, inflammation, oxidative stress, or endothelial function, including total, HDL-, LDL-cholesterol, serum CRP, soluble adhesion molecules, plasma oxidized LDL, urinary 8-isoprostaglandin F2α, serum endothelin-1, serum ACE, and plasma endogenous NOS inhibitor.

Additional trials may help establish whether the blood pressure-lowering effect of some flavonoids could be translated into long-term benefits for cardiovascular health.

Type 2 diabetes mellitus

The association between flavonoid consumption and risk for type 2 diabetes mellitus has been examined in a recent European, multicenter, nested case-control study — the "EPIC-InterAct" project — that included 16,835 diabetes-free participants and 12,043 diabetics. In this study, participants in the highest quintile of total flavonoid intake (>608.1 mg/day) had a 10% lower risk of diabetes than those in the lowest quintile (<178.2 mg/day) (98). Specifically, the risk of diabetes was inversely correlated with the intake of flavan-3-ols (monomers and dimers only) and flavonols (98, 99). Recent meta-analyses of randomized controlled trials have examined the possible health effects of green tea flavan-3-ol monomers (catechins) on glucose metabolism and have provided conflicting results. A meta-analysis of seven trials in pre-diabetic and diabetic patients found no effect of green tea or green tea extracts on fasting plasma glucose, fasting serum insulin, or measures of glycemic control (glycated hemoglobin, HbA1c) and insulin sensitivity (HOMA-IR) (100). Conversely, another meta-analysis of 17 trials in pre-diabetic, diabetic, or overweight/obese subjects found that administration of green tea extracts for 4 to 16 weeks improved fasting plasma glucose and HbA1c level (101). The effect on fasting glucose was observed only with high doses of catechins (≥457 mg/day) and when the confounding effect of caffeine was removed. Finally, a third meta-analysis of 25 trials found that ingestion of green tea extracts for at least two weeks could lower fasting blood glucose in both the presence or absence of caffeine (102).

Dark chocolate is another good source of flavan-3-ols such that the effects of cocoa flavan-3-ols have been examined in individuals at-risk or with established type 2 diabetes. In a 15-day, cross-over, randomized controlled study, the daily consumption of 100 g of dark chocolate bars containing 110.9 mg of (-)-EC and 36.1 mg of (+)-C significantly improved measures of pancreatic β-cell function and insulin sensitivity, along with cardiometabolic markers in glucose-intolerant and hypertensive subjects (103). Daily supplementation with flavonoid-enriched chocolate containing 850 mg of flavan-3-ols and 100 mg of isoflavones for one year significantly improved insulin sensitivity and reduced a predicted risk of coronary heart disease (CHD) at 10 years in 93 postmenopausal women treated for type 2 diabetes (104).

The EPIC-InterAct study did not find any association between dietary anthocyanin intake and risk of diabetes (98, 99). Yet, a 10-fold increase in anthocyanin consumption was correlated with a 15% lower risk of diabetes in the pooled analysis of three large US prospective cohorts (120,003 participants) (105). Of note, this pooled analysis also reported a moderately higher risk of diabetes (+6%) in individuals in the highest versus lowest quintiles of flavone and flavanone intakes. Moreover, the consumption of berries, rich in anthocyanins, has been shown to trigger favorable glycemic responses in type 2 diabetics (reviewed in 70). In recent intervention studies, anthocyanins demonstrated beneficial effects on metabolic abnormalities in patients at-risk or diagnosed with diabetes. In an eight-week, randomized, double-blind, placebo-controlled trial in 38 healthy overweight and obese subjects, the consumption of 2 g/day of grape polyphenols rich in proanthocyanidins and anthocyanins prevented increases in oxidative stress and insulin resistance induced by a six-day, high-fructose challenge (106). Another six-week randomized trial in individuals with diabetes showed that daily supplementation with Cornelian cherry (Cornus mas) extracts containing 600 mg of anthocyanins significantly lowered serum levels of HbA1c and triglycerides and increased serum insulin concentrations (107). The administration of 320 mg/day of anthocyanins for 24 weeks also improved serum lipid and lipoprotein profile, decreased markers of oxidative stress and inflammation, elevated antioxidant capacity, and reduced insulin resistance compared to a placebo in patients with diabetes (108). Further, supplemental anthocyanins up-regulated adiponectin expression and improved nitric oxide-mediated endothelium-dependent vasodilation within 12 weeks of treatment (see also Cardiovascular disease) (78).

These promising findings warrant additional randomized controlled trials to confirm preventive and/or therapeutic benefits of (cocoa) flavan-3-ols and anthocyanins in type 2 diabetes.

Cancer

Although various flavonoids have been found to inhibit the development of chemically-induced cancers in animal models of lung (109), oral (110), esophageal (111), gastric (112), colon (113), skin (114), prostate (115, 116), and mammary cancer (117), observational studies do not provide convincing evidence that high intakes of dietary flavonoids are associated with substantial reductions in human cancer risk (reviewed in 118). A meta-analysis of 13 case-control and 10 prospective cohort studies found little-to-no evidence to support a preventive role of dietary flavonoid intake in gastric and colorectal cancer (119). In addition, a recently published analysis of two large prospective studies (the Health Professionals Follow-up Study [HPFS] and the Nurses’ Health Study [NHS]) — using the most up-to-date flavonoid food composition databases — found no association between the risk of colorectal cancer and intakes of each subclass of flavonoids or flavonoid-rich foods (tea, blueberries, oranges) (120). A meta-analysis of 19 case-control studies and 15 cohort studies found that total flavonoid intake and intakes of specific flavonoid subclasses (i.e., flavonols, flavones, flavanones) were inversely correlated with the risk of smoking-sensitive cancers of the aerodigestive tract (mouth, pharynx, larynx, esophagus, and stomach) in smokers but not in nonsmokers (121). The risk of lung cancer was not significantly associated with high flavonoid intakes (121), although an earlier meta-analysis of eight prospective studies (with substantial heterogeneity across them) suggested a protective role of flavonoids against lung cancer in smokers only (122). Further, a prospective analysis of over 45,000 postmenopausal women from the Multiethnic Cohort Study found a reduced risk of endometrial cancer with the highest intakes of total isoflavones, daidzein, and genistein (123). Additionally, limited evidence from observational studies suggests no relationship between total flavonoid intake and ovarian cancer (124-127). To date, there is little evidence that flavonoid-rich diets might protect against various cancers, but larger prospective cohort studies are needed to address the association.

Hormone-dependent cancers

Because isoflavones are phytoestrogens, it is thought that they may interfere with the synthesis and activity of endogenous hormones, eventually influencing hormone-dependent signaling pathways and protecting against breast and prostate cancers (128). A meta-analysis of 14 observational studies that examined breast cancer incidence in 369,934 women found an overall 11% reduced risk of breast cancer with the highest versus lowest intake of soy isoflavones (129). Subgroup analyses revealed a 24% lower risk of cancer in Asian but not in European or US women, and the risk was 22% lower in postmenopausal but not lower in premenopausal women. In addition to the ethnicity and menopausal status, polymorphisms for hormone receptors (130) and phase I biotransformation enzymes (131) have been found to modify the association between isoflavone intake and breast cancer. Another recent meta-analysis of 12 observational studies (six prospective cohort studies, one nested case-control study, and five case-control studies) investigated the chemopreventive effects of flavonoids (except isoflavones) (132). The results suggested that intakes of flavonols and flavones may also be inversely associated with the risk of breast cancer. Further, a pooled analysis of four case-control studies that stratified by menopausal status showed inverse associations between breast cancer and intakes of flavonols, flavones, or flavan-3-ols in postmenopausal women only. Finally, a meta-analysis of four prospective cohort studies found an overall 16% reduced risk of breast cancer recurrence in women with high versus low isoflavone intakes (129).

A meta-analysis of 13 observational studies also suggested an inverse relationship between prostate cancer risk and consumption of soy products, especially tofu (133). Yet, further analyses supported a protective role of soy food based only on case-control studies, which have inherent flaws such that associations may often be overestimated or underestimated. In a recent 12-month, multicenter, randomized, double-blind, placebo-controlled phase II clinical trial in 158 Japanese men (aged ≥50 years) with elevated risk of prostate cancer, oral isoflavone (60 mg/day) resulted in a significant decrease in prostate cancer incidence in participants aged 65 years and older (134). In this study, no changes were reported in sex hormone concentrations in blood, suggesting that isoflavones may reduce prostate cancer incidence without interfering with hormone-dependent pathways.

Additional investigations will be necessary to determine whether supplementation with specific flavonoids could benefit cancer prevention or treatment.

For more information on flavonoid-rich foods and cancer, see articles on Fruit and Vegetables, Legumes, and Tea.

Cognitive function

Inflammation, oxidative stress, and transition metal accumulation appear to play a role in the pathology of several neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease (135). Therefore, the various properties of flavonoids, including their role in protecting vascular health, could have beneficial effects on the brain, possibly in the protection against cerebrovascular disorders, cognitive impairments, and subsequent stroke and dementias. Dietary flavonoids and/or their metabolites have been shown to cross the blood-brain barrier (54) and exert preventive effects towards cognitive impairments in animal models of normal and pathological aging (53).

The cross-sectional data analysis of 2,031 participants (ages, 70-74 years) from the Hordaland Health Study in Norway indicated that, when compared to non-consumers, consumers of flavonoid-rich chocolate, tea, and wine had better global cognitive function, assessed by a battery of six cognitive tests (136). The risk of poor performance in all tests was estimated to be 60 to 74% lower in consumers of all three flavonoid-rich foods compared to non-consumers. An early prospective cohort study in 1,367 older French men and women (aged ≥65 years; free from dementia at baseline) found that those with the lowest flavonoid intakes (<11.5 mg/day) had a 50% higher risk of developing dementia over the next five years than those with higher intakes (137). In addition, those with higher dietary flavonoid intakes at baseline experienced significantly less age-related cognitive decline over a 10-year period than those with the lowest flavonoid intakes (138).

The effect of cocoa flavan-3-ols have been investigated in an eight-week, randomized, double-blind trial — the Cognitive, Cocoa, and Aging (CoCoA) study — in 90 individuals (ages, 64-82 years) with mild cognitive impairments (MCI); participants were given dairy-based cocoa drinks with either high (993 mg/day) or low (48 mg/day) levels of flavan-3-ols (139). The daily consumption of the cocoa drink high in flavan-3-ols improved some, but not all, measures of cognitive process speed and flexibility and verbal fluency compared to baseline test scores and scores following low flavan-3-ol drink consumption. A composite test score reflecting overall cognitive performance was found to be significantly greater in those given cocoa drinks high rather than low in flavan-3-ols. The study also reported reductions in cardiovascular risk markers (i.e., systolic and diastolic blood pressure, total and LDL-cholesterol, insulin resistance), and these changes were proposed to partly contribute to ameliorate cognitive performance in those who consumed the flavan-3-ol-rich cocoa drink (139). The data could be replicated in cognitively healthy older people (ages, 61-85 years), suggesting that cocoa flavan-3-ols might enhance some aspects of cognitive function during healthy aging (140). Interestingly, a two-week, randomized, double-blind, controlled study has reported an increase in blood flow velocity in the middle cerebral artery of 21 healthy subjects (mean age, 72 years) following the daily intake of a flavan-3-ol-rich cocoa drink (900 mg/day of flavan-3-ols) (141). Because cerebral blood flow is correlated with cognitive function in humans, these preliminary data suggest that cocoa flavan-3-ol consumption could exert a protective effect against dementia (54).

Yet, in other randomized controlled trials (142-144), the lack of an effect of cocoa flavan-3-ols on blood pressure, cerebral blood flow, mental fatigue, and cognitive performance in healthy young and old adults suggested that benefits may only be seen in very demanding cognitive exercises (145).

Some randomized controlled studies also reported improvements in measures of cognitive function in healthy and cognitively impaired subjects with other flavonoid subclasses, including anthocyanins (146), flavanones (147, 148), and isoflavones (149, 150). Although some flavonoids and flavonoid-rich foods may enhance cognitive function in the aging brain, it is not yet clear whether their consumption could lower the risk of cognitive impairments and dementia in humans.

For more detailed information on flavan-3-ol-rich tea and cognitive function, see the article on Tea.

Sources

Food sources

Recent data analyses of the National Health and Nutrition Examination Survey (NHANES) estimated flavonoid intakes in US adults (aged ≥19 years) average between 200 and 250 mg/day, with 80% being flavan-3-ols, 8% for flavonols, 6% for flavanones, 5% for anthocyanidins, and ≤1% for isoflavones and flavones (151, 152). The main dietary sources of flavonoids include tea, citrus fruit, citrus fruit juices, berries, red wine, apples, and legumes. Individual flavonoid intakes may vary considerably depending on whether tea, red wine, soy products, or fruit and vegetables are commonly consumed (reviewed in 2). Information on the flavonoid content of some flavonoid-rich foods is presented in Tables 2-8. These values should be considered approximate since a number of factors may affect the flavonoid content of foods, including agricultural practices, environmental conditions, ripening, storage, and food processing. For additional information about the flavonoid content of food, the USDA provides databases for the content of selected foods in flavonoids (60) and proanthocyanidins (58). For more information on the isoflavone content of soy foods, see the article on Soy Isoflavones or the USDA database for the isoflavone content of selected foods (59).

Table 2. Anthocyanidin Content of Anthocyanidin-rich Foods (mg/100 g or 100 mL*)
Food Anthocyanidins
Cyanidin Delphinidin Malvidin Pelargonidin Peonidin Petunidin
Blackberries, raw  100  0  0  <1  <1  0
Blood orange juice  5.5  <1  -  -  <1  -
Blueberries, raw  8.5  35.4  67.6  0  20.3  31.5
Currants, black, raw  62.5  89.6  -  1.2  <1  3.9
Elderberries, raw  485.3  0  -  <1  -  0
Grapes, red  1.2  2.3 39  <1  3.6  2
Onions, red, raw  3.2  4.3  -  <1  2.1 -
Plums, raw  5.6  0  0  0  <1  0
Radishes, raw  0  0  0 63.1  0  0
Raspberries, raw 45.8 1.3 <1 1 <1 <1
Red cabbage, raw 209.8 <1 - <1 - -
Strawberries, raw 1.7 <1 <1 24.9 <1 <1
Wine, red, Shiraz - 9.3 121.6 - 7.8 14.2
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
 
Table 3. Flavan-3-ol Content of Flavan-3-ol-rich Foods (mg/100 g or 100 mL*)
Food Flavon-3-ol Monomers# and Thearubigins
C GC EC ECG EGC EGCG Thearubigins
Apples, Red Delicious, raw, with skin 2  0 9.8  0 <1  <1  -
Apricots, raw 3.7 0 4.7 0 0 0 -
Chocolate, dark  24.2 -  84.4 - -  - -
Tea, black, brewed 1.5 1.2 2.1 5.9  8 9.4 81.3
Tea, green, brewed 4.5 1.5 8.3 17.9 29.2  70.2 1.1
Tea, oolong, brewed  <1 - 2.5  6.3 6.1 34.5 -
Tea, white, brewed  -  -  -  8.3  18.6  42.4 -
Wine, red, Shiraz  6.8 - 10 - - - -
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
#Catechins: C, (+)-catechin; GC, (-)-gallocatechin; EC (-)-epicatechin; ECG, (-)-epigallocatechin; ECG, (-)-epicatechin gallate; EGCG, (-)-epigallocatechin gallate.
 
Table 4. Proanthocyanidin Content of Flavan-3-ol-rich Foods (mg/100 g or 100 mL*)
Food Proanthocyanidins (Flavon-3-ol Polymers)
Monomers Dimers Trimers ≥4mers
Apples, Red Delicious, raw, with skin 8.3 15.1 10.1 94.2
Baking chocolate, unsweetened 198.5 206.5 130.9 1,100
Cocoa, dry powder, unsweetened 316.6 183.5 159.5 713.4
Cranberries, raw 7.3 25.9 18.9 385.6
Currants, black, raw <1 2.9 3 142.9
Grapes, red, raw 1.4 2.4 1 56.9
Nuts, pecan 17.2 42.1 26 408.6
Nuts, pistachio 10.9 13.3 10.5 202.6
Peaches, yellow, with peel, raw 4.5 12.2 4.4 50.6
Plums, with peel, raw 10.9 38.5 22.2 149.1
Spices, cinnamon, ground 23.9 256.3 1252.2 6,576
Strawberries, raw 3.7 5.3 4.9 127.8
Wine, table, red 16.6 20.5 1.8 22.7
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
 
Table 5. Flavonol Content of Flavonol-rich Foods (mg/100 g or 100 mL*)
Food Flavonols
Isorhamnetin Kaempferol Myricetin Quercetin
Blueberries, raw - 1.7 1.3 7.7
Broccoli, raw - 7.8 <1 3.3
Chili peppers, green, raw - 0 1.2 14.7
Cowpea, black seeds, raw - 1.9 2.7 17.2
Kale, raw 23.6 46.8 0 22.6
Onions, red, raw 4.6 <1 2.2 39.2
Parsley, fresh 0 1.5 14.8 <1
Rocket, wild, raw <1 1.8 - 66.2
Scallions, raw - 1.4 0 10.7
Spinach, raw - 6.4 <1 4
Tea, black, brewed - 1.4 <1 2.2
Tea, green, brewed - 1.3 1 2.5
Watercress, raw 0 23 <1 30
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
 
Table 6. Flavone Content of Flavone-rich Foods (mg/100 g or 100 mL*)
Food Flavones
Apigenin Luteolin
Celery hearts, green 19.1 3.5
Celery, raw 2.8 1
Chili peppers, green, raw 1.4 3.9
Oregano, fresh 2.6 1
Parsley, fresh 215.5 1.1
Peppermint, fresh 5.4 12.7
Thyme, fresh 2.5 45.2
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
 
Table 7. Flavanone Content of Flavanone-rich Foods (mg/100 g or 100 mL*)
Food Flavanones
Eriodictyol Hesperetin Naringenin
Grapefruit juice, white, fresh <1 2.3 18.2
Grapefruit, white, raw - <1 21.3
Lemon juice, fresh 4.9 14.5 1.4
Lemon, raw 21.4 27.9 <1
Orange juice, fresh <1 12 2.1
Orange, raw - 27.2 15.3
Pummelo juice, fresh 2.9 1.8 25.3
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
 
Table 8. Isoflavone Content of Isoflavone-rich Foods (mg/100 g or 100 mL*)
Food Isoflavones
Diadzein Genistein Glycitein
Black bean sauce 6 4 <1
Natto 33.2 37.7 10.5
Soybeans, mature seeds, raw 62.1 81 15
Soymilk, low-fat 1 1.5 <1
Tofu, firm, cooked 10.3 10.9 1.3
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.

Supplements

Anthocyanins

Bilberry, elderberry, black currant, blueberry, red grape, and mixed berry extracts that are rich in anthocyanins are available as dietary supplements without a prescription in the US. The anthocyanin content of these products may vary considerably. Standardized extracts that list the amount of anthocyanins per dose are available.

Flavan-3-ols

Numerous tea extracts are available in the US as dietary supplements and may be labeled as tea catechins or tea polyphenols. Green tea extracts are the most commonly marketed, but black and oolong tea extracts are also available. Green tea extracts generally have higher levels of catechins (flavan-3-ol monomers), while black tea extracts are richer in theaflavins and thearubigins (tea flavan-3-ol dimers and polymers, respectively). Oolong tea extracts fall somewhere in between green and black tea extracts with respect to their flavan-3-ol content. Some tea extracts contain caffeine, while others are decaffeinated. Flavan-3-ol and caffeine content vary considerably among different products, so it is important to check the label or consult the manufacturer to determine the amounts of flavan-3-ols and caffeine that would be consumed daily with each supplement (for more information on tea flavan-3-ols, see the article on Tea).

Flavanones

Citrus bioflavonoid supplements may contain glycosides of hesperetin (hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin is also available in hesperidin-complex supplements, with daily doses from 500 mg to 2 g (153).

Flavones

The peels and tissues of citrus fruit (e.g., oranges, tangerines, and clementines) are rich in polymethoxylated flavones: tangeretin, nobiletin, and sinensetin (2). Although dietary intakes of these naturally occurring flavones are generally low, they are often present in citrus bioflavonoid complex supplements. Several dietary supplements may also contain various amounts of baicalein (aglycone) and/or baicalin (glycoside). Some tea preparations may also include baicalein-7-glucuronide (153).

Flavonols

The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the US. Other names for rutin include rutoside, quercetin-3-rutinoside, and sophorin (153). Citrus bioflavonoid supplements may also contain quercetin or rutin.

Isoflavones

A 50-mg soy isoflavone supplement usually includes glycosides of the isoflavones: genistein (genistin; 25 mg), daidzein (daidzin; 19 mg), and glycitein (glycitin; about 6 mg). Smaller amounts of daidzein, genistein, and formononetin are also found in biochanin A-containing supplements (derived from red clover) (153).

Safety

Adverse effects

No adverse effects have been associated with high dietary intakes of flavonoids from plant-based food. This lack of adverse effects may be explained by the relatively low bioavailability and rapid metabolism and elimination of most flavonoids.

Quercetin

Oral supplementation with quercetin glycosides at doses ranging between 3 mg/day-1,000 mg/day for up to three months has not resulted in significant adverse effects in clinical studies (reviewed in 154). A randomized, placebo-controlled study in 30 patients with chronic prostatitis reported one case of headache and another of tingling of the extremities associated with supplemental quercetin (1,000 mg/day for one month); both issues resolved after the study ended (155). In a phase I clinical trial in cancer patients unresponsive to standard treatments, administration of quercetin via intravenous infusion resulted in symptoms of nausea, vomiting, sweating, flushing, and dyspnea (difficulty breathing) at doses ≥10.5 mg/kg body weight (~756 mg of quercetin for a 70 kg individual) (156). Higher doses up to 51.3 mg/kg body weight (~3,591 mg of quercetin) were associated with renal (kidney) toxicity, yet without evidence of nephritis, infection, or obstructive uropathy (reviewed in 154).

Cocoa flavan-3-ols

In a recent randomized, double-blind, controlled study in healthy adults, the daily intake of 2 g of cocoa flavan-3-ols for 12 weeks was found to be well tolerated with no adverse side effects (157).

Tea extracts

In clinical trials employing caffeinated green tea extracts, cancer patients who took 6 g/day in three to six divided doses reported mild-to-moderate gastrointestinal side effects, including nausea, vomiting, abdominal pain, and diarrhea (158, 159). Central nervous system symptoms, including agitation, restlessness, insomnia, tremors, dizziness, and confusion, have also been reported. In one case, confusion was severe enough to require hospitalization (158). In a systematic review published in 2008, the US Pharmacopeia (USP) Dietary Supplement Information Expert Committee identified 34 adverse event reports implicating the use of green tea extract products (containing 25%-97% of polyphenols) as the likely cause of liver damage (hepatotoxicity) in humans (160). In a four-week clinical trial that assessed the safety of decaffeinated green tea extracts (800 mg/day of EGCG) in healthy individuals, a few of the participants reported mild nausea, stomach upset, dizziness, or muscle pain (161). In the Minnesota Green Tea Trial (MGTT), 1,075 postmenopausal women were randomized to receive green tea extracts (1,315±116 mg/day of catechins; the equivalent of four 8-ounce mugs of brewed decaffeinated green tea) or a placebo for one year. The total number of adverse events and the number of serious adverse events were not different between the treatment and placebo groups (162). However, the use of green tea extracts was directly associated with abnormally high liver enzyme levels in 7 out of the 12 women who experienced serious adverse events. Also, the incidence of nausea was twice as high in the green tea arm as in the placebo group (162).

Pregnancy and lactation

The safety of flavonoid supplements in pregnancy and lactation has not been established (153).

Drug interactions

Inhibition of ABC drug transporters

ATP-binding cassette (ABC) drug transporters, including P-glycoprotein, multidrug resistance protein (MRP), and breast cancer-resistant protein (BCRP), function as ATP-dependent efflux pumps that actively regulate the excretion of a number of drugs limiting their systemic bioavailability (8). ABC transporters are found throughout the body, yet they are especially important in organs with a barrier function like the intestines, the blood-brain barrier, blood-testis barrier, and the placenta, as well as in liver and kidneys (163). There is some evidence that the consumption of grapefruit juice inhibits the activity of P-glycoprotein (164). Genistein, biochanin A, quercetin, naringenin, hesperetin, green tea flavan-3-ol (-)-CG, (-)-ECG, and (-)-EGCG, and others have been found to inhibit the efflux activity of P-glycoprotein in cultured cells and in animal models (163). Thus, very high or supplemental intakes of these flavonoids could potentially increase the toxicity of drugs that are substrates of P-glycoprotein, e.g., digoxin, antihypertensive agents, antiarrhythmic agents, chemotherapeutic (anticancer) agents, antifungal agents, HIV protease inhibitors, immunosuppressive agents, H2 receptor antagonists, some antibiotics, and others (reviewed in 165).

Many anthocyanins and anthocyanidins, as well as some flavones (apigenin, chrysin), isoflavones (biochanin A, genistein), flavonols (kaempferol), and flavanones (naringenin), have been identified as inhibitors of BRCP-mediated transport, theoretically affecting drugs like anticancer agents (mitoxantrone, topotecan, thyrosine kinase inhibitors), antibiotics (fluoroquinolones), β-blockers (prazosin), and antiarthritics (sulfasalazine). Finally, flavonols (quercetin, kaempferol, myricetin), flavanones (naringenin), flavones (apigenin, robinetin), and isoflavones (genistein) have been reported to inhibit MRP, potentially affecting MRP-mediated transport of many anticancer drugs, e.g., vincristin, etoposide, cisplatin, irinotecan, methotrexate, camptothecin, anthracyclines, vinca alkaloids (reviewed in 163).

Anticoagulant and antiplatelet drugs

High intakes of flavonoids from purple grape juice (500 mL/day) and dark chocolate (235 mg/day of flavan-3-ols) have been found to inhibit platelet aggregation in ex vivo assays (166-169). Theoretically, high intakes of flavonoids (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin), heparin, dalteparin (Fragmin), enoxaparin (Lovenox), and antiplatelet drugs, such as clopidogrel (Plavix), dipyridamole (Persantine), non-steroidal anti-inflammatory drugs (NSAIDs: diclofenac, ibuprofen, naproxen), aspirin, and others (170).

Inhibition of CYP 3A4 by flavonoid-rich grapefruit

Cytochrome P450 (CYP) enzymes are phase I biotransformation enzymes involved in the metabolism of a broad range of compounds, from endogenous molecules to therapeutic agents. The most abundant CYP isoform in the liver and intestines is cytochrome P450 3A4 (CYP3A4); the CYP3A family catalyzes the metabolism of about one-half of all marketed drugs in the US and Canada (171). One grapefruit or as little as 200 mL (7 fluid ounces) of grapefruit juice have been found to irreversibly inhibit intestinal CYP3A4 (164). The most potent inhibitors of CYP3A4 in grapefruit are thought to be furanocoumarins, particularly dihydroxybergamottin, rather than flavonoids. All forms of the fruit — freshly squeezed juice, frozen concentrate, or whole fruit — can potentially affect the activity of CYP3A4. Some varieties of other citrus fruit (Seville oranges, limes, and pomelos) that contain furanocoumarins can also interfere with CYP3A4 activity.

Specifically, the inhibition of intestinal CYP3A4 by grapefruit consumption is known or predicted to increase the bioavailability and the risk of toxicity of more than 85 drugs. Because drugs with very low bioavailability are more likely to be toxic when CYP3A4 activity is inhibited, they are associated with a higher risk of overdose with grapefruit compared to drugs with high bioavailability. Some of the drugs with low bioavailability include, but are not limited to, anticancer drugs (everolimus); anti-infective agents halofantrine, maraviroc); statins (atorvastatin, lovastatin, and simvastatin); cardioactive drugs (amiodarone, clopidogrel, dronedarone, eplenorone, ticagrelor); HIV protease inhibitors (saquinavir), immunosuppressants (cyclosporine, sirolimus, tacrolimus, everolimus); antihistamines (terfenadine); gastrointestinal agents (domperidone); central nervous system agents (buspirone, dextromethorphan, oral ketamine, lurasidone, quetiapine, selective serotonin reuptake inhibitors [sertraline]); and urinary tract agents (darifenacin) (reviewed in 171). Because of the potential for adverse drug interactions, some clinicians recommend that people taking medications with low bioavailability (i.e., undergoing extensive metabolism by CYP3A4) avoid consuming grapefruit and grapefruit juice altogether during the treatment period (171).

Nutrient interactions

Iron

Flavonoids can bind nonheme iron, inhibiting its intestinal absorption (172, 173). Nonheme iron is the principal form of iron in plant foods, dairy products, and iron supplements. The consumption of one cup of tea or cocoa with a meal has been found to decrease the absorption of nonheme iron in that meal by about 70% (174, 175). Flavonoids can also inhibit intestinal heme iron absorption (176). Interestingly, ascorbic acid greatly enhances the absorption of iron (see the article on Iron) and is able to counteract the inhibitory effect of flavonoids on nonheme and heme iron absorption (173, 176, 177). To maximize iron absorption from a meal or iron supplements, flavonoid-rich food and beverages and flavonoid supplements should not be consumed at the same time.


Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2016 by:
Alan Crozier, Ph.D.
Professor, Department of Nutrition
University of California, Davis

Copyright 2005-2017  Linus Pauling Institute 


References

1.  Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal. 2013; 2013:162750.  (PubMed)

2.  Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727-747.  (PubMed)

3.  Xiao J, Kai G, Yamamoto K, Chen X. Advance in dietary polyphenols as α-glucosidases inhibitors: a review on structure-activity relationship aspect. Crit Rev Food Sci Nutr. 2013;53(8):818-836.  (PubMed)

4.  Rothwell JA, Urpi-Sarda M, Boto-Ordonez M, et al. Systematic analysis of the polyphenol metabolome using the Phenol-Explorer database. Mol Nutr Food Res. 2016;60(1):203-211.  (PubMed)

5.  Lotito SB, Zhang WJ, Yang CS, Crozier A, Frei B. Metabolic conversion of dietary flavonoids alters their anti-inflammatory and antioxidant properties. Free Radic Biol Med. 2011;51(2):454-463.  (PubMed)

6.  Williamson G. Common features in the pathways of absorption and metabolism of flavonoids. In: Meskin MS, R. BW, Davies AJ, Lewis DS, Randolph RK, eds. Phytochemicals: Mechanisms of Action. Boca Raton: CRC Press; 2004:21-33.

7.  Nemeth K, Plumb GW, Berrin JG, et al. Deglycosylation by small intestinal epithelial cell β-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr. 2003;42(1):29-42.  (PubMed)

8.  Gonzales GB, Smagghe G, Grootaert C, Zotti M, Raes K, Van Camp J. Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity. Drug Metab Rev. 2015;47(2):175-190.  (PubMed)

9.  Monagas M, Urpi-Sarda M, Sanchez-Patan F, et al. Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Food Funct. 2010;1(3):233-253.  (PubMed)

10.  Bordenave N, Hamaker BR, Ferruzzi MG. Nature and consequences of non-covalent interactions between flavonoids and macronutrients in foods. Food Funct. 2014;5(1):18-34.  (PubMed)

11.  Zhang H, Yu D, Sun J, et al. Interaction of plant phenols with food macronutrients: characterisation and nutritional-physiological consequences. Nutr Res Rev. 2014;27(1):1-15.  (PubMed)

12.  Xiao J, Mao F, Yang F, Zhao Y, Zhang C, Yamamoto K. Interaction of dietary polyphenols with bovine milk proteins: molecular structure-affinity relationship and influencing bioactivity aspects. Mol Nutr Food Res. 2011;55(11):1637-1645.  (PubMed)

13.  Lorenz M, Jochmann N, von Krosigk A, et al. Addition of milk prevents vascular protective effects of tea. Eur Heart J. 2007;28(2):219-223.  (PubMed)

14.  Roowi S, Stalmach A, Mullen W, Lean ME, Edwards CA, Crozier A. Green tea flavan-3-ols: colonic degradation and urinary excretion of catabolites by humans. J Agric Food Chem. 2010;58(2):1296-1304.  (PubMed)

15.  Setchell KD, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002;132(12):3577-3584.  (PubMed)

16.  Yuan JP, Wang JH, Liu X. Metabolism of dietary soy isoflavones to equol by human intestinal microflora--implications for health. Mol Nutr Food Res. 2007;51(7):765-781.  (PubMed)

17.  Marin L, Miguelez EM, Villar CJ, Lombo F. Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed Res Int. 2015;2015:905215.  (PubMed)

18.  Inoue-Choi M, Yuan JM, Yang CS, et al. Genetic Association Between the COMT Genotype and Urinary Levels of Tea Polyphenols and Their Metabolites among Daily Green Tea Drinkers. Int J Mol Epidemiol Genet. 2010;1(2):114-123.  (PubMed)

19.  Wu AH, Tseng CC, Van Den Berg D, Yu MC. Tea intake, COMT genotype, and breast cancer in Asian-American women. Cancer Res. 2003;63(21):7526-7529.  (PubMed)

20.  Jiang W, Hu M. Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways. RSC Adv. 2012;2(21):7948-7963.  (PubMed)

21.  Xiao J, Kai G. A review of dietary polyphenol-plasma protein interactions: characterization, influence on the bioactivity, and structure-affinity relationship. Crit Rev Food Sci Nutr. 2012;52(1):85-101.  (PubMed)

22.  Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1 Suppl):230S-242S.  (PubMed)

23.  Kroon PA, Clifford MN, Crozier A, et al. How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr. 2004;80(1):15-21.  (PubMed)

24.  Heijnen CG, Haenen GR, van Acker FA, van der Vijgh WJ, Bast A. Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups. Toxicol In Vitro. 2001;15(1):3-6.  (PubMed)

25.  Chun OK, Kim DO, Lee CY. Superoxide radical scavenging activity of the major polyphenols in fresh plums. J Agric Food Chem. 2003;51(27):8067-8072.  (PubMed)

26.  Frei B, Higdon JV. Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr. 2003;133(10):3275S-3284S.  (PubMed)

27.  Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med. 2004;36(7):838-849.  (PubMed)

28.  Lotito SB, Frei B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic Biol Med. 2006;41(12):1727-1746.  (PubMed)

29.  Mira L, Fernandez MT, Santos M, Rocha R, Florencio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res. 2002;36(11):1199-1208.  (PubMed)

30.  Cheng IF, Breen K. On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the Fenton reaction of the iron-ATP complex. Biometals. 2000;13(1):77-83.  (PubMed)

31.  Spencer JP, Rice-Evans C, Williams RJ. Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem. 2003;278(37):34783-34793.  (PubMed)

32.  Spencer JP, Schroeter H, Crossthwaithe AJ, Kuhnle G, Williams RJ, Rice-Evans C. Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radic Biol Med. 2001;31(9):1139-1146.  (PubMed)

33.  Hou Z, Lambert JD, Chin KV, Yang CS. Effects of tea polyphenols on signal transduction pathways related to cancer chemoprevention. Mutat Res. 2004;555(1-2):3-19.  (PubMed)

34.  Lambert JD, Yang CS. Mechanisms of cancer prevention by tea constituents. J Nutr. 2003;133(10):3262S-3267S.  (PubMed)

35.  Espley RV, Butts CA, Laing WA, et al. Dietary flavonoids from modified apple reduce inflammation markers and modulate gut microbiota in mice. J Nutr. 2014;144(2):146-154.  (PubMed)

36.  Kim MC, Kim SJ, Kim DS, et al. Vanillic acid inhibits inflammatory mediators by suppressing NF-kappaB in lipopolysaccharide-stimulated mouse peritoneal macrophages. Immunopharmacol Immunotoxicol. 2011;33(3):525-532.  (PubMed)

37.  Lee SG, Kim B, Yang Y, et al. Berry anthocyanins suppress the expression and secretion of proinflammatory mediators in macrophages by inhibiting nuclear translocation of NF-kappaB independent of NRF2-mediated mechanism. J Nutr Biochem. 2014;25(4):404-411.  (PubMed)

38.  Mauray A, Felgines C, Morand C, Mazur A, Scalbert A, Milenkovic D. Bilberry anthocyanin-rich extract alters expression of genes related to atherosclerosis development in aorta of apo E-deficient mice. Nutr Metab Cardiovasc Dis. 2012;22(1):72-80.  (PubMed)

39.  Wang D, Wei X, Yan X, Jin T, Ling W. Protocatechuic acid, a metabolite of anthocyanins, inhibits monocyte adhesion and reduces atherosclerosis in apolipoprotein E-deficient mice. J Agric Food Chem. 2010;58(24):12722-12728.  (PubMed)

40.  Edirisinghe I, Banaszewski K, Cappozzo J, McCarthy D, Burton-Freeman BM. Effect of black currant anthocyanins on the activation of endothelial nitric oxide synthase (eNOS) in vitro in human endothelial cells. J Agric Food Chem. 2011;59(16):8616-8624.  (PubMed)

41.  Hidalgo M, Martin-Santamaria S, Recio I, et al. Potential anti-inflammatory, anti-adhesive, anti/estrogenic, and angiotensin-converting enzyme inhibitory activities of anthocyanins and their gut metabolites. Genes Nutr. 2012;7(2):295-306.  (PubMed)

42.  Chen XQ, Wang XB, Guan RF, et al. Blood anticoagulation and antiplatelet activity of green tea (-)-epigallocatechin (EGC) in mice. Food Funct. 2013;4(10):1521-1525.  (PubMed)

43.  Ahmad A, Khan RM, Alkharfy KM. Effects of selected bioactive natural products on the vascular endothelium. J Cardiovasc Pharmacol. 2013;62(2):111-121.  (PubMed)

44.  Hanhineva K, Torronen R, Bondia-Pons I, et al. Impact of dietary polyphenols on carbohydrate metabolism. Int J Mol Sci. 2010;11(4):1365-1402.  (PubMed)

45.  Babu PV, Liu D, Gilbert ER. Recent advances in understanding the anti-diabetic actions of dietary flavonoids. J Nutr Biochem. 2013;24(11):1777-1789.  (PubMed)

46.  Delgado ME, Haza AI, Arranz N, Garcia A, Morales P. Dietary polyphenols protect against N-nitrosamines and benzo(a)pyrene-induced DNA damage (strand breaks and oxidized purines/pyrimidines) in HepG2 human hepatoma cells. Eur J Nutr. 2008;47(8):479-490.  (PubMed)

47.  Erba D, Casiraghi MC, Martinez-Conesa C, Goi G, Massaccesi L. Isoflavone supplementation reduces DNA oxidative damage and increases O-β-N-acetyl-D-glucosaminidase activity in healthy women. Nutr Res. 2012;32(4):233-240.  (PubMed)

48.  Moon YJ, Wang X, Morris ME. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro. 2006;20(2):187-210.  (PubMed)

49.  Schwarz D, Kisselev P, Roots I. CYP1A1 genotype-selective inhibition of benzo[a]pyrene activation by quercetin. Eur J Cancer. 2005;41(1):151-158.  (PubMed)

50.  Suh Y, Afaq F, Johnson JJ, Mukhtar H. A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 2009;30(2):300-307.  (PubMed)

51.  Ravishankar D, Watson KA, Boateng SY, Green RJ, Greco F, Osborn HM. Exploring quercetin and luteolin derivatives as antiangiogenic agents. Eur J Med Chem. 2015;97:259-274.  (PubMed)

52.  Santos BL, Oliveira MN, Coelho PC, et al. Flavonoids suppress human glioblastoma cell growth by inhibiting cell metabolism, migration, and by regulating extracellular matrix proteins and metalloproteinases expression. Chem Biol Interact. 2015;242:123-138.  (PubMed)

53.  Sokolov AN, Pavlova MA, Klosterhalfen S, Enck P. Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior. Neurosci Biobehav Rev. 2013;37(10 Pt 2):2445-2453.  (PubMed)

54.  Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JP. The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr. 2008;3(3-4):115-126.  (PubMed)

55.  Wang X, Ouyang YY, Liu J, Zhao G. Flavonoid intake and risk of CVD: a systematic review and meta-analysis of prospective cohort studies. Br J Nutr. 2014;111(1):1-11.  (PubMed)

56.  Wang ZM, Zhao D, Nie ZL, et al. Flavonol intake and stroke risk: a meta-analysis of cohort studies. Nutrition. 2014;30(5):518-523.  (PubMed)

57.  Jacques PF, Cassidy A, Rogers G, Peterson JJ, Dwyer JT. Dietary flavonoid intakes and CVD incidence in the Framingham Offspring Cohort. Br J Nutr. 2015;114(9):1496-1503.  (PubMed)

58.  US Department of Agriculture. USDA Database for the Proanthocyanidin Content of Selected Foods. August, 2004. Available at: http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/PA/PA.pdf. Accessed 8/25/15.

59.  US Department of Agriculture. USDA Database for the Isoflavone Content of Selected Foods, release 2.0. September 2008. Available at: http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/isoflav/Isoflav_R2.pdf. Accessed 8/25/15.

60.  US Department of Agriculture. USDA Database for the Flavonoid Content of Selected Foods, release 3.1. May 2014. Available at: http://www.ars.usda.gov/SP2UserFiles/Place/80400525/Data/Flav/Flav_R03-1.pdf. Accessed 8/25/15.

61.  Vogiatzoglou A, Mulligan AA, Bhaniani A, et al. Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk). Free Radic Biol Med. 2015;84:1-10.  (PubMed)

62.  Cassidy A, Rogers G, Peterson JJ, Dwyer JT, Lin H, Jacques PF. Higher dietary anthocyanin and flavonol intakes are associated with anti-inflammatory effects in a population of US adults. Am J Clin Nutr. 2015;102(1):172-181.  (PubMed)

63.  Grassi D, Desideri G, Ferri C. Protective effects of dark chocolate on endothelial function and diabetes. Curr Opin Clin Nutr Metab Care. 2013;16(6):662-668.  (PubMed)

64.  Sansone R, Rodriguez-Mateos A, Heuel J, et al. Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study. Br J Nutr. 2015;114(8):1246-1255.  (PubMed)

65.  Basu A, Fu DX, Wilkinson M, et al. Strawberries decrease atherosclerotic markers in subjects with metabolic syndrome. Nutr Res. 2010;30(7):462-469.  (PubMed)

66.  Kelley DS, Rasooly R, Jacob RA, Kader AA, Mackey BE. Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women. J Nutr. 2006;136(4):981-986.  (PubMed)

67.  Moazen S, Amani R, Homayouni Rad A, Shahbazian H, Ahmadi K, Taha Jalali M. Effects of freeze-dried strawberry supplementation on metabolic biomarkers of atherosclerosis in subjects with type 2 diabetes: a randomized double-blind controlled trial. Ann Nutr Metab. 2013;63(3):256-264.  (PubMed)

68.  Edirisinghe I, Banaszewski K, Cappozzo J, et al. Strawberry anthocyanin and its association with postprandial inflammation and insulin. Br J Nutr. 2011;106(6):913-922.  (PubMed)

69.  Karlsen A, Retterstol L, Laake P, et al. Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults. J Nutr. 2007;137(8):1951-1954.  (PubMed)

70.  Basu A, Lyons TJ. Strawberries, blueberries, and cranberries in the metabolic syndrome: clinical perspectives. J Agric Food Chem. 2012;60(23):5687-5692.  (PubMed)

71.  Zhu Y, Ling W, Guo H, et al. Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: a randomized controlled trial. Nutr Metab Cardiovasc Dis. 2013;23(9):843-849.  (PubMed)

72.  Qin Y, Xia M, Ma J, et al. Anthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjects. Am J Clin Nutr. 2009;90(3):485-492.  (PubMed)

73.  Zhu Y, Huang X, Zhang Y, et al. Anthocyanin supplementation improves HDL-associated paraoxonase 1 activity and enhances cholesterol efflux capacity in subjects with hypercholesterolemia. J Clin Endocrinol Metab. 2014;99(2):561-569.  (PubMed)

74.  Curtis PJ, Kroon PA, Hollands WJ, et al. Cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. J Nutr. 2009;139(12):2266-2271.  (PubMed)

75.  Grassi D, Desideri G, Di Giosia P, et al. Tea, flavonoids, and cardiovascular health: endothelial protection. Am J Clin Nutr. 2013;98(6 Suppl):1660S-1666S.  (PubMed)

76.  Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829-837, 837a-837d.  (PubMed)

77.  Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol. 2013;168(1):344-351.  (PubMed)

78.  Liu Y, Li D, Zhang Y, Sun R, Xia M. Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction. Am J Physiol Endocrinol Metab. 2014;306(8):E975-988.  (PubMed)

79.  Zhu Y, Xia M, Yang Y, et al. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem. 2011;57(11):1524-1533.  (PubMed)

80.  Ras RT, Zock PL, Draijer R. Tea consumption enhances endothelial-dependent vasodilation; a meta-analysis. PLoS One. 2011;6(3):e16974.  (PubMed)

81.  Hooper L, Kay C, Abdelhamid A, et al. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2012;95(3):740-751.  (PubMed)

82.  Grassi D, Necozione S, Lippi C, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005;46(2):398-405.  (PubMed)

83.  Grassi D, Desideri G, Necozione S, et al. Protective effects of flavanol-rich dark chocolate on endothelial function and wave reflection during acute hyperglycemia. Hypertension. 2012;60(3):827-832.  (PubMed)

84.  Davison K, Coates AM, Buckley JD, Howe PR. Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int J Obes (Lond). 2008;32(8):1289-1296.  (PubMed)

85.  West SG, McIntyre MD, Piotrowski MJ, et al. Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults. Br J Nutr. 2014;111(4):653-661.  (PubMed)

86.  Flammer AJ, Sudano I, Wolfrum M, et al. Cardiovascular effects of flavanol-rich chocolate in patients with heart failure. Eur Heart J. 2012;33(17):2172-2180.  (PubMed)

87.  Schroeter H, Heiss C, Balzer J, et al. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A. 2006;103(4):1024-1029.  (PubMed)

88.  Gomez-Guzman M, Jimenez R, Sanchez M, et al. Epicatechin lowers blood pressure, restores endothelial function, and decreases oxidative stress and endothelin-1 and NADPH oxidase activity in DOCA-salt hypertension. Free Radic Biol Med. 2012;52(1):70-79.  (PubMed)

89.  Bachmair EM, Ostertag LM, Zhang X, de Roos B. Dietary manipulation of platelet function. Pharmacol Ther. 2014;144(2):97-113.  (PubMed)

90.  Pearson DA, Paglieroni TG, Rein D, et al. The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function. Thromb Res. 2002;106(4-5):191-197.  (PubMed)

91.  Ried K, Sullivan TR, Fakler P, Frank OR, Stocks NP. Effect of cocoa on blood pressure. Cochrane Database Syst Rev. 2012;8:CD008893.  (PubMed)

92.  Khalesi S, Sun J, Buys N, Jamshidi A, Nikbakht-Nasrabadi E, Khosravi-Boroujeni H. Green tea catechins and blood pressure: a systematic review and meta-analysis of randomised controlled trials. Eur J Nutr. 2014;53(6):1299-1311.  (PubMed)

93.  Guerrero L, Castillo J, Quinones M, et al. Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies. PLoS One. 2012;7(11):e49493.  (PubMed)

94.  Egert S, Bosy-Westphal A, Seiberl J, et al. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr. 2009;102(7):1065-1074.  (PubMed)

95.  Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects. J Nutr. 2007;137(11):2405-2411.  (PubMed)

96.  Zahedi M, Ghiasvand R, Feizi A, Asgari G, Darvish L. Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial. Int J Prev Med. 2013;4(7):777-785.  (PubMed)

97.  Brull V, Burak C, Stoffel-Wagner B, et al. Effects of a quercetin-rich onion skin extract on 24 h ambulatory blood pressure and endothelial function in overweight-to-obese patients with (pre-)hypertension: a randomised double-blinded placebo-controlled cross-over trial. Br J Nutr. 2015;114(8):1263-1277.  (PubMed)

98.  Zamora-Ros R, Forouhi NG, Sharp SJ, et al. The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study. Diabetes Care. 2013;36(12):3961-3970.  (PubMed)

99.  Zamora-Ros R, Forouhi NG, Sharp SJ, et al. Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations. J Nutr. 2014;144(3):335-343.  (PubMed)

100.  Wang X, Tian J, Jiang J, et al. Effects of green tea or green tea extract on insulin sensitivity and glycaemic control in populations at risk of type 2 diabetes mellitus: a systematic review and meta-analysis of randomised controlled trials. J Hum Nutr Diet. 2014;27(5):501-512.  (PubMed)

101.  Liu K, Zhou R, Wang B, et al. Effect of green tea on glucose control and insulin sensitivity: a meta-analysis of 17 randomized controlled trials. Am J Clin Nutr. 2013;98(2):340-348.  (PubMed)

102.  Zheng XX, Xu YL, Li SH, Hui R, Wu YJ, Huang XH. Effects of green tea catechins with or without caffeine on glycemic control in adults: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2013;97(4):750-762.  (PubMed)

103.  Grassi D, Desideri G, Necozione S, et al. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J Nutr. 2008;138(9):1671-1676.  (PubMed)

104.  Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care. 2012;35(2):226-232.  (PubMed)

105.  Wedick NM, Pan A, Cassidy A, et al. Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. Am J Clin Nutr. 2012;95(4):925-933.  (PubMed)

106.  Hokayem M, Blond E, Vidal H, et al. Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. Diabetes Care. 2013;36(6):1454-1461.  (PubMed)

107.  Soltani R, Gorji A, Asgary S, Sarrafzadegan N, Siavash M. Evaluation of the Effects of Cornus mas L. Fruit Extract on Glycemic Control and Insulin Level in Type 2 Diabetic Adult Patients: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Evid Based Complement Alternat Med. 2015;2015:740954.  (PubMed)

108.  Li D, Zhang Y, Liu Y, Sun R, Xia M. Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients. J Nutr. 2015;145(4):742-748.  (PubMed)

109.  Yang CS, Yang GY, Landau JM, Kim S, Liao J. Tea and tea polyphenols inhibit cell hyperproliferation, lung tumorigenesis, and tumor progression. Exp Lung Res. 1998;24(4):629-639.  (PubMed)

110.  Balasubramanian S, Govindasamy S. Inhibitory effect of dietary flavonol quercetin on 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Carcinogenesis. 1996;17(4):877-879.  (PubMed)

111.  Li ZG, Shimada Y, Sato F, et al. Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. Int J Oncol. 2002;21(6):1275-1283.  (PubMed)

112.  Yamane T, Nakatani H, Kikuoka N, et al. Inhibitory effects and toxicity of green tea polyphenols for gastrointestinal carcinogenesis. Cancer. 1996;77(8 Suppl):1662-1667.  (PubMed)

113.  Guo JY, Li X, Browning JD, Jr., et al. Dietary soy isoflavones and estrone protect ovariectomized ERαKO and wild-type mice from carcinogen-induced colon cancer. J Nutr. 2004;134(1):179-182.  (PubMed)

114.  Huang MT, Xie JG, Wang ZY, et al. Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically important constituent of tea. Cancer Res. 1997;57(13):2623-2629.  (PubMed)

115.  Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A. 2001;98(18):10350-10355.  (PubMed)

116.  Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 2006;9(1):68-76.  (PubMed)

117.  Yamagishi M, Natsume M, Osakabe N, et al. Effects of cacao liquor proanthocyanidins on PhIP-induced mutagenesis in vitro, and in vivo mammary and pancreatic tumorigenesis in female Sprague-Dawley rats. Cancer Lett. 2002;185(2):123-130.  (PubMed)

118.  Romagnolo DF, Selmin OI. Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr. 2012;31(3):206-238.  (PubMed)

119.  Woo HD, Kim J. Dietary flavonoid intake and risk of stomach and colorectal cancer. World J Gastroenterol. 2013;19(7):1011-1019.  (PubMed)

120.  Nimptsch K, Zhang X, Cassidy A, et al. Habitual intake of flavonoid subclasses and risk of colorectal cancer in 2 large prospective cohorts. Am J Clin Nutr. 2016;103(1):184-191.  (PubMed)

121.  Woo HD, Kim J. Dietary flavonoid intake and smoking-related cancer risk: a meta-analysis. PLoS One. 2013;8(9):e75604.  (PubMed)

122.  Tang NP, Zhou B, Wang B, Yu RB, Ma J. Flavonoids intake and risk of lung cancer: a meta-analysis. Jpn J Clin Oncol. 2009;39(6):352-359.  (PubMed)

123.  Ollberding NJ, Lim U, Wilkens LR, et al. Legume, soy, tofu, and isoflavone intake and endometrial cancer risk in postmenopausal women in the multiethnic cohort study. J Natl Cancer Inst. 2012;104(1):67-76.  (PubMed)

124.  Bandera EV, King M, Chandran U, Paddock LE, Rodriguez-Rodriguez L, Olson SH. Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study. BMC Womens Health. 2011;11:40.  (PubMed)

125.  Cassidy A, Huang T, Rice MS, Rimm EB, Tworoger SS. Intake of dietary flavonoids and risk of epithelial ovarian cancer. Am J Clin Nutr. 2014;100(5):1344-1351.  (PubMed)

126.  Gates MA, Vitonis AF, Tworoger SS, et al. Flavonoid intake and ovarian cancer risk in a population-based case-control study. Int J Cancer. 2009;124(8):1918-1925.  (PubMed)

127.  Rossi M, Negri E, Lagiou P, et al. Flavonoids and ovarian cancer risk: A case-control study in Italy. Int J Cancer. 2008;123(4):895-898.  (PubMed)

128.  Ko KP. Isoflavones: chemistry, analysis, functions and effects on health and cancer. Asian Pac J Cancer Prev. 2014;15(17):7001-7010.  (PubMed)

129.  Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;125(2):315-323.  (PubMed)

130.  Iwasaki M, Hamada GS, Nishimoto IN, et al. Isoflavone, polymorphisms in estrogen receptor genes and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians. Cancer Sci. 2009;100(5):927-933.  (PubMed)

131.  Wang Q, Li H, Tao P, et al. Soy isoflavones, CYP1A1, CYP1B1, and COMT polymorphisms, and breast cancer: a case-control study in southwestern China. DNA Cell Biol. 2011;30(8):585-595.  (PubMed)

132.  Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M. Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One. 2013;8(1):e54318.  (PubMed)

133.  Hwang YW, Kim SY, Jee SH, Kim YN, Nam CM. Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer. 2009;61(5):598-606.  (PubMed)

134.  Miyanaga N, Akaza H, Hinotsu S, et al. Prostate cancer chemoprevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Sci. 2012;103(1):125-130.  (PubMed)

135.  Ramassamy C. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol. 2006;545(1):51-64.  (PubMed)

136.  Nurk E, Refsum H, Drevon CA, et al. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr. 2009;139(1):120-127.  (PubMed)

137.  Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF. Intake of flavonoids and risk of dementia. Eur J Epidemiol. 2000;16(4):357-363.  (PubMed)

138.  Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, Barberger-Gateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol. 2007;165(12):1364-1371.  (PubMed)

139.  Desideri G, Kwik-Uribe C, Grassi D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study. Hypertension. 2012;60(3):794-801.  (PubMed)

140.  Mastroiacovo D, Kwik-Uribe C, Grassi D, et al. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial. Am J Clin Nutr. 2015;101(3):538-548.  (PubMed)

141.  Sorond FA, Lipsitz LA, Hollenberg NK, Fisher ND. Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat. 2008;4(2):433-440.  (PubMed)

142.  Crews WD, Jr., Harrison DW, Wright JW. A double-blind, placebo-controlled, randomized trial of the effects of dark chocolate and cocoa on variables associated with neuropsychological functioning and cardiovascular health: clinical findings from a sample of healthy, cognitively intact older adults. Am J Clin Nutr. 2008;87(4):872-880.  (PubMed)

143.  Massee LA, Ried K, Pase M, et al. The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: a randomized, controlled trial. Front Pharmacol. 2015;6:93.  (PubMed)

144.  Pase MP, Scholey AB, Pipingas A, et al. Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial. J Psychopharmacol. 2013;27(5):451-458.  (PubMed)

145.  Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL, Haskell CF. Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol. 2010;24(10):1505-1514.  (PubMed)

146.  Kent K, Charlton K, Roodenrys S, et al. Consumption of anthocyanin-rich cherry juice for 12 weeks improves memory and cognition in older adults with mild-to-moderate dementia. Eur J Nutr. 2015; Oct 19. [Epub ahead of print].  (PubMed)

147.  Alharbi MH, Lamport DJ, Dodd GF, et al. Flavonoid-rich orange juice is associated with acute improvements in cognitive function in healthy middle-aged males. Eur J Nutr. 2015; Aug 18. [Epub ahead of print].  (PubMed)

148.  Kean RJ, Lamport DJ, Dodd GF, et al. Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults. Am J Clin Nutr. 2015;101(3):506-514.  (PubMed)

149.  Casini ML, Marelli G, Papaleo E, Ferrari A, D'Ambrosio F, Unfer V. Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril. 2006;85(4):972-978.  (PubMed)

150.  Kritz-Silverstein D, Von Muhlen D, Barrett-Connor E, Bressel MA. Isoflavones and cognitive function in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study. Menopause. 2003;10(3):196-202.  (PubMed)

151.  Kim K, Vance TM, Chun OK. Estimated intake and major food sources of flavonoids among US adults: changes between 1999-2002 and 2007-2010 in NHANES. Eur J Nutr. 2015; May 31. [Epub ahead of print].  (PubMed)

152.  Sebastian RS, Wilkinson Enns C, Goldman JD, et al. A New Database Facilitates Characterization of Flavonoid Intake, Sources, and Positive Associations with Diet Quality among US Adults. J Nutr. 2015;145(6):1239-1248.  (PubMed)

153.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. 2nd ed: Thomson Reuters; 2008.

154.  Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45(11):2179-2205.  (PubMed)

155.  Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial. Urology. 1999;54(6):960-963.  (PubMed)

156.  Ferry DR, Smith A, Malkhandi J, et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996;2(4):659-668.  (PubMed)

157.  Ottaviani JI, Balz M, Kimball J, et al. Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. Am J Clin Nutr. 2015;102(6):1425-1435.  (PubMed)

158.  Jatoi A, Ellison N, Burch PA, et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer. 2003;97(6):1442-1446.  (PubMed)

159.  Pisters KM, Newman RA, Coldman B, et al. Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol. 2001;19(6):1830-1838.  (PubMed)

160.  Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea extracts : a systematic review by the US Pharmacopeia. Drug Saf. 2008;31(6):469-484.  (PubMed)

161.  Chow HH, Cai Y, Hakim IA, et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003;9(9):3312-3319.  (PubMed)

162.  Dostal AM, Samavat H, Bedell S, et al. The safety of green tea extract supplementation in postmenopausal women at risk for breast cancer: results of the Minnesota Green Tea Trial. Food Chem Toxicol. 2015;83:26-35.  (PubMed)

163.  Li Y, Paxton JW. The effects of flavonoids on the ABC transporters: consequences for the pharmacokinetics of substrate drugs. Expert Opin Drug Metab Toxicol. 2013;9(3):267-285.  (PubMed)

164.  Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs. 2004;4(5):281-297.  (PubMed)

165.  Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004;75(1):13-33.  (PubMed)

166.  Freedman JE, Parker C, 3rd, Li L, et al. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. 2001;103(23):2792-2798.  (PubMed)

167.  Keevil JG, Osman HE, Reed JD, Folts JD. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr. 2000;130(1):53-56.  (PubMed)

168.  Polagruto JA, Schramm DD, Wang-Polagruto JF, Lee L, Keen CL. Effects of flavonoid-rich beverages on prostacyclin synthesis in humans and human aortic endothelial cells: association with ex vivo platelet function. J Med Food. 2003;6(4):301-308.  (PubMed)

169.  Murphy KJ, Chronopoulos AK, Singh I, et al. Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function. Am J Clin Nutr. 2003;77(6):1466-1473.  (PubMed)

170.  Natural Medicines. Hesperidin Professional Monograph; 2015.

171.  Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: forbidden fruit or avoidable consequences? CMAJ. 2013;185(4):309-316.  (PubMed)

172.  Kim EY, Ham SK, Shigenaga MK, Han O. Bioactive dietary polyphenolic compounds reduce nonheme iron transport across human intestinal cell monolayers. J Nutr. 2008;138(9):1647-1651.  (PubMed)

173.  Thankachan P, Walczyk T, Muthayya S, Kurpad AV, Hurrell RF. Iron absorption in young Indian women: the interaction of iron status with the influence of tea and ascorbic acid. Am J Clin Nutr. 2008;87(4):881-886.  (PubMed)

174.  Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999;81(4):289-295.  (PubMed)

175.  Zijp IM, Korver O, Tijburg LB. Effect of tea and other dietary factors on iron absorption. Crit Rev Food Sci Nutr. 2000;40(5):371-398.  (PubMed)

176.  Ma Q, Kim EY, Lindsay EA, Han O. Bioactive dietary polyphenols inhibit heme iron absorption in a dose-dependent manner in human intestinal Caco-2 cells. J Food Sci. 2011;76(5):H143-150.  (PubMed)

177.  Kim EY, Ham SK, Bradke D, Ma Q, Han O. Ascorbic acid offsets the inhibitory effect of bioactive dietary polyphenolic compounds on transepithelial iron transport in Caco-2 intestinal cells. J Nutr. 2011;141(5):828-834.  (PubMed)

Garlic

You should be automatically redirected to the current page, if not click here.

Indole-3-Carbinol

Summary

  • Indole-3-carbinol (I3C) is derived from the breakdown of glucobrassicin, a compound found in cruciferous vegetables. (More information)
  • In the stomach, I3C molecules undergo acid-catalyzed condensation that generates a number of biologically active I3C oligomers, such as 3,3'-diindolylmethane (DIM) and 5,11-dihydroindolo-[3,2-b]carbazole (ICZ). (More information)
  • I3C and DIM have been found to modulate the expression and activity of biotransformation enzymes that are involved in the metabolism and elimination of many biologically active compounds, including steroid hormones, drugs, carcinogens, and toxins. (More information)
  • Preclinical studies suggested that anti-estrogenic activities of I3C and DIM might help reduce the risk of hormone-dependent cancers. Although supplementation with I3C and DIM could alter urinary estrogen metabolite profiles in women, the effects of I3C and DIM on breast cancer risk are not known. (More information)
  • Preclinical studies showed that I3C and I3C oligomers could affect multiple signaling pathways that are dysregulated in cancer cells, such as those controlling cell proliferation, apoptosis, migration, invasion, and angiogenesis. (More information)
  • Limited evidence from preliminary trials suggested that I3C supplementation may help treat conditions related to human papilloma virus (HPV) infection, such as cervical/vulvar intraepithelial neoplasias and recurrent respiratory papillomatosis. However, randomized controlled trials are needed to determine whether I3C supplementation is beneficial. (More information)
  • The timing of I3C exposure in animal models of chemically-induced cancers seems to determine whether I3C inhibits or promotes the development of tumors. Some experts have cautioned against the widespread use of I3C and DIM supplements for cancer prevention in humans until their potential risks and benefits are better understood(More information)

Introduction

Some observational studies have reported significant associations between high intakes of cruciferous vegetables and lower risk of several types of cancer (1). Cruciferous vegetables differ from other classes of vegetables in that they are rich sources of sulfur-containing compounds known as glucosinolates (for detailed information, see the article on Cruciferous Vegetables) (2). The potential health benefits of consuming cruciferous vegetables are attributed to compounds derived from the enzymatic hydrolysis (breakdown) of glucosinolates. Among these compounds is indole-3-carbinol (I3C), a compound derived from the degradation of an indole glucosinolate commonly known as glucobrassicin (Figure 1).

Figure 1. Breakdown of Glucobrassicin. Glucobrassicin is metabolized by myrosinase to the unstable intermediate, thiohydroximate-O-sulfonate form, then in neutral pH to the unstable intermediate, 3-inolylmethyl-isothiocyanate, then eventually degrades to form indole-3-carbinol and a thiocyanate ion.

[Figure 1 - Click to Enlarge]

Metabolism and Bioavailability

A number of commonly consumed cruciferous vegetables, including broccoli, Brussels sprouts, and cabbage, are good sources of glucobrassicin — the glucosinolate precursor of I3C (see Food sources).

Myrosinase (β-thioglucosidase), an enzyme that catalyzes the hydrolysis of glucosinolates, is physically separated from glucosinolates in intact plant cells (3). When raw cruciferous vegetables are chopped or chewed, plant cells are damaged such that glucobrassicin is exposed to myrosinase. The hydrolysis of glucobrassicin initially produces a glucose molecule and the unstable aglycone, thiohydroximate-O-sulfonate. The spontaneous release of a sulfate ion results in the formation of another unstable intermediate form, 3-indolylmethylisothiocyanate (4). This compound easily splits into thiocyanate ion and I3C (Figure 1). In the acidic environment of the stomach, I3C molecules can combine with each other to form a complex mixture of polycyclic aromatic compounds, known collectively as acid condensation products (Figure 2) (5). Some of the most prominent acid condensation products include 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and a cyclic triindole (CT) (Figure 2). The biological activities of individual acid condensation products may differ from those of I3C (see Biological Activities).

When cruciferous vegetables are cooked, plant myrosinase is inactivated thus the hydrolysis of glucosinolates is prevented. Intact glucosinolates then transit to the colon and are metabolized by human intestinal bacteria. The generation of I3C from glucobrassicin may still occur to a lesser degree in the large intestine, due to the myrosinase activity of colonic bacteria (4). Thus, when cruciferous vegetables are cooked, I3C can still form in the colon, but I3C-derived acid condensation products are less likely to form in the more alkaline environment of the intestine.

No I3C could be detected in plasma following oral administration of single doses of I3C, ranging from 200 to 1,200 mg, to healthy women at high risk for breast cancer (6). However, DIM was detected and peaked in plasma around two hours after I3C ingestion, at concentrations from <100 nanograms per milliliter (ng/mL) with oral doses of 400 to 600 mg of I3C up to 500 ng/mL-600 ng/mL with oral doses of 1,000 to 1,200 mg of I3C. All DIM disappeared from the blood within 24 hours (6).

Formulation strategies, such as the encapsulation of I3C and DIM into nanoparticles or liposomes (7-9), are being developed with the aim of increasing the bioavailability and evaluating the safety and efficacy of these compounds in humans.

Figure 2. Condensation Derivatives of Indole-3-Carbinol: 3,3'-diindolylmethane (DIM), 5,6,11,12,17,18-hexahydrocyclononal [1,2-b:4,5-b':7,8-b"]triindole (CT), and 5,11-dihydroindolo-[3,2-b]carbazole (ICZ) 

[Figure 2 - Click to Enlarge]

Biological Activities

Effects on biotransformation enzymes

Biotransformation enzymes play major roles in the metabolism and elimination of many biologically active compounds, including physiologic regulators (e.g., estrogens), drugs, and environmental chemicals (xenobiotics; e.g., carcinogens, toxins). In general, phase I metabolizing enzymes, including the cytochrome P450 (CYP) family, catalyze reactions that increase the reactivity of hydrophobic (fat-soluble) compounds, which prepares them for reactions catalyzed by phase II detoxifying enzymes. Reactions catalyzed by phase II enzymes usually increase water solubility and promote the elimination of these compounds (10).

Aryl hydrocarbon receptor (AhR) pathway

I3C and some I3C condensation products can bind to a protein in the cytoplasm of cells called the aryl hydrocarbon receptor (AhR) (Figure 3) (11-13). In fact, ICZ is one of the most potent ligands for the AhR known with an affinity approaching that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). I3C acid condensation products, as well as indoles and their acid condensation products formed from tryptophan metabolism, appear to be important endogenous ligands for the AhR (13). Binding allows AhR to enter the nucleus where it forms a complex with the AhR nuclear translocator (Arnt) protein. This AhR/Arnt complex binds to specific DNA sequences, known as xenobiotic response elements (XRE), in the regulatory regions (promoters) of target genes, especially those involved in xenobiotic metabolism (14). The promoters of genes coding for a number of CYP enzymes and several phase II enzymes contain XREs. Microarray gene expression profiling of I3C- or DIM-treated human prostate cancer cells showed that both compounds upregulated the phase I enzyme, CYP1A1, and the phase II enzymes, glutathione S-transferase theta-1 (GST q1) and aldo-keto reductase (15). Another study in human prostate cancer cells demonstrated that the removal of AhR abolished I3C- or DIM-induced CYP1A1 mRNA expression (16). The expression of CYP1A1 and CYP1A2 was also upregulated in human primary liver cells challenged with DIM (17). Further, I3C and DIM have been found to interfere with CYP activities involved in estrogen metabolism (see Anti-estrogenic activities).

Increasing the activity of biotransformation enzymes is generally considered a beneficial effect because the elimination of potential carcinogens or toxins is enhanced. However, there is a potential for adverse effects because some procarcinogens require biotransformation by phase I enzymes to become active carcinogens (18).

Figure 3. I3C and DIM Regulate Phase I Biotransformation Enzymes via AhR Signaling. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) regulate the expression of phase I metabolizing enzymes via the AhR signaling pathway.

[Figure 3 - Click to Enlarge]

Nuclear factor E2-related factor 2-dependent pathway

I3C and DIM have been shown to induce the expression of phase II detoxifying and antioxidant enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway.

Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol (Figure 4). Keap1 responds to oxidative stress signals or chemical inducers by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoters of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for numerous mediators of the antioxidant response, including glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (19). DIM induced Nrf2/ARE-dependent upregulation of HO-1, and I3C stimulated NQO-1 and GST (µ2 isoform) expression in liver cancer cells (20). In addition, the transcription of Nrf2 coding gene, which was abnormally repressed through promoter DNA hypermethylation, was enhanced in mouse prostate cancer cells treated with DIM. DIM subsequently restored the expression of the Nrf2-target genes, NQO1 and GSTµ1 (21). DIM also reversed Nrf2 gene silencing in transgenic mouse prostate cancer tissues, inducing Nrf2 expression, and subsequently, NQO1 expression (Figure 4). This was accompanied by the suppression of proliferation and the induction of apoptosis in prostate cancer tissues (21). Similar observations have been reported with I3C (22).

Figure 4. I3C and DIM Regulate Phase II Biotransformation Enzymes via Nrf2 Signaling. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) increase the expression of phase II detoxifying/antioxidant enzymes via the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. (A) I3C and DIM restore the transcription of Nrf2 gene by reversing promoter methylation, (B) I3C and DIM iinduce the nuclear translocation of Nrf2, and (C) I3C and DIM increase the expression of Nrf2 target genes coding for phase II enzymes and antioxidant enzymes. 

[Figure 4 - Click to Enlarge]

Anti-estrogenic activities

Endogenous estrogens are steroid hormones synthesized by humans and other mammals.

Inhibition of estrogen synthesis

In breast tissue, CYP19 (aromatase) catalyzes the final steps in the conversion of androgens (testosterone or androstenedione) to estrogens (17β-estradiol or estrone, respectively). Both I3C and DIM have been found to downregulate the expression of CYP19 in non-tumorigenic and tumorigenic estrogen-responsive (ER+) breast cells, whereas CYP19 expression was increased in I3C/DIM-treated tumorigenic estrogen-independent (ER-) breast cells (23).

Inhibition of estrogen metabolic activation

Prolonged exposure to estrogens is thought to play a role in cancer development through CYP-mediated generation of estrogen reactive metabolites that can damage DNA (24, 25).

Phase I metabolizing enzymes, CYP1A1, CYP1A2, and CYP1B1, have been involved in the oxidative metabolism of estrogens. 17β-estradiol can be converted to 2-hydroxyestradiol (2HE2) and 4-hydroxyestradiol (4HE2) by CYP1A1/2 and CYP1B1, respectively. 2HE2 and 4HE2 are further metabolized to 2- and 4-metoxymetabolites by the phase II enzyme, catechol-O-methyltransferase (COMT) (25). 2HE2 is a noncarcinogenic agent with weaker estrogenic potential than 17β-estradiol, while 4-HE2 can be converted to free radicals that can form DNA adducts and promote carcinogenesis (26, 27). In different breast cancer cell lines, I3C and DIM have been shown to upregulate the expression of CYP1A1, CYP1A2, and CYP1B1 at the transcript (mRNA) level but not at the protein level (28).

Additionally, the endogenous estrogens 17β-estradiol and estrone can be irreversibly metabolized to 16a-hydroxyestrone (16HE1) (29). In contrast to 2-hydroxyestrone (2HE1), 16HE1 is highly estrogenic and has been found to stimulate the proliferation of several estrogen-sensitive cancer cell lines (30, 31). It has been hypothesized that shifting the metabolism of 17β-estradiol toward 2HE1, and away from 16HE1, could decrease the risk of estrogen-sensitive cancers, such as breast cancer (32). In controlled clinical trials, oral supplementation with I3C or DIM has consistently increased urinary 2HE1 concentrations or urinary 2HE1:16HE1 ratios in women (33-39). However, large case-control and prospective cohort studies have failed to find significant associations between urinary 2HE1:16HE1 ratios and risk of breast and endometrial cancer (40-43).

Inhibition of estrogen signaling

Endogenous estrogens, including 17β-estradiol, exert their estrogenic effects by binding to specific nuclear receptors called estrogen receptors (ERs). Within the nucleus, estrogen-activated ERs can bind to specific DNA sequences, known as estrogen response elements (EREs), in the promoters of estrogen-responsive genes. ERE-bound estrogen-ER complexes act as transcription factors by recruiting coactivator proteins and chromatin remodeling factors to promoters, thereby triggering the transcription of target genes (44). There are two major ER subtypes, ERα and ERβ, coded by two separate genes ESR1 and ESR2, respectively. ERα is the main driver of the proliferative effect of estrogens, while the expression of ERβ has been inversely associated with mammary gland tumorigenesis (45). Elevated ERα levels promote cellular proliferation in the breast and uterus, possibly increasing the risk of developing estrogen-sensitive cancers (46).

Inhibition of estrogen-dependent cell proliferation

In estrogen-sensitive human breast cancer cells challenged with 17β-estradiol, I3C has been found to inhibit the transcription of estrogen-responsive genes without binding to either ERβ or ERα (47, 48). In fact, the binding of I3C to AhR was shown to trigger the proteasome-dependent degradation of ERα (49). I3C-induced loss of ERα resulted in the downregulation of ERα-responsive gene products like the transcription factor GATA3. Since GATA3 regulates the transcription of the ERα coding gene ESR1, I3C prevented the synthesis of new ERα transcripts and proteins, eventually abolishing the ERα signaling pathway. The disruption of the GATA3/ERα cross-regulatory loop by I3C ultimately halted ERα-dependent cell proliferation (49). Acid condensation products of I3C that bind and activate AhR may also inhibit the transcription of estrogen-responsive genes by competing for co-activators or increasing ERα degradation (14, 50). I3C treatment also affected the expression of other ERα-responsive genes, including those coding for insulin-like growth factor-1 receptor (IGFR1) and insulin receptor substrate-1 (IRS-1), involved in cell proliferation and deregulated in breast cancer (Figure 5) (51).

Figure 5. Overview of Anti-estrogenic Actions of I3C and DIM.  

[Figure 5 - Click to Enlarge]

Modulation of cell-signaling pathways

I3C and condensation derivatives have been found to affect multiple signaling pathways that are often deregulated in cancer cells. Below are some examples illustrating how I3C, DIM, or ICZ may influence cell proliferation, apoptosis, migration, invasion, angiogenesis, and immunity by targeting specific signaling pathways (23).

Induction of cell cycle arrest and apoptosis

Once a cell divides, it passes through a sequence of stages — collectively known as the cell cycle — before it divides again. Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage is irreparable (52). Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. In addition, unlike normal cells, cancerous cells lose their ability to respond to death signals that initiate apoptosis.

I3C-induced downregulation of the phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt) cell survival signaling pathway in mice with nasopharyngeal carcinoma resulted in inhibition of cell proliferation and induction of apoptosis (53). Inactivation of the Wnt/β-catenin signaling pathway in DIM-treated colon cancer cells decreased the expression of downstream targets, c-myc and cyclin D1, that promote cell proliferation and survival (54). In prostate cancer cells, I3C opposed the anti-apoptotic effect of epidermal growth factor (EGF) by limiting EGF receptor autophosphorylation (activation) and reducing EGF-induced activation of the PI3K/Akt signaling pathway and expression of the pro-survival target molecules, Bcl-x(L) and BAD (55). In another study, DIM caused apoptosis of prostate cancer cells by stimulating p38 mitogen-activated protein kinase (p38 MAPK)-induced upregulation of tumor suppressor p75NTR (56). The anti-proliferative effect of DIM in cancer cells has also been linked to the inhibition of histone deacetylase (HDAC) activity. Specifically, DIM was found to reverse HDAC-mediated epigenetic silencing of genes coding for key regulators of the cell cycle (57, 58). A recent genome-wide analysis of DNA methylation also showed that DIM could reverse aberrant promoter methylation in prostate cancer cells, at least partly through downregulating the expression of DNA methyltransferases (DNMTs) (59).

Inhibition of cell migration and invasion

The epithelial-to-mesenchymal transition (EMT) describes a process of epithelial cell transformation whereby cells lose their polarity and adhesion properties while gaining migratory and invasive properties through the expression of mesenchymal genes. Inhibition of EMT by I3C and ICZ in breast cancer cells has been associated with upregulation of an epithelial marker, E-cadherin, and downregulation of vimentin, focal adhesion kinase (FAK), and matrix metalloproteins (MMPs) — proteins and enzymes known to promote migration (60). DIM also inhibited migration and invasion of liver cancer cells in vitro and in vivo through inactivating the FAK signaling pathway (61). Moreover, DIM has been shown to reverse methylation-associated dysregulation of genes involved in cell adhesion, chemotaxis, and inflammation that contributes to cancer progression (59). DIM was able to inhibit lung metastasis in mice with liver (61) or mammary tumors (62).

Inhibition of angiogenesis

To fuel their rapid growth, invasive tumors must also develop new capillaries from preexisting blood vessels by a process known as angiogenesis. I3C inhibited lipopolysaccharide (LPS)-induced macrophage activation and secretion of proangiogenic molecules, such as nitric oxide (NO), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and MMP-9, and prevented the formation of capillary-like structures from co-cultured human umbilical endothelial cells (63). Similarly, I3C inhibited capillary-like tube formation from phorbol myristate acetate (PMA)-stimulated endothelial cells (64). DIM also blocked PMA-induced angiogenic activities in human umbilical endothelial cells (65).

Regulation of inflammation and cell-mediated immunity

Uncontrolled inflammation has been associated with several chronic diseases, including cancer. In the mouse ear edema model, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced upregulation of pro-inflammatory mediators, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), has been found to be mitigated by DIM treatment (66). Nuclear factor-kappa B (NF-κB) is a major transcription factor regulating the expression of many pro-inflammatory genes like those coding for COX-2 and iNOS. Specifically, DIM inhibited TPA-induced activation of kinases (inhibitor of kappa B kinase [IκK] and extracellular signal-regulated kinase [ERK]) that control the transcriptional activity of NF-κB (66). In addition, recent animal studies showed that I3C and/or DIM could modulate cell-mediated immune response in experimental autoimmune encephalomyelitis (67), staphylococcal enterotoxin-induced lung inflammation (68), and delayed-type hypersensitivity (69). Specifically, I3C and/or DIM differentially regulated T-cell subpopulations via the activation or suppression of microRNA-dependent pathways controlling cell cycle progression and apoptosis.

Transplacental cancer prevention

The inclusion of I3C in the maternal diet was found to protect the offspring from lymphoma and lung tumors induced by dibenzo[a]pyrene, a polycyclic aromatic hydrocarbon (70, 71). Polycyclic aromatic hydrocarbons are chemical pollutants formed during incomplete combustion of organic substances, such as coal, oil, wood, and tobacco (72).

However, the physiological relevance of cell culture and animal studies to human health is unclear since little or no I3C is available to tissues after oral administration (see Metabolism and Bioavailability) (6).

Disease Prevention

Cancer

Some observational studies provide some support for the hypothesis that higher intakes of cruciferous vegetables are associated with lower risk for some types of cancer (see the article on Cruciferous Vegetables) (1). Cruciferous vegetables are relatively good sources of nutrients that may have protective effects against cancer, including vitamin C, folate, selenium, carotenoids, and fiber. In addition, glucosinolates can be hydrolyzed to a variety of potentially protective isothiocyanates, in addition to indole-3-carbinol (see the article on Isothiocyanates). Consequently, evidence for an inverse association between cruciferous vegetable intake and cancer risk provides relatively little information about the specific effects of indole-3-carbinol on cancer risk.

At present, the effects of I3C or DIM supplementation on cancer risk in humans are not known.

Disease Treatment

Human papilloma virus infection-related diseases

Cervical intraepithelial neoplasia

Infection with certain strains of human papilloma virus (HPV) is an important risk factor for cervical cancer (73). Transgenic mice that express cancer-promoting HPV genes develop cervical cancer with chronic 17β-estradiol administration. In this model, feeding I3C markedly reduced the number of mice that developed cervical cancer (74). A small placebo-controlled trial in women examined the effect of oral I3C supplementation on the progression of precancerous cervical lesions classified as cervical intraepithelial neoplasia (CIN) 2 or CIN 3 (75). After 12 weeks, four out of the eight women who took 200 mg/day had complete regression of CIN, and four out of the nine who took 400 mg/day had complete regression; none of the 10 women who took a placebo had complete regression. HPV was present in 7 out of the 10 women in the placebo group, seven out of eight women in the 200 mg I3C group, and eight out of nine women in the 400 mg I3C group (75). However compared to placebo, oral supplementation with DIM (2 mg/kg/day) for 12 weeks in 64 women with CIN 2 or CIN 3 lesions failed to improve clinical parameters during a one-year follow-up period (76). In another six-month randomized, double-blind controlled trial, DIM supplementation (150 mg/day) failed to promote HPV clearance and prevent CIN progression in 551 women with low-grade cell abnormalities in cervical smears (77).

Although oral supplementation of I3C or DIM appears relatively safe and well tolerated, results obtained with I3C are only preliminary, and interventions with DIM failed to show preventative or therapeutic efficacy in women with precancerous lesions of the cervix. The intravaginal administration of DIM in the form of suppositories may prove to be a more effective approach to reverse CIN in women (78).

Vulvar intraepithelial neoplasia

HPV infection has also been associated with vulvar intraepithelial neoplasia (VIN), a precancerous condition that may progress to vulval cancer (79). A small randomized trial in 12 women with VIN found that supplementation with 200 mg/day or 400 mg/day of I3C for six months improved overall symptoms, as well as lesion size and appearance (80). Additional trials are necessary to determine whether I3C might be an effective treatment for VIN.

Recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP) is a rare disease of children and adults, characterized by generally benign growths (papillomas) in the respiratory tract, which are caused by HPV infection (81). These papillomas occur most commonly on or around the vocal cords in the larynx (voice box), but they may also affect the trachea, bronchi, and lungs. The most common treatment for RRP is surgical removal of the papillomas. Since papillomas often recur, adjunct treatments may be used to help prevent or reduce recurrences (82). In immune-compromised mice transplanted with HPV-infected laryngeal tissue, only 25% of the mice fed I3C developed laryngeal papillomas compared to 100% of the control mice (83). In a small observational study of RRP patients, increased ratios of urinary 2HE1:16HE1 resulting from increased cruciferous vegetable consumption were associated with less severe RRP (84). In an uncontrolled pilot study, the effect of daily I3C supplementation (400 mg/day for adults and 10 mg/kg daily for children) on papilloma recurrence has been examined in RRP patients (85). Over a five-year follow-up period, 11 of the original 49 patients experienced no recurrence, 10 experienced a reduction in the rate of recurrence, 12 experienced no improvement, and 12 were lost to follow-up (86). I3C given for 6 months to 3 years to five children with an aggressive form of the disease halted the growth of the papillomas in three children after two years of treatment (87). In some patients, I3C may be an effective adjunct treatment to reduce the growth or recurrence of respiratory papillomas.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation that may result in damage to the joints, skin, kidneys, heart, lungs, blood vessels, or brain (88). Estrogen is thought to play a role in the pathology of SLE because the disorder is much more common in women than men, and its onset is most common during the reproductive years when endogenous estrogen levels are highest (89). The potential for I3C supplementation to shift endogenous estrogen metabolism toward the less estrogenic metabolite 2HE1, and away from the highly estrogenic metabolite 16HE1 (see Anti-estrogenic activities), led to interest in its use in SLE (35). In an animal model of SLE, I3C feeding decreased the severity of kidney disease and prolonged survival (90). A small uncontrolled trial of I3C supplementation (375 mg/day) in female SLE patients found that I3C supplementation increased urinary 2HE1:16HE1 ratios, but the trial found no significant change in SLE symptoms after three months (90). Controlled clinical trials are needed to determine whether I3C supplementation could have beneficial effects in SLE patients.

Sources

Food sources

Glucobrassicin, the glucosinolate precursor of I3C, is found in a number of cruciferous vegetables, including broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard greens, radish, rutabaga, and turnip (91, 92). Although glucosinolates are present in relatively high concentrations in cruciferous vegetables, glucobrassicin makes up only about 8%-12% of the total glucosinolates (93). Total glucosinolate contents of selected cruciferous vegetables are presented in Table 1. However, the amount of total glucosinolates and the amount of indole-3-carbinol formed from glucobrassicin in food is variable and depends, in part, on the processing and preparation of foods (for more detailed information, see the article on Cruciferous Vegetables).

Table 1. Glucosinolate Content of Selected Cruciferous Vegetables (94)
Food (raw) Serving Total Glucosinolates (mg)
Brussels sprouts ½ cup
104
Garden cress ½ cup
98
Mustard greens ½ cup, chopped
79
Kale 1 cup, chopped
67
Turnip ½ cup, cubes
60
Cabbage, savoy ½ cup, chopped
35
Watercress 1 cup, chopped
32
Kohlrabi ½ cup, chopped
31
Cabbage, red ½ cup, chopped
29
Broccoli ½ cup, chopped
27
Horseradish 1 tablespoon (15 g)
24
Cauliflower ½ cup, chopped
22
Bok choi (pak choi) ½ cup, chopped
19

Supplements

Indole-3-Carbinol (I3C)

I3C is available without a prescription as a dietary supplement, alone or in combination products. Dosage ranges between 200 mg/day and 800 mg/day (95). I3C supplementation increased urinary 2HE1 concentrations in adults at doses of 300 to 400 mg/day (39). I3C doses of 200 mg/day or 400 mg/day improved the regression of cervical intraepithelial neoplasia (CIN) in a preliminary clinical trial (75). I3C in doses up to 400 mg/day has been used to treat recurrent respiratory papillomatosis (see Disease Treatment) (85, 86).

3,3'-Diindolylmethane (DIM)

DIM is available without a prescription as a dietary supplement, alone or in combination products. In a small clinical trial, DIM supplementation at a dose of 108 mg/day for 30 days increased urinary 2HE1 excretion in postmenopausal women with a history of breast cancer (34).

Safety

Adverse effects

Slight increases in the serum concentrations of the liver enzyme, alanine aminotransferase (ALT) were observed in two women who took unspecified doses of I3C supplements for four weeks (39). One person reported a skin rash while taking 375 mg/day of I3C (35). High doses of I3C (800 mg/day) have been associated with symptoms of disequilibrium and tremor, which resolved when the dose was decreased (85). In a phase I study in women at high risk for breast cancer, 5 out of 20 participants had gastrointestinal symptoms with single doses ≥600 mg, although others had no adverse effects with single doses up to 1,200 mg (6). No adverse effects were reported with daily consumption of 400 mg of I3C for four weeks (6).

In some animal models, I3C supplementation was found to enhance carcinogen-induced cancer development when given chronically after the carcinogen (96-99). When administered before or at the same time as the carcinogen, oral I3C inhibited tumorigenesis in animal models of cancers of the mammary gland (100, 101), uterus (102), stomach (103), colon (104, 105), lung (106), and liver (107, 108). Although the long-term effects of I3C supplementation on cancer risk in humans are not known, the contradictory results of animal studies have led several experts to caution against the widespread use of I3C and DIM supplements in humans until their potential risks and benefits are better understood (99, 109, 110).

Pregnancy and lactation

The safety of I3C or DIM supplements during pregnancy or lactation has not been established (95).

Drug interactions

No drug interactions with I3C or DIM supplementation in humans have been reported. However, preliminary evidence that I3C and DIM can increase the activity of CYP1A2 (111, 112) suggests the potential for I3C or DIM supplementation to decrease serum concentrations of medications metabolized by CYP1A2 (113). Both I3C and DIM modestly increase the activity of CYP3A4 in rats when administered chronically (114). This observation raises the potential for adverse drug interactions in humans since CYP3A4 is involved in the metabolism of approximately 60% of therapeutic drugs.

The acidic environment of the stomach allows I3C molecules to condense and generate a number of biologically active I3C oligomers (Figure 2). Drugs that block the production of stomach acids, like antacids, Histamine2 (H2) receptor antagonists, and proton-pump inhibitors, would likely prevent the generation of DIM and ICZ. However, it is not known whether these drugs limit the biological activities attributed to I3C and its derivatives (95).


Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2017 by:
David E. Williams, Ph.D.
Principal Investigator, and Helen P. Rumbel Professor for Cancer Prevention
Linus Pauling Institute
Professor, Department of Environmental and Molecular Toxicology
Oregon State University

Copyright 2005-2017  Linus Pauling Institute


References

1.  Traka M. Chapter nine-health benefits of glucosinolates. Advances in Botanical Research. 2016;80:247-279. 

2.  Ishida M, Hara M, Fukino N, Kakizaki T, Morimitsu Y. Glucosinolate metabolism, functionality and breeding for the improvement of Brassicaceae vegetables. Breed Sci. 2014;64(1):48-59.  (PubMed)

3.  Holst B, Williamson G. A critical review of the bioavailability of glucosinolates and related compounds. Nat Prod Rep. 2004;21(3):425-447.  (PubMed)

4.  Barba FJ, Nikmaram N, Roohinejad S, Khelfa A, Zhu Z, Koubaa M. Bioavailability of glucosinolates and their breakdown products: impact of processing. Front Nutr. 2016;3:24.  (PubMed)

5.  Wang SQ, Cheng LS, Liu Y, Wang JY, Jiang W. Indole-3-carbinol (I3C) and its major derivatives: their pharmacokinetics and important roles in hepatic protection. Curr Drug Metab. 2016;17(4):401-409.  (PubMed)

6.  Reed GA, Arneson DW, Putnam WC, et al. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2477-2481.  (PubMed)

7.  Anderton MJ, Manson MM, Verschoyle R, et al. Physiological modeling of formulated and crystalline 3,3'-diindolylmethane pharmacokinetics following oral administration in mice. Drug Metab Dispos. 2004;32(6):632-638.  (PubMed)

8.  Luo Y, Wang TT, Teng Z, Chen P, Sun J, Wang Q. Encapsulation of indole-3-carbinol and 3,3'-diindolylmethane in zein/carboxymethyl chitosan nanoparticles with controlled release property and improved stability. Food Chem. 2013;139(1-4):224-230.  (PubMed)

9.  Song JM, Kirtane AR, Upadhyaya P, et al. Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability. Int J Pharm. 2014;477(1-2):96-101.  (PubMed)

10.  Lampe JW, Peterson S. Brassica, biotransformation and cancer risk: genetic polymorphisms alter the preventive effects of cruciferous vegetables. J Nutr. 2002;132(10):2991-2994.  (PubMed)

11.  Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci U S A. 1991;88(21):9543-9547.  (PubMed)

12.  Bonnesen C, Eggleston IM, Hayes JD. Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res. 2001;61(16):6120-6130.  (PubMed)

13.  Hubbard TD, Murray IA, Perdew GH. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab Dispos. 2015;43(10):1522-1535.  (PubMed)

14.  Safe S. Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol Lett. 2001;120(1-3):1-7.  (PubMed)

15.  Li Y, Li X, Sarkar FH. Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J Nutr. 2003;133(4):1011-1019.  (PubMed)

16.  Wang TT, Schoene NW, Milner JA, Kim YS. Broccoli-derived phytochemicals indole-3-carbinol and 3,3'-diindolylmethane exerts concentration-dependent pleiotropic effects on prostate cancer cells: comparison with other cancer preventive phytochemicals. Mol Carcinog. 2012;51(3):244-256.  (PubMed)

17.  Gross-Steinmeyer K, Stapleton PL, Liu F, et al. Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes. Xenobiotica. 2004;34(7):619-632.  (PubMed)

18.  Baird WM, Hooven LA, Mahadevan B. Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ Mol Mutagen. 2005;45(2-3):106-114.  (PubMed)

19.  Watson GW, Beaver LM, Williams DE, Dashwood RH, Ho E. Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention. AAPS J. 2013;15(4):951-961.  (PubMed)

20.  Saw CL, Cintron M, Wu TY, et al. Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. Biopharm Drug Dispos. 2011;32(5):289-300.  (PubMed)

21.  Wu TY, Khor TO, Su ZY, et al. Epigenetic modifications of Nrf2 by 3,3'-diindolylmethane in vitro in TRAMP C1 cell line and in vivo TRAMP prostate tumors. AAPS J. 2013;15(3):864-874.  (PubMed)

22.  Wu TY, Saw CL, Khor TO, Pung D, Boyanapalli SS, Kong AN. In vivo pharmacodynamics of indole-3-carbinol in the inhibition of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: involvement of Nrf2 and cell cycle/apoptosis signaling pathways. Mol Carcinog. 2012;51(10):761-770.  (PubMed)

23.  Licznerska BE, Szaefer H, Murias M, Bartoszek A, Baer-Dubowska W. Modulation of CYP19 expression by cabbage juices and their active components: indole-3-carbinol and 3,3'-diindolylmethene in human breast epithelial cell lines. Eur J Nutr. 2013;52(5):1483-1492.  (PubMed)

24.  Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF. Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation. Cancer Res. 2007;67(2):812-817.  (PubMed)

25.  Jefcoate CR, Liehr JG, Santen RJ, et al. Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr. 2000(27):95-112.  (PubMed)

26.  Kwon YJ, Baek HS, Ye DJ, Shin S, Kim D, Chun YJ. CYP1B1 enhances cell proliferation and metastasis through induction of EMT and activation of Wnt/beta-catenin signaling via Sp1 upregulation. PLoS One. 2016;11(3):e0151598.  (PubMed)

27.  Park SA, Lee MH, Na HK, Surh YJ. 4-Hydroxyestradiol induces mammary epithelial cell transformation through Nrf2-mediated heme oxygenase-1 overexpression. Oncotarget. 2016;8(1):164-178.  (PubMed)

28.  Szaefer H, Licznerska B, Krajka-Kuzniak V, Bartoszek A, Baer-Dubowska W. Modulation of CYP1A1, CYP1A2 and CYP1B1 expression by cabbage juices and indoles in human breast cell lines. Nutr Cancer. 2012;64(6):879-888.  (PubMed)

29.  Ziegler RG, Fuhrman BJ, Moore SC, Matthews CE. Epidemiologic studies of estrogen metabolism and breast cancer. Steroids. 2015;99(Pt A):67-75.  (PubMed)

30.  Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL. Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992;84(8):634-638.  (PubMed)

31.  Yuan F, Chen DZ, Liu K, Sepkovic DW, Bradlow HL, Auborn K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999;19(3A):1673-1680.  (PubMed)

32.  Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2-Hydroxyestrone: the 'good' estrogen. J Endocrinol. 1996;150 Suppl:S259-265.  (PubMed)

33.  Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev. 1994;3(7):591-595.  (PubMed)

34.  Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-167.  (PubMed)

35.  McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, Nuite M. Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus. 2001;10(11):779-783.  (PubMed)

36.  Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord. 1998;22(3):227-229.  (PubMed)

37.  Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997;89(10):718-723.  (PubMed)

38.  Reed GA, Peterson KS, Smith HJ, et al. A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1953-1960.  (PubMed)

39.  Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl. 1997;28-29:111-116.  (PubMed)

40.  Arslan AA, Shore RE, Afanasyeva Y, Koenig KL, Toniolo P, Zeleniuch-Jacquotte A. Circulating estrogen metabolites and risk for breast cancer in premenopausal women. Cancer Epidemiol Biomarkers Prev. 2009;18(8):2273-2279.  (PubMed)

41.  Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE. Circulating 2-hydroxy- and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2008;17(8):2029-2035.  (PubMed)

42.  Modugno F, Kip KE, Cochrane B, et al. Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. Int J Cancer. 2006;118(5):1292-1301.  (PubMed)

43.  Zeleniuch-Jacquotte A, Shore RE, Afanasyeva Y, et al. Postmenopausal circulating levels of 2- and 16alpha-hydroxyestrone and risk of endometrial cancer. Br J Cancer. 2011;105(9):1458-1464.  (PubMed)

44.  Jordan VC, Gapstur S, Morrow M. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J Natl Cancer Inst. 2001;93(19):1449-1457.  (PubMed)

45.  Omoto Y, Iwase H. Clinical significance of estrogen receptor beta in breast and prostate cancer from biological aspects. Cancer Sci. 2015;106(4):337-343.  (PubMed)

46.  Liehr JG. Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev. 2000;21(1):40-54.  (PubMed)

47.  Ashok BT, Chen Y, Liu X, Bradlow HL, Mittelman A, Tiwari RK. Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol. Nutr Cancer. 2001;41(1-2):180-187.  (PubMed)

48.  Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr. 2000;130(12):2927-2931.  (PubMed)

49.  Marconett CN, Sundar SN, Poindexter KM, Stueve TR, Bjeldanes LF, Firestone GL. Indole-3-carbinol triggers aryl hydrocarbon receptor-dependent estrogen receptor (ER)alpha protein degradation in breast cancer cells disrupting an ERalpha-GATA3 transcriptional cross-regulatory loop. Mol Biol Cell. 2010;21(7):1166-1177.  (PubMed)

50.  Chen I, McDougal A, Wang F, Safe S. Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis. 1998;19(9):1631-1639.  (PubMed)

51.  Marconett CN, Singhal AK, Sundar SN, Firestone GL. Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells. Mol Cell Endocrinol. 2012;363(1-2):74-84.  (PubMed)

52.  Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci. 2003;24(3):139-145.  (PubMed)

53.  Mao CG, Tao ZZ, Chen Z, Chen C, Chen SM, Wan LJ. Indole-3-carbinol inhibits nasopharyngeal carcinoma cell growth in vivo and in vitro through inhibition of the PI3K/Akt pathway. Exp Ther Med. 2014;8(1):207-212.  (PubMed)

54.  Leem SH, Li XJ, Park MH, Park BH, Kim SM. Genome-wide transcriptome analysis reveals inactivation of Wnt/beta-catenin by 3,3'-diindolylmethane inhibiting proliferation of colon cancer cells. Int J Oncol. 2015;47(3):918-926.  (PubMed)

55.  Chinni SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH. Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene. 2001;20(23):2927-2936.  (PubMed)

56.  Khwaja FS, Wynne S, Posey I, Djakiew D. 3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway in prostate cancer cells. Cancer Prev Res. 2009;2(6):566-571.  (PubMed)

57.  Beaver LM, Yu TW, Sokolowski EI, Williams DE, Dashwood RH, Ho E. 3,3'-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells. Toxicol Appl Pharmacol. 2012;263(3):345-351.  (PubMed)

58.  Li Y, Li X, Guo B. Chemopreventive agent 3,3'-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases. Cancer Res. 2010;70(2):646-654.  (PubMed)

59.  Wong CP, Hsu A, Buchanan A, et al. Effects of sulforaphane and 3,3'-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. PLoS One. 2014;9(1):e86787.  (PubMed)

60.  Ho JN, Jun W, Choue R, Lee J. I3C and ICZ inhibit migration by suppressing the EMT process and FAK expression in breast cancer cells. Mol Med Rep. 2013;7(2):384-388.  (PubMed)

61.  Li WX, Chen LP, Sun MY, Li JT, Liu HZ, Zhu W. 3'3-Diindolylmethane inhibits migration, invasion and metastasis of hepatocellular carcinoma by suppressing FAK signaling. Oncotarget. 2015;6(27):23776-23792.  (PubMed)

62.  Kim EJ, Shin M, Park H, et al. Oral administration of 3,3'-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice. J Nutr. 2009;139(12):2373-2379.  (PubMed)

63.  Wang ML, Shih CK, Chang HP, Chen YH. Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages. Food Chem. 2012;134(2):811-820.  (PubMed)

64.  Wu HT, Lin SH, Chen YH. Inhibition of cell proliferation and in vitro markers of angiogenesis by indole-3-carbinol, a major indole metabolite present in cruciferous vegetables. J Agric Food Chem. 2005;53(13):5164-5169.  (PubMed)

65.  Kunimasa K, Kobayashi T, Kaji K, Ohta T. Antiangiogenic effects of indole-3-carbinol and 3,3'-diindolylmethane are associated with their differential regulation of ERK1/2 and Akt in tube-forming HUVEC. J Nutr. 2010;140(1):1-6.  (PubMed)

66.  Kim EJ, Park H, Kim J, Park JH. 3,3'-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators. Mol Carcinog. 2010;49(7):672-683.  (PubMed)

67.  Rouse M, Rao R, Nagarkatti M, Nagarkatti PS. 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways. J Pharmacol Exp Ther. 2014;350(2):341-352.  (PubMed)

68.  Elliott DM, Nagarkatti M, Nagarkatti PS. 3,3-Diindolylmethane ameliorates Staphylococcal enterotoxin B-induced acute lung injury through alterations in the expression of microRNA that target apoptosis and cell-cycle arrest in activated T cells. J Pharmacol Exp Ther. 2016;357(1):177-187.  (PubMed)

69.  Singh NP, Singh UP, Rouse M, et al. Dietary indoles suppress delayed-type hypersensitivity by inducing a switch from proinflammatory Th17 Cells to anti-inflammatory regulatory T cells through regulation of microRNA. J Immunol. 2016;196(3):1108-1122.  (PubMed)

70.  Shorey LE, Madeen EP, Atwell LL, et al. Differential modulation of dibenzo[def,p]chrysene transplacental carcinogenesis: maternal diets rich in indole-3-carbinol versus sulforaphane. Toxicol Appl Pharmacol. 2013;270(1):60-69.  (PubMed)

71.  Yu Z, Mahadevan B, Lohr CV, et al. Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene. Carcinogenesis. 2006;27(10):2116-2123.  (PubMed)

72.  ATSDR. Toxicological profile for polycyclic aromatic hydrocarbons (PAHs). Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Atlanta, GA; August 1995. 

73.  Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ. 2007;177(5):469-479.  (PubMed)

74.  Jin L, Qi M, Chen DZ, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 1999;59(16):3991-3997.  (PubMed)

75.  Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000;78(2):123-129.  (PubMed)

76.  Del Priore G, Gudipudi DK, Montemarano N, Restivo AM, Malanowska-Stega J, Arslan AA. Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol. 2010;116(3):464-467.  (PubMed)

77.  Castanon A, Tristram A, Mesher D, et al. Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial. Br J Cancer. 2012;106(1):45-52.  (PubMed)

78.  Ashrafian L, Sukhikh G, Kiselev V, et al. Double-blind randomized placebo-controlled multicenter clinical trial (phase IIa) on diindolylmethane's efficacy and safety in the treatment of CIN: implications for cervical cancer prevention. EPMA J. 2015;6:25.  (PubMed)

79.  Pepas L, Kaushik S, Nordin A, Bryant A, Lawrie TA. Medical interventions for high-grade vulval intraepithelial neoplasia. Cochrane Database Syst Rev. 2015(8):Cd007924.  (PubMed)

80.  Naik R, Nixon S, Lopes A, Godfrey K, Hatem MH, Monaghan JM. A randomized phase II trial of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. Int J Gynecol Cancer. 2006;16(2):786-790.  (PubMed)

81.  Recurrent Respiratory Papillomatosis Foundation. What is recurrent respiratory papillomatosis? Recurrent Respiratory Papillomatosis Foundation [Web page]. Available at: http://www.rrpf.org/whatisRRP.html. Accessed 7/22/17.

82.  Auborn KJ. Therapy for recurrent respiratory papillomatosis. Antivir Ther. 2002;7(1):1-9.  (PubMed)

83.  Newfield L, Goldsmith A, Bradlow HL, Auborn K. Estrogen metabolism and human papillomavirus-induced tumors of the larynx: chemo-prophylaxis with indole-3-carbinol. Anticancer Res. 1993;13(2):337-341.  (PubMed)

84.  Auborn K, Abramson A, Bradlow HL, Sepkovic D, Mullooly V. Estrogen metabolism and laryngeal papillomatosis: a pilot study on dietary prevention. Anticancer Res. 1998;18(6B):4569-4573.  (PubMed)

85.  Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1998;118(6):810-815.  (PubMed)

86.  Rosen CA, Bryson PC. Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results. J Voice. 2004;18(2):248-253.  (PubMed)

87.  Boltezar IH, Bahar MS, Zargi M, Gale N, Maticic M, Poljak M. Adjuvant therapy for laryngeal papillomatosis. Acta Dermatovenerol Alp Pannonica Adriat. 2011;20(3):175-180.  (PubMed)

88.  Handout on health: systemic lupus erythematosus. National Institute of Arthritis and Musculoskeletal and Skin Diseases [Web page]. June 2016. Available at: https://www.niams.nih.gov/health_info/lupus/. Accessed 1/21/17.

89.  McMurray RW, May W. Sex hormones and systemic lupus erythematosus: review and meta-analysis. Arthritis Rheum. 2003;48(8):2100-2110.  (PubMed)

90.  Auborn KJ, Qi M, Yan XJ, et al. Lifespan is prolonged in autoimmune-prone (NZB/NZW) F1 mice fed a diet supplemented with indole-3-carbinol. J Nutr. 2003;133(11):3610-3613.  (PubMed)

91.  Carlson DG, Kwolek WF, Williams PH. Glucosinolates in crucifer vegetables: broccoli, Brussels sprouts, cauliflower, collards, kale, mustard greens, and kohlrabi. J Amer Soc Hort Sci. 1987;112(1):173-178. 

92.  Fenwick GR, Heaney RK, Mullin WJ. Glucosinolates and their breakdown products in food and food plants. Crit Rev Food Sci Nutr. 1983;18(2):123-201.  (PubMed)

93.  Kushad MM, Brown AF, Kurilich AC, et al. Variation of glucosinolates in vegetable crops of Brassica oleracea. J Agric Food Chem. 1999;47(4):1541-1548.  (PubMed)

94.  McNaughton SA, Marks GC. Development of a food composition database for the estimation of dietary intakes of glucosinolates, the biologically active constituents of cruciferous vegetables. Br J Nutr. 2003;90(3):687-697.  (PubMed)

95.  Hendler SS, Rorvik DM. PDR for Nutritional Supplements. 2nd ed: Thomson Reuters; 2008.

96.  Kim DJ, Han BS, Ahn B, et al. Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model. Carcinogenesis. 1997;18(2):377-381.  (PubMed)

97.  Yoshida M, Katashima S, Ando J, et al. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis. 2004;25(11):2257-2264.  (PubMed)

98.  Pence BC, Buddingh F, Yang SP. Multiple dietary factors in the enhancement of dimethylhydrazine carcinogenesis: main effect of indole-3-carbinol. J Natl Cancer Inst. 1986;77(1):269-276.  (PubMed)

99.  Stoner G, Casto B, Ralston S, Roebuck B, Pereira C, Bailey G. Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis. 2002;23(2):265-272.  (PubMed)

100.  Grubbs CJ, Steele VE, Casebolt T, et al. Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res. 1995;15(3):709-716.  (PubMed)

101.  Bradlow HL, Michnovicz J, Telang NT, Osborne MP. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis. 1991;12(9):1571-1574.  (PubMed)

102.  Kojima T, Tanaka T, Mori H. Chemoprevention of spontaneous endometrial cancer in female Donryu rats by dietary indole-3-carbinol. Cancer Res. 1994;54(6):1446-1449.  (PubMed)

103.  Wattenberg LW, Loub WD. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res. 1978;38(5):1410-1413.  (PubMed)

104.  Wargovich MJ, Chen CD, Jimenez A, et al. Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat. Cancer Epidemiol Biomarkers Prev. 1996;5(5):355-360.  (PubMed)

105.  Guo D, Schut HA, Davis CD, Snyderwine EG, Bailey GS, Dashwood RH. Protection by chlorophyllin and indole-3-carbinol against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced DNA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis. 1995;16(12):2931-2937.  (PubMed)

106.  Morse MA, LaGreca SD, Amin SG, Chung FL. Effects of indole-3-carbinol on lung tumorigenesis and DNA methylation induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and on the metabolism and disposition of NNK in A/J mice. Cancer Res. 1990;50(9):2613-2617.  (PubMed)

107.  Dashwood RH, Arbogast DN, Fong AT, Hendricks JD, Bailey GS. Mechanisms of anti-carcinogenesis by indole-3-carbinol: detailed in vivo DNA binding dose-response studies after dietary administration with aflatoxin B1. Carcinogenesis. 1988;9(3):427-432.  (PubMed)

108.  Oganesian A, Hendricks JD, Williams DE. Long term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated hepatocarcinogenesis in the infant mouse model. Cancer Lett. 1997;118(1):87-94.  (PubMed)

109.  Dashwood RH. Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Chem Biol Interact. 1998;110(1-2):1-5.  (PubMed)

110.  Lee BM, Park KK. Beneficial and adverse effects of chemopreventive agents. Mutat Res. 2003;523-524:265-278.  (PubMed)

111.  He YH, Friesen MD, Ruch RJ, Schut HA. Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metabolism, and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol. 2000;38(1):15-23.  (PubMed)

112.  Lake BG, Tredger JM, Renwick AB, Barton PT, Price RJ. 3,3'-Diindolylmethane induces CYP1A2 in cultured precision-cut human liver slices. Xenobiotica. 1998;28(8):803-811.  (PubMed)

113.  Natural Medicines. Professional monograph: Indole-3-carbinol/Interactions with drugs; 2016.

114.  Leibelt DA, Hedstrom OR, Fischer KA, Pereira CB, Williams DE. Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3'-diindolylmethane in Sprague-Dawley rats. Toxicol Sci. 2003;74(1):10-21.  (PubMed)

Isothiocyanates

Summary

  • Isothiocyanates are derived from the hydrolysis of glucosinolates — sulfur-containing compounds found in cruciferous vegetables. (More information)
  • Each glucosinolate forms a different isothiocyanate when hydrolyzed. For example, broccoli is a good source of glucoraphanin, the glucosinolate precursor of sulforaphane, and sinigrin, the glucosinolate precursor of allyl isothiocyanate. (More information)
  • Absorbed isothiocyanates are rapidly conjugated to glutathione in the liver, and then sequentially metabolized in the mercapturic acid pathway, before being excreted in the urine. (More information)
  • Isothiocyanates may modulate the expression and activity of biotransformation enzymes that are involved in the metabolism and elimination of xenobiotics (e.g., carcinogens) from the body. In cultured cells and animal models, isothiocyanates also exhibited antioxidant and anti-inflammatory activities and interfered with numerous cancer-related targets and pathways. (More information)
  • Although high intakes of cruciferous vegetables have been associated with a lower risk for cancer, there is insufficient evidence that exposure to isothiocyanates through cruciferous vegetable consumption decreases cancer risk. (More information)
  • Glucosinolates are present in relatively high concentrations in cruciferous vegetables, but the amounts of isothiocyanates formed from glucosinolates in foods are variable and depend partly on food processing and preparation. (More information)

Introduction

Cruciferous vegetables, such as broccoli, cabbage, and kale, are rich sources of sulfur-containing compounds called glucosinolates (see the article on Cruciferous Vegetables). Isothiocyanates are biologically active hydrolysis (breakdown) products of glucosinolates. Cruciferous vegetables contain a variety of glucosinolates, each of which forms a different isothiocyanate when hydrolyzed (Figure 1) (1). For example, broccoli is a good source of glucoraphanin, the glucosinolate precursor of sulforaphane, and sinigrin, the glucosinolate precursor of allyl isothiocyanate (AITC) (see Food sources) (2). Watercress is a rich source of gluconasturtiin, the precursor of phenethyl isothiocyanate (PEITC), while garden cress is rich in glucotropaeolin, the precursor of benzyl isothiocyanate (BITC) (see Food sources). At present, scientists are interested in the cancer-preventive activities of vegetables that are rich in glucosinolates (see the article on Cruciferous Vegetables), as well as individual isothiocyanates (3).

Metabolism and Bioavailability

Metabolism

The hydrolysis of glucosinolates, which is catalyzed by a class of enzymes called myrosinases (β-thioglucosidases), leads to the formation of breakdown compounds, such as thiocyanates, isothiocyanates, indoles, oxazolidine-2-thiones (e.g., goitrin), epithionitrile, and nitrile (see the article on Cruciferous Vegetables). In intact plant cells, myrosinase is physically separated from glucosinolates. Yet, when plant cells are damaged, myrosinase is released and comes in contact with glucosinolates, catalyzing their conversion into highly reactive metabolites that impart a pungent aroma and spicy (some say bitter) taste. Likewise, when raw cruciferous vegetables are chopped during the food preparation process, glucosinolates are rapidly hydrolyzed by myrosinase, generating metabolites that are then absorbed in the proximal intestine. In contrast, cooking cruciferous vegetables before consumption inactivates myrosinase, thus preventing the breakdown of glucosinolates. However, lightly cooking (i.e., light steam for <5 minutes) will preserve some of the myrosinase and allow for isothiocyanate conversion. A small fraction of intact glucosinolates may be absorbed in the small intestine, but a large proportion reaches the colon (4). In the colon, myrosinase produced by the microbiota can catalyze the generation of a wide range of metabolites from glucosinolates, depending on the pH and the presence of cofactors (4, 5).

The hydrolysis of glucosinolates at neutral pH results in the formation of unique isothiocyanates (Figure 1). For example, sinigrin, glucoraphanin, glucotropaeolin, and gluconasturtiin are the glucosinolate precursors of AITC, sulforaphane, BITC, and PEITC, respectively (Figure 1). Once absorbed, glucosinolate-derived isothiocyanates (like sulforaphane) are promptly conjugated to glutathione by a class of phase II detoxification enzymes known as glutathione S-transferases (GSTs) in the liver, and then sequentially metabolized in the mercapturic acid pathway (Figure 2). This mechanism is meant to increase the solubility of isothiocyanates, thereby promoting a rapid excretion in the urine. Using sulforaphane as the model isothiocyanate, it has indeed been established that its metabolites — sulforaphane-glutathione, sulforaphane-cysteine-glycine, sulforaphane-cysteine, and sulforaphane N-acetylcysteine — collectively known as dithiocarbamates (Figure 2), are ultimately excreted in the urine (4).

Figure 1. Chemical Structures of Some Glucosinolates and their Isothiocyanate Derivatives. Chemical structures of the alpiphatic glucosinolates (sinigrin and glucoraphanin) and the aromatic glucosinolates (glucotropaeolin and gluconasturtiin). These are hydrolyzed to various isothiocyanates: allyl isothiocyanate, sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate.

[Figure 1 - Click to Enlarge]

Figure 2. Metabolism of Glucoraphanin via the Mercapturic Acid Pathway. Glucoraphanin is converted to sulforaphane (via myrosinase),  converted to sulforaphane-gluathione conjugate (via glutathione S-transferase), metabolized to sulforaphane-cysteine-glycine via gamma-glutamyltranspeptidase, then converted to sulforaphane-cysteine (via cysteinyl-glycinase), and then sulforaphane N-aceylcysteine (via N-acetyltransferase).

[Figure 2 - Click to Enlarge]

Bioavailability

The composition and content of glucosinolates in cruciferous vegetables are relatively stable but depend on the genus and species and can vary with plant growing and post-harvest storage conditions and culinary processing (6, 7). Since most cruciferous vegetables are cooked prior to eating, bacterial myrosinase in the gut, rather than plant myrosinase, is responsible for the initial step in glucosinolate degradation (Figure 2). In a feeding study involving 45 healthy subjects, the mean conversion rate of glucosinolates (of which 85% was glucoraphanin) to dithiocarbamates over a 24-hour period was estimated to be around 12% with wide variations among participants (range, 1.1 to 40.7%) (6). In contrast, 70%-75% of ingested isothiocyanates were found to be metabolized to dithiocarbamates. Therefore, following the ingestion of cooked cruciferous vegetables, the conversion of glucosinolates into isothiocyanates by gut bacteria appears to be a limiting step in the generation of dithiocarbamates (6). However, differences in individuals’ capacity to metabolize glucosinolates have not been linked to differences in gut microbiota composition (8).

Biological Activities

Antioxidant activity

Many isothiocyanates, particularly sulforaphane, have been shown to induce the expression of antioxidant enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (9, 10). Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol (Figure 3). Keap1 responds to oxidative stress signals or chemical inducers by freeing Nrf2. Isothiocyanates can react with sulfhydryl residues of Keap1, causing the release of Nrf2. Nrf2 can then translocate to the nucleus and bind to the antioxidant response element (ARE) located in the promoters of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for several mediators of the antioxidant response, including glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (11).

In numerous animal models, sulforaphane (often administered ip, iv, or sc, rather than po) was shown to exert protective effects on many tissues and organs by activating the Nrf2/ARE-dependent pathway (12). For example, sulforaphane reduced contrast agent-induced kidney damage in rats by increasing Nrf2 nuclear translocation and upregulating the expression of HO-1 and NQO-1 (13). Upregulation of the Nrf2 pathway by sulforaphane also attenuated oxidative damage-induced vascular endothelial cell injury in a mouse model of type 2 diabetes mellitus (14). In a rat model of hepatic ischemia reperfusion injury — whereby cellular damage is caused by the restoration of oxygen delivery to a hypoxic liver — pre-treatment with sulforaphane limited the reduction in glutathione (GSH) and the antioxidant enzymes, superoxide dismutase (SOD) and GSH peroxidase (GPx). Sulforaphane also upregulated the expression of Nrf2, NQO-1, and HO-1, and decreased ischemic death and apoptosis of liver cells (15).

Human studies are limited. In a placebo-controlled study, oral sulforaphane (in the form of broccoli sprout homogenate) increased the expression of NQO-1 and HO-1 in the upper airway within two hours of ingestion (16). Yet, in a recent trial in patients with chronic obstructive pulmonary disease (COPD), oral administration of sulforaphane for four weeks failed to induce the expression of Nrf2, NQO-1, and HO-1 in alveolar macrophages, bronchial epithelial cells, or peripheral blood mononuclear cells (17).

Figure 3. Isothiocyanates Target Nrf2 and NF-kappaB Pathways. Isothiocyanates inhibit NF-kappaB-mediated inflammation and increase the expression of phase II detoxifying/antioxidant enzymes via the Nrf2 signaling pathway. [A] Isothiocyanates induce the nuclear translocation of Nrf2 and increase the expression of Nrf2 target genes coding for phase II enzymes and antioxidant enzymes. [B] Isothiocyanates may prevent (1) the phosphorylation of NF-kappaB inhibitor, IkappaB; (2) th nuclear translocation of NF-kappaB; and (3) the transcriptional activity of NF-kappa B.

[Figure 3 - Click to Enlarge]

Anti-inflammatory activity

The therapeutic potential of sulforaphane has also been linked to its capacity to target pro-inflammatory pathways. Sulforaphane was found to attenuate pancreatic injury in a mouse model of acute pancreatitis by stimulating Nrf2-induced antioxidant enzymes (18). Concomitantly, sulforaphane significantly reduced the nuclear translocation of the pro-inflammatory transcription factor nuclear factor (NF)-κB in pancreatic acinar cells, downregulating the expression of NF-κB target genes that code for pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and IL-6 (Figure 3) (18). Through inhibiting the NF-κB pathway, sulforaphane also targets other mediators of the inflammatory response, including the enzymes cyclooxygenase-2 (COX-2), prostaglandin E (PGE) synthase, and inducible nitric oxide synthase (iNOS). Sulforaphane exhibited anti-inflammatory effects in the lungs of mice with lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) by downregulating the expression of NF-κB, IL-6, TNF-α and COX-2, as well as decreasing production of nitric oxide (NO) and PGE2 (19). Other isothiocyanates have been shown to prevent the degradation of the NF-κB inhibitor, IκB, the nuclear translocation of NF-κB, and/or the transcriptional activity of NF-κB in vitro or in cultured cells (Figure 3) (20), which all can lead to a decrease in inflammatory responses.

The modulation of Nrf2 and NF-κB signaling pathways by isothiocyanates is especially relevant to the prevention of cancer because both oxidative stress and inflammation are significant contributors in the development and progression of cancer.

Anticancer activity

Biotransformation enzymes play important roles in the metabolism and elimination of a variety of chemicals, including drugs, toxins, and carcinogens. In general, phase I metabolizing enzymes catalyze reactions that increase the reactivity of hydrophobic (fat-soluble) compounds, preparing them for reactions catalyzed by phase II biotransformation enzymes. Reactions catalyzed by phase II enzymes generally increase water solubility and promote the elimination of the compound from the body (21).

Inhibition of phase I biotransformation enzymes

Isothiocyanates have been found to modulate the activity of phase I biotransformation enzymes, especially those of the cytochrome P450 (CYP) family. Using a primary rat hepatocyte-based model, both aliphatic (e.g., sulforaphane, AITC) and aromatic (e.g., BITC, PEITC) isothiocyanates (at 20-40 μM) have been found to downregulate CYP3A2 mRNA expression, as well as the activity of benzyloxyquinoline debenzylase, a marker of CYP3As (22). Aromatic isothiocyanates were also able to upregulate CYP1A1 and CYP1A2 mRNA expression and the activity of ethoxyresorufin-O-deethylase (EROD), a marker of CYP1A1/2 activities (22). In this model, sulforaphane inhibited EROD activity, yet failed to affect CYP1A1/2 mRNA expression (22). Using human liver microsomes, it was also recently reported that sulforaphane metabolites (0-200 μM) had little-to-no effect on the activities of CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (23). The ability of PEITC to alter the expression and activity of CYP enzymes has been generally associated with a protective effect against (pro)carcinogen-induced tumor development in animal experiments (reviewed in 24). Increasing the activity of biotransformation enzymes may be beneficial if the elimination of potential carcinogens or toxins is enhanced. Yet, some procarcinogens require phase I enzymes in order to become active carcinogens capable of binding DNA and forming cancer-causing DNA adducts. Inhibition of specific CYP enzymes involved in carcinogen activation has been found to prevent the development of cancer in animal models (3).

Induction of phase II detoxifying enzymes

Many isothiocyanates are potent inducers of phase II detoxifying enzymes, including GSTs, UDP-glucuronosyl transferases (UGTs), NQO1, and glutamate cysteine ligase (GCL), that protect cells from DNA damage by carcinogens and reactive oxygen species (ROS) (25). The genes for these and other phase II enzymes contain AREs and are therefore under the control of Nrf2 (see Antioxidant activity). Limited data from clinical trials suggest that glucosinolate-rich foods can increase phase II enzyme activity in humans. When smokers consumed 170 g/day (6 oz/day) of watercress, urinary excretion of glucuronidated nicotine metabolites increased significantly, suggesting UGT activity increased (26). Brussels sprouts are rich in a number of glucosinolates, including precursors of AITC and sulforaphane. Consumption of 300 g/day (11 oz/day) of Brussels sprouts for one week significantly increased plasma and intestinal GST concentrations in nonsmoking men (27, 28).

Induction of cell cycle arrest and apoptosis

After a cell divides, it passes through a sequence of stages — collectively known as the cell cycle — before dividing again. Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to programmed cell death (apoptosis) when the damage cannot be repaired (29). Defective cell cycle regulation and pro-survival mechanisms may result in the propagation of mutations that contribute to the development of cancer. Isothiocyanates have been found to modulate the expression of the cell cycle regulators, cyclins and cyclin-dependent kinases (CDK), as well as trigger apoptosis in a number of cancer cell lines (20). In a mouse model of colorectal cancer, oral administration of PEITC reduced both the number and size of polyps; these changes were associated with activation of the CDK inhibitor, p21, inhibition of various cyclins (A, D1, and E), and induction of apoptosis (30). In a transgenic prostate adenocarcinoma mouse model, BITC limited the progress of prostatic intraepithelial neoplasia (PIN) to a well-differentiated carcinoma (31). This was related to a decreased expression of Ki67 (a marker of cell proliferation) and a downregulation of cyclin A, cyclin D1, and CDK2, which regulate cell cycle progression (31).

Inhibition of cell migration and invasion

The epithelial-to-mesenchymal transition (EMT) describes a process of epithelial cell transformation whereby cells lose their polarity and adhesion properties while gaining migratory and invasive properties through the expression of mesenchymal genes. Inhibition of the EMT by sulforaphane in thyroid cancer cells has been associated with upregulation of an epithelial marker, E-cadherin, and downregulation of a transcription factor (SNAI2), a filament protein (vimentin), and various enzymes (matrix metalloprotein [MMP]-2 and MMP-9) known to contribute to EMT and promote migration (32). In a xenograft mouse model of breast cancer, BITC inhibited high fat diet-driven promotion of breast tumor growth, as well as lung and liver metastasis (33). This study suggested that BITC might prevent the infiltration of macrophages in the tumor environment (33). In another model of breast tumor metastasis, PEITC inhibited the migration of tumor cells to the brain after injection into the heart of mice, limiting the growth of metastatic brain tumors (34).

Inhibition of angiogenesis

To fuel their rapid growth, invasive tumors must also develop new capillaries from preexisting blood vessels by a process known as angiogenesis. Isothiocyanates have been shown to prevent the formation of capillary-like structures from human umbilical endothelial cells (reviewed in 35). Isothiocyanates likely inhibit the expression and function of hypoxia inducible factors (HIFs) that control angiogenesis, as reported in endothelial cells and malignant cell lines (35).

Epigenetic regulation of gene expression

In the nucleus of a cell, DNA is coiled around proteins called histones, thereby forming the chromatin. The N-terminal tails of histones are targets for multiple modifications, including phosphorylation, methylation, acetylation, ubiquitination, poly ADP ribosylation, and sumoylation. Histone modification patterns have differential effects on chromatin structure, and, in synergy with DNA methylation, are implicated in the regulating expression of the genome (36). Within gene regulatory regions, the acetylation of lysine residues of histone tails has been correlated with activation of transcription. Conversely, the deacetylation of histones by histone deacetylases (HDAC) restricts access of transcription factors to the DNA and suppresses transcription. Because abnormal epigenetic marks disrupt the expression of specific tumor suppressor genes in cancer cells, compounds that re-induce their transcription, like those inhibiting HDACs, can potentially promote differentiation and apoptosis in transformed (precancerous) cells (37).

Isothiocyanates have been found to inhibit HDAC expression and/or activity in cultured cancer cells (38-43). Moreover, in vivo evidence for HDAC inhibition by sulforaphane came from a mouse model using prostate cancer xenografts (44). In humans, HDAC activity was reduced in blood cells following ingestion of 68 g (one cup) of sulforaphane-rich broccoli sprouts (44). Isothiocyanates may also affect microRNA-mediated gene silencing. In bladder cancer cells, E-cadherin induction by sulforaphane was partly due to the upregulation of miR-200c expression resulting in the miR-200c-dependent suppression of ZEB-1, a transcriptional repressor of E-cadherin (45). PEITC inhibited androgen receptor (AR) transcriptional activity in prostate cancer cells by repressing miR-141 expression and miR-141-mediated downregulation of small heterodimer partner (shp), a repressor of AR (46).

Antibacterial activity

Bacterial infection with Helicobacter pylori is associated with a marked increase in the risk of peptic ulcer disease and gastric cancer (47). In the test tube and in tissue culture, purified sulforaphane inhibited the growth and killed multiple strains of H. pylori, including antibiotic resistant strains (48). In an animal model of H. pylori infection, sulforaphane administration for five days eradicated H. pylori from 8 out of 11 xenografts of human gastric tissue implanted in immune-compromised mice (49). In another H. pylori-infected mouse model, a functional Nrf2 pathway was found to be required for the reduction of gastric inflammation and infection in mice fed broccoli sprouts (50). In a small clinical trial, consumption of up to 56 g/day (2 oz/day) of glucoraphanin-rich broccoli sprouts for one week was associated with H. pylori eradication in only three out of nine gastritis patients (51). In another trial, daily consumption of 70 g/day (~2-3 servings/day) of glucoraphanin-rich broccoli sprouts for two months significantly reduced markers of inflammation and infection in H. pylori–infected volunteers compared to those who consumed alfalfa sprouts (50). However, the extent to which glucoraphanin was converted to sulforaphane in broccoli sprout-fed participants was not measured.

Disease Prevention

Cancer

Isothiocyanates are thought to play a prominent role in the potential anticancer and cardiovascular benefits associated with cruciferous vegetable consumption (52, 53). Genetic variations in the sequence of genes coding for GSTs may affect the activity of GSTs. Such variations have been identified in humans. Specifically, null variants of the GSTM1 and GSTT1 alleles contain large deletions, and individuals who inherit two copies of the GSTM1-null or GSTT1-null alleles cannot produce the corresponding GST enzymes (54). It has been proposed that a reduced GST activity in these individuals would slow the rate of excretion of isothiocyanates, thereby increasing tissue exposure to isothiocyanates after cruciferous vegetable consumption (55). In addition, GSTs are involved in "detoxifying" potentially harmful substances like carcinogens, suggesting that individuals with reduced GST activity might also be more susceptible to cancer (56-58). Further, induction of the expression and activity of GSTs and other phase II detoxification/antioxidant enzymes by isothiocyanates is an important defense mechanism against oxidative stress and damage associated with the development of diseases like cancer and cardiovascular disease (11). The ability of glucoraphanin-derived sulforaphane to reduce oxidative stress in different settings is linked to activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (see Biological Activities). Yet, whether potential protection conferred by isothiocyanates via the Nrf2-dependent pathway is diminished in individuals carrying GST null variants is currently unknown. Some, but not all, observational studies have suggested that GST genotypes could influence the associations between cruciferous vegetable consumption and risk of disease (59).

Naturally occurring isothiocyanates and their metabolites have been found to inhibit the development of chemically-induced cancers of the lung, liver, esophagus, stomach, small intestine, colon, and breast in a variety of animal models (20). Although observational studies provide some evidence that higher intakes of cruciferous vegetables are associated with decreased cancer risk in humans (59), it is difficult to determine whether such protective effects are related to isothiocyanates or other factors associated with cruciferous vegetable consumption (see the article on Cruciferous Vegetables). Clinical evidence of a protective effect of isothiocyanates in humans is scarce. For example, in a recent randomized, cross-over intervention, administration of PEITC (40 mg/day for five days) caused a modest, yet significant, 7.7% reduction in the metabolic activation of the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in cigarette smokers (60). Another randomized controlled trial in men with biochemically relapsing cancer after radical prostatectomy suggested that prostate-specific antigen (PSA) values tended to increase less in those given daily oral sulforaphane (4.4 or 26.6 mg/day) for six months compared to those receiving the placebo (61). In a recent double-blind, randomized, placebo-controlled trial in women with abnormal mammograms, two-to-eight week consumption of about 250 mg/day of broccoli seed extract (~220 g of glucoraphanin/day) before surgery failed to affect the expression of markers of proliferation and gene expression, including ki-67, p21, HDACs, and acetylated histones, in breast tissues collected after surgery (62).

Sources

Food sources

Cruciferous vegetables

Cruciferous vegetables, such as bok choi, broccoli, Brussels sprouts, cabbage, cauliflower, horseradish, kale, kohlrabi, mustard, radish, rutabaga, turnip, and watercress, are rich sources of glucosinolate precursors of isothiocyanates (63). Unlike some other phytochemicals, glucosinolates are present in relatively high concentrations in commonly consumed portions of cruciferous vegetables. For example one-half cup of raw broccoli might provide more than 25 mg of total glucosinolates. The glucosinolate content of selected cruciferous vegetables is presented in Table 1 (64). Note that while the composition and content of glucosinolates in cruciferous vegetables are relatively stable, they depend on the genus and species and can vary greatly with plant growing and post-harvest storage conditions, as well as culinary processing.

Table 1. Glucosinolate Content of Selected Cruciferous Vegetables
Food (raw) Serving Total Glucosinolates (mg)
Brussels sprouts ½ cup (44 g)
104
Garden cress ½ cup (25 g)
98
Mustard greens ½ cup, chopped (28 g)
79
Turnip ½ cup, cubes (65 g)
60
Cabbage, savoy ½ cup, chopped (45 g)
35
Kale 1 cup, chopped (67 g)
67
Watercress 1 cup, chopped (34 g)
32
Kohlrabi ½ cup, chopped (67 g)
31
Cabbage, red ½ cup, chopped (45 g)
29
Broccoli ½ cup, chopped (44 g)
27
Horseradish 1 tablespoon (15 g)
24
Cauliflower ½ cup, chopped (50 g)
22
Bok choy (pak choi) ½ cup, chopped (35 g)
19

Table 2 lists vegetables that are relatively good sources of some of the isothiocyanates that are currently being studied for their potential anticancer properties (65).

Table 2. Food Sources of Selected Isothiocyanates and Their Glucosinolate Precursors
Isothiocyanate Glucosinolate (precursor) Food Sources
Allyl isothiocyanate (AITC) Sinigrin Broccoli, Brussels sprouts, cabbage, horseradish, kohlrabi, mustard, radish
Benzyl isothiocyanate (BITC) Glucotropaeolin Cabbage, garden cress, Indian cress
Phenethyl isothiocyanate (PEITC) Gluconasturtiin Watercress
Sulforaphane Glucoraphanin Broccoli, Brussels sprouts, cabbage, cauliflower, kale

Amounts of isothiocyanates formed from glucosinolates in foods are variable and depend partly on food processing and preparation (see the article on Cruciferous Vegetables). In a recent study that examined total isothiocyanate content in 73 samples from nine types of raw cruciferous vegetables commonly consumed in the US (namely broccoli, cabbage, cauliflower, Brussels sprout, kale, collard green, mustard green, and turnip greens), an average yield of 16.2 µmol/100 g wet weight was reported, with a 41-fold difference of isothiocyanate yield across the vegetables. The lowest mean level of isothiocyanate yield was found with raw cauliflower (1.5 µmol/100 g), while raw mustard greens had the highest yield (61.3 µmol/100g) (66)

Broccoli sprouts

The amount of glucoraphanin, the precursor of sulforaphane, in broccoli seeds remains more or less constant as those seeds germinate and grow into mature plants. Thus, three-day old broccoli sprouts are concentrated sources of glucoraphanin, which contain 10 to 100 times more glucoraphanin by weight than mature broccoli plants (67). Broccoli sprouts that are certified to contain at least 73 mg of glucoraphanin (also called sulforaphane glucosinolate) per 1-oz serving are available in some health food and grocery stores.

Supplements

Dietary supplements containing extracts of broccoli sprouts, broccoli, and other cruciferous vegetables are available without a prescription. Some products are standardized to contain a minimum amount of glucosinolates and/or sulforaphane. However, the bioavailability of isothiocyanates was found to be much lower with the consumption of broccoli supplements devoid of myrosinase than with the consumption of fresh broccoli sprouts. Peak concentrations of sulforaphane metabolites were found to be eight- and five-times greater in plasma and urine, respectively, following fresh broccoli versus supplement consumption (68). Interestingly, total HDAC activity in peripheral blood mononuclear cells (PBMC) of broccoli sprout consumers was reported to be significantly lower than in PBMC of subjects who consumed the supplement (see Biological Activities) (69).

Safety

Adverse effects

No serious adverse effects of isothiocyanates in humans have been reported. The majority of animal studies have found that isothiocyanates inhibited the development of cancer when given prior to the chemical carcinogen (pre-initiation). However, very high intakes of PEITC or BITC (25 to 250 times higher than average human dietary isothiocyanate intakes) have been found to promote bladder cancer in rats when given after cancer initiation by a chemical carcinogen (70). The relevance of these findings to human urinary bladder cancer is not clear, since at least one prospective cohort study found cruciferous vegetable consumption to be inversely associated with the risk of bladder cancer in men (71). Other potential toxic effects reported in rodents have not been corroborated by observations in humans (20).

Pregnancy and lactation

Although high dietary intakes of glucosinolates from cruciferous vegetables are not known to have adverse effects during pregnancy or lactation, there is no information on the safety of purified isothiocyanates or supplements containing high doses of glucosinolates and/or isothiocyanates during pregnancy or lactation in humans.

Drug interactions

Isothiocyanates are not known to interact with any drugs or medications. However, the potential for isothiocyanates to inhibit various isoforms of the cytochrome P450 (CYP) family of enzymes raises the potential for interactions with drugs that are CYP substrates (see Biological Activities). Isothiocyanates may sensitize cancer cells to anticancer drugs and/or increase drug cytotoxicity, as shown in in vitro and animal models. Yet, these potential benefits of isothiocyanates in cancer therapy have not been explored in clinical trials (72).


Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in April 2017 by:
Emily Ho, Ph.D.
Principal Investigator, Linus Pauling Institute
Professor, College of Public Health and Human Sciences
Endowed Director, Moore Family Center for Whole Grain Foods,
Nutrition and Preventive Health
Oregon State University

Copyright 2005-2017  Linus Pauling Institute


References

1.  Fahey JW, Zalcmann AT, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry. 2001;56(1):5-51.  (PubMed)

2.  Zhang Y. Cancer-preventive isothiocyanates: measurement of human exposure and mechanism of action. Mutat Res. 2004;555(1-2):173-190.  (PubMed)

3.  Hecht SS. Chemoprevention by Isothiocyanates. In: Kelloff GJ, Hawk ET, Sigman CC, eds. Promising Cancer Chemopreventive Agents, Volume 1: Cancer Chemopreventive Agents Totowa, NJ: Humana Press; 2004:21-35.

4.  Barba FJ, Nikmaram N, Roohinejad S, Khelfa A, Zhu Z, Koubaa M. Bioavailability of Glucosinolates and Their Breakdown Products: Impact of Processing. Front Nutr. 2016;3:24.  (PubMed)

5.  Luang-In V, Albaser AA, Nueno-Palop C, Bennett MH, Narbad A, Rossiter JT. Glucosinolate and Desulfo-glucosinolate Metabolism by a Selection of Human Gut Bacteria. Curr Microbiol. 2016;73(3):442-451.  (PubMed)

6.  Fahey JW, Wehage SL, Holtzclaw WD, et al. Protection of humans by plant glucosinolates: efficiency of conversion of glucosinolates to isothiocyanates by the gastrointestinal microflora. Cancer Prev Res (Phila). 2012;5(4):603-611.  (PubMed)

7.  Verkerk R, Schreiner M, Krumbein A, et al. Glucosinolates in Brassica vegetables: the influence of the food supply chain on intake, bioavailability and human health. Mol Nutr Food Res. 2009;53 Suppl 2:S219.  (PubMed)

8.  Li F, Hullar MA, Beresford SA, Lampe JW. Variation of glucoraphanin metabolism in vivo and ex vivo by human gut bacteria. Br J Nutr. 2011;106(3):408-416.  (PubMed)

9.  Hu R, Xu C, Shen G, et al. Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. Life Sci. 2006;79(20):1944-1955.  (PubMed)

10.  Wagner AE, Boesch-Saadatmandi C, Dose J, Schultheiss G, Rimbach G. Anti-inflammatory potential of allyl-isothiocyanate--role of Nrf2, NF-(kappa) B and microRNA-155. J Cell Mol Med. 2012;16(4):836-843.  (PubMed)

11.  Bryan HK, Olayanju A, Goldring CE, Park BK. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol. 2013;85(6):705-717.  (PubMed)

12.  Guerrero-Beltran CE, Calderon-Oliver M, Pedraza-Chaverri J, Chirino YI. Protective effect of sulforaphane against oxidative stress: recent advances. Exp Toxicol Pathol. 2012;64(5):503-508.  (PubMed)

13.  Zhao Z, Liao G, Zhou Q, Lv D, Holthfer H, Zou H. Sulforaphane attenuates contrast-induced nephropathy in rats via Nrf2/HO-1 pathway. Oxid Med Cell Longev. 2016;2016:9825623.  (PubMed)

14.  Wang Y, Zhang Z, Sun W, et al. Sulforaphane attenuation of type 2 diabetes-induced aortic damage was associated with the upregulation of Nrf2 expression and function. Oxid Med Cell Longev. 2014;2014:123963.  (PubMed)

15.  Chi X, Zhang R, Shen N, et al. Sulforaphane reduces apoptosis and oncosis along with protecting liver injury-induced ischemic reperfusion by activating the Nrf2/ARE pathway. Hepatol Int. 2015;9(2):321-329.  (PubMed)

16.  Riedl MA, Saxon A, Diaz-Sanchez D. Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clin Immunol. 2009;130(3):244-251.  (PubMed)

17.  Wise RA, Holbrook JT, Criner G, et al. Lack of effect of oral sulforaphane administration on Nrf2 expression in COPD: a randomized, double-blind, placebo controlled trial. PLoS One. 2016;11(11):e0163716.  (PubMed)

18.  Dong Z, Shang H, Chen YQ, Pan LL, Bhatia M, Sun J. Sulforaphane protects pancreatic acinar cell injury by modulating Nrf2-mediated oxidative stress and NLRP3 inflammatory pathway. Oxid Med Cell Longev. 2016;2016:7864150.  (PubMed)

19.  Qi T, Xu F, Yan X, Li S, Li H. Sulforaphane exerts anti-inflammatory effects against lipopolysaccharide-induced acute lung injury in mice through the Nrf2/ARE pathway. Int J Mol Med. 2016;37(1):182-188.  (PubMed)

20.  Kumar G, Tuli HS, Mittal S, Shandilya JK, Tiwari A, Sandhu SS. Isothiocyanates: a class of bioactive metabolites with chemopreventive potential. Tumour Biol. 2015;36(6):4005-4016.  (PubMed)

21.  Lampe JW, Peterson S. Brassica, biotransformation and cancer risk: genetic polymorphisms alter the preventive effects of cruciferous vegetables. J Nutr. 2002;132(10):2991-2994.  (PubMed)

22.  La Marca M, Beffy P, Della Croce C, et al. Structural influence of isothiocyanates on expression of cytochrome P450, phase II enzymes, and activation of Nrf2 in primary rat hepatocytes. Food Chem Toxicol. 2012;50(8):2822-2830.  (PubMed)

23.  Vanduchova A, Tomankova V, Anzenbacher P, Anzenbacherova E. Influence of Sulforaphane Metabolites on Activities of Human Drug-Metabolizing Cytochrome P450 and Determination of Sulforaphane in Human Liver Cells. J Med Food. 2016;19(12):1141-1146.  (PubMed)

24.  Ioannides C, Konsue N. A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism. Drug Metab Rev. 2015;47(3):356-373.  (PubMed)

25.  Kensler TW, Talalay P. Inducers of enzymes that protect against carcinogens and oxidants: drug- and food-based approaches with dithiolethiones and sulforaphane. In: Kelloff GJ, Hawk ET, Sigman CC, eds. Promising Cancer Chemopreventive Agents, Volume 1: Cancer Chemopreventive Agents Totowa, NJ: Humana Press; 2004:3-20.

26.  Hecht SS, Carmella SG, Murphy SE. Effects of watercress consumption on urinary metabolites of nicotine in smokers. Cancer Epidemiol Biomarkers Prev. 1999;8(10):907-913.  (PubMed)

27.  Nijhoff WA, Grubben MJ, Nagengast FM, et al. Effects of consumption of Brussels sprouts on intestinal and lymphocytic glutathione S-transferases in humans. Carcinogenesis. 1995;16(9):2125-2128.  (PubMed)

28.  Nijhoff WA, Mulder TP, Verhagen H, van Poppel G, Peters WH. Effects of consumption of brussels sprouts on plasma and urinary glutathione S-transferase class-alpha and -pi in humans. Carcinogenesis. 1995;16(4):955-957.  (PubMed)

29.  Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci. 2003;24(3):139-145.  (PubMed)

30.  Khor TO, Cheung WK, Prawan A, Reddy BS, Kong AN. Chemoprevention of familial adenomatous polyposis in Apc(Min/+) mice by phenethyl isothiocyanate (PEITC). Mol Carcinog. 2008;47(5):321-325.  (PubMed)

31.  Cho HJ, Lim do Y, Kwon GT, et al. Benzyl isothiocyanate inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate (TRAMP) model, which is associated with the induction of cell cycle G1 arrest. Int J Mol Sci. 2016;17(2):264.  (PubMed)

32.  Wang L, Tian Z, Yang Q, et al. Sulforaphane inhibits thyroid cancer cell growth and invasiveness through the reactive oxygen species-dependent pathway. Oncotarget. 2015;6(28):25917-25931.  (PubMed)

33.  Kim M, Cho HJ, Kwon GT, et al. Benzyl isothiocyanate suppresses high-fat diet-stimulated mammary tumor progression via the alteration of tumor microenvironments in obesity-resistant BALB/c mice. Mol Carcinog. 2015;54(1):72-82.  (PubMed)

34.  Gupta P, Adkins C, Lockman P, Srivastava SK. Metastasis of breast tumor cells to brain is suppressed by phenethyl isothiocyanate in a novel in vivo metastasis model. PLoS One. 2013;8(6):e67278.  (PubMed)

35.  Cavell BE, Syed Alwi SS, Donlevy A, Packham G. Anti-angiogenic effects of dietary isothiocyanates: mechanisms of action and implications for human health. Biochem Pharmacol. 2011;81(3):327-336.  (PubMed)

36.  Delage B, Dashwood RH. Targeting the epigenome with dietary agents. Dietary Modulation of Cell Signaling Pathways: CRC Press; 2008.

37.  Marks PA, Richon VM, Miller T, Kelly WK. Histone deacetylase inhibitors. Adv Cancer Res. 2004;91:137-168.  (PubMed)

38.  Abbaoui B, Telu KH, Lucas CR, et al. The impact of cruciferous vegetable isothiocyanates on histone acetylation and histone phosphorylation in bladder cancer. J Proteomics. 2017;156:94-103.  (PubMed)

39.  Batra S, Sahu RP, Kandala PK, Srivastava SK. Benzyl isothiocyanate-mediated inhibition of histone deacetylase leads to NF-kappaB turnoff in human pancreatic carcinoma cells. Mol Cancer Ther. 2010;9(6):1596-1608.  (PubMed)

40.  Clarke JD, Hsu A, Yu Z, Dashwood RH, Ho E. Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells. Mol Nutr Food Res. 2011;55(7):999-1009.  (PubMed)

41.  Pledgie-Tracy A, Sobolewski MD, Davidson NE. Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther. 2007;6(3):1013-1021.  (PubMed)

42.  Rajendran P, Delage B, Dashwood WM, et al. Histone deacetylase turnover and recovery in sulforaphane-treated colon cancer cells: competing actions of 14-3-3 and Pin1 in HDAC3/SMRT corepressor complex dissociation/reassembly. Mol Cancer. 2011;10:68.  (PubMed)

43.  Rajendran P, Kidane AI, Yu TW, et al. HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics. 2013;8(6):612-623.  (PubMed)

44.  Myzak MC, Tong P, Dashwood WM, Dashwood RH, Ho E. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Exp Biol Med (Maywood). 2007;232(2):227-234.  (PubMed)

45.  Shan Y, Zhang L, Bao Y, et al. Epithelial-mesenchymal transition, a novel target of sulforaphane via COX-2/MMP2, 9/Snail, ZEB1 and miR-200c/ZEB1 pathways in human bladder cancer cells. J Nutr Biochem. 2013;24(6):1062-1069.  (PubMed)

46.  Xiao J, Gong AY, Eischeid AN, et al. miR-141 modulates androgen receptor transcriptional activity in human prostate cancer cells through targeting the small heterodimer partner protein. Prostate. 2012;72(14):1514-1522.  (PubMed)

47.  US National Cancer Institute. Helicobacter pylori and cancer. Available at: https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/h-pylori-fact-sheet. Accessed 2/28/17. 

48.  Fahey JW, Haristoy X, Dolan PM, et al. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci U S A. 2002;99(11):7610-7615.  (PubMed)

49.  Haristoy X, Angioi-Duprez K, Duprez A, Lozniewski A. Efficacy of sulforaphane in eradicating Helicobacter pylori in human gastric xenografts implanted in nude mice. Antimicrob Agents Chemother. 2003;47(12):3982-3984.  (PubMed)

50.  Yanaka A, Fahey JW, Fukumoto A, et al. Dietary sulforaphane-rich broccoli sprouts reduce colonization and attenuate gastritis in Helicobacter pylori-infected mice and humans. Cancer Prev Res (Phila). 2009;2(4):353-360.  (PubMed)

51.  Galan MV, Kishan AA, Silverman AL. Oral broccoli sprouts for the treatment of Helicobacter pylori infection: a preliminary report. Dig Dis Sci. 2004;49(7-8):1088-1090.  (PubMed)

52.  Bai Y, Wang X, Zhao S, Ma C, Cui J, Zheng Y. Sulforaphane protects against cardiovascular disease via Nrf2 activation. Oxid Med Cell Longev. 2015;2015:407580.  (PubMed)

53.  Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224-236.  (PubMed)

54.  Coles BF, Kadlubar FF. Detoxification of electrophilic compounds by glutathione S-transferase catalysis: determinants of individual response to chemical carcinogens and chemotherapeutic drugs? Biofactors. 2003;17(1-4):115-130.  (PubMed)

55.  Seow A, Shi CY, Chung FL, et al. Urinary total isothiocyanate (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione S-transferase M1/T1/P1 genotypes. Cancer Epidemiol Biomarkers Prev. 1998;7(9):775-781.  (PubMed)

56.  Economopoulos KP, Choussein S, Vlahos NF, Sergentanis TN. GSTM1 polymorphism, GSTT1 polymorphism, and cervical cancer risk: a meta-analysis. Int J Gynecol Cancer. 2010;20(9):1576-1580.  (PubMed)

57.  Egner PA, Chen JG, Zarth AT, et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prev Res (Phila). 2014;7(8):813-823.  (PubMed)

58.  Yuan JM, Murphy SE, Stepanov I, et al. 2-Phenethyl Isothiocyanate, Glutathione S-transferase M1 and T1 Polymorphisms, and Detoxification of Volatile Organic Carcinogens and Toxicants in Tobacco Smoke. Cancer Prev Res (Phila). 2016;9(7):598-606.  (PubMed)

59.  Traka MH. Chapter 9: Health benefits of glucosinolates. Advances in Botanical Research. 2016;80:247-279. 

60.  Yuan JM, Stepanov I, Murphy SE, et al. Clinical trial of 2-phenethyl isothiocyanate as an inhibitor of metabolic activation of a tobacco-specific lung carcinogen in cigarette smokers. Cancer Prev Res (Phila). 2016;9(5):396-405.  (PubMed)

61.  Cipolla BG, Mandron E, Lefort JM, et al. Effect of sulforaphane in men with biochemical recurrence after radical prostatectomy. Cancer Prev Res (Phila). 2015;8(8):712-719.  (PubMed)

62.  Atwell LL, Zhang Z, Mori M, et al. Sulforaphane bioavailability and chemopreventive activity in women scheduled for breast biopsy. Cancer Prev Res (Phila). 2015;8(12):1184-1191.  (PubMed)

63.  International Agency for Research on Cancer. Cruciferous vegetables, isothiocyanates and indoles. Cruciferous vegetables. France: IARC; 2004:1-12. 

64.  McNaughton SA, Marks GC. Development of a food composition database for the estimation of dietary intakes of glucosinolates, the biologically active constituents of cruciferous vegetables. Br J Nutr. 2003;90(3):687-697.  (PubMed)

65.  Ishida M, Hara M, Fukino N, Kakizaki T, Morimitsu Y. Glucosinolate metabolism, functionality and breeding for the improvement of Brassicaceae vegetables. Breed Sci. 2014;64(1):48-59.  (PubMed)

66.  Tang L, Paonessa JD, Zhang Y, Ambrosone CB, McCann SE. Total isothiocyanate yield from raw cruciferous vegetables commonly consumed in the United States. J Funct Foods. 2013;5(4):1996-2001.  (PubMed)

67.  Fahey JW, Zhang Y, Talalay P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci U S A. 1997;94(19):10367-10372.  (PubMed)

68.  Clarke JD, Hsu A, Riedl K, et al. Bioavailability and inter-conversion of sulforaphane and erucin in human subjects consuming broccoli sprouts or broccoli supplement in a cross-over study design. Pharmacol Res. 2011;64(5):456-463.  (PubMed)

69.  Clarke JD, Riedl K, Bella D, Schwartz SJ, Stevens JF, Ho E. Comparison of isothiocyanate metabolite levels and histone deacetylase activity in human subjects consuming broccoli sprouts or broccoli supplement. J Agric Food Chem. 2011;59(20):10955-10963.  (PubMed)

70.  Okazaki K, Umemura T, Imazawa T, Nishikawa A, Masegi T, Hirose M. Enhancement of urinary bladder carcinogenesis by combined treatment with benzyl isothiocyanate and N-butyl-N-(4-hydroxybutyl)nitrosamine in rats after initiation. Cancer Sci. 2003;94(11):948-952.  (PubMed)

71.  Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC, Giovannucci EL. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl Cancer Inst. 1999;91(7):605-613.  (PubMed)

72.  Minarini A, Milelli A, Fimognari C, Simoni E, Turrini E, Tumiatti V. Exploring the effects of isothiocyanates on chemotherapeutic drugs. Expert Opin Drug Metab Toxicol. 2014;10(1):25-38.  (PubMed)

Lignans

Summary

  • Lignans are polyphenols found in plants. (More information)
  • Lignan precursors are found in a wide variety of plant-based foods, including seeds, whole grains, legumes, fruit, and vegetables. (More information)
  • Flaxseeds are the richest dietary source of lignan precursors. (More information)
  • When consumed, lignan precursors are converted to the enterolignans, enterodiol and enterolactone, by bacteria that normally colonize the human intestine. (More information)
  • Enterodiol and enterolactone have weak estrogenic activity but may also exert biological effects through nonestrogenic mechanisms. (More information)
  • Lignan-rich foods are part of a healthful dietary pattern, but the role of lignans in the prevention of hormone-associated cancers, osteoporosis, and cardiovascular disease is not yet clear. (More information)

Introduction

The enterolignans, enterodiol and enterolactone (Figure 1), are formed by the action of intestinal bacteria on lignan precursors found in plants (1). Because enterodiol and enterolactone can mimic some of the effects of estrogens, their plant-derived precursors are classified as phytoestrogens. Lignan precursors that have been identified in the human diet include pinoresinol, lariciresinol, secoisolariciresinol, matairesinol, and others (Figure 2). Secoisolariciresinol and matairesinol were among the first lignan precursors identified in the human diet and are therefore the most extensively studied. Lignan precursors are found in a wide variety of foods, including flaxseeds, sesame seeds, legumes, whole grains, fruit, and vegetables. While most research on phytoestrogen-rich diets has focused on soy isoflavones, lignans are the principal source of dietary phytoestrogens in typical Western diets (2, 3).

Figure 1. Chemical Structures of the Enterolignans, Enterodiol and Enterolactone.

Figure 2. Chemical Structures of Some Dietary Lignan Precursors: secoisolariciresinol, matairesinol, lariciresinol, and pinoresinol.

Metabolism and Bioavailability

When plant lignans are ingested, they can be metabolized by intestinal bacteria to the enterolignans, enterodiol and enterolactone, in the intestinal lumen (4). Enterodiol can also be converted to enterolactone by intestinal bacteria. Not surprisingly, antibiotic use has been associated with lower serum enterolactone levels (5). Thus, enterolactone levels measured in serum and urine reflect the activity of intestinal bacteria in addition to dietary intake of plant lignans. Because data on the lignan content of foods are limited, serum and urinary enterolactone levels are sometimes used as markers of dietary lignan intake. A pharmacokinetic study that measured plasma and urinary levels of enterodiol and enterolactone after a single dose (0.9 mg/kg of body weight) of secoisolariciresinol, the principal lignan in flaxseed, found that at least 40% was available to the body as enterodiol and enterolactone (6). Plasma enterodiol concentrations peaked at 73 nanomoles/liter (nmol/L) an average of 15 hours after ingestion of secoisolariciresinol, and plasma enterolactone concentrations peaked at 56 nmol/L an average of 20 hours after ingestion. Thus, substantial amounts of ingested plant lignans are available to humans in the form of enterodiol and enterolactone. Considerable variation among individuals in urinary and serum enterodiol:enterolactone ratios has been observed in flaxseed feeding studies, suggesting that some individuals convert most enterodiol to enterolactone, while others convert relatively little (1). It is likely that individual differences in the metabolism of lignans, possibly due to gut microbes, influence the biological activities and health effects of these compounds.

Biological Activities

Estrogenic and anti-estrogenic activities

Estrogens are signaling molecules (hormones) that exert their effects by binding to estrogen receptors within cells (Figure 3). The estrogen-receptor complex interacts with DNA to change the expression of estrogen-responsive genes. Estrogen receptors are present in numerous tissues other than those associated with reproduction, including bone, liver, heart, and brain (7). Although phytoestrogens can also bind to estrogen receptors, their estrogenic activity is much weaker than endogenous estrogens, and they may actually block or antagonize the effects of estrogen in some tissues (8). Scientists are interested in the tissue-selective activities of phytoestrogens because anti-estrogenic effects in reproductive tissue could help reduce the risk of hormone-associated cancers (breast, uterine, ovarian, and prostate), while estrogenic effects in bone could help maintain bone density. The enterolignans, enterodiol and enterolactone, are known to have weak estrogenic activity. At present, the extent to which enterolignans exert weak estrogenic and/or anti-estrogenic effects in humans is not well understood.

Figure 3. Chemical Structures of Some Endogenous Mammalian Estrogens: 17 beta-estradiol, estriol, and estrone.

Estrogen receptor-independent activities

Enterolignans also have biological activities that are unrelated to their interactions with estrogen receptors. By altering the activity of enzymes involved in estrogen metabolism, lignans may change the biological activity of endogenous estrogens (9). Lignans can act as antioxidants in the test tube, but the significance of such antioxidant activity in humans is not clear because lignans are rapidly and extensively metabolized (4). Although one cross-sectional study found that a biomarker of oxidative damage was inversely associated with serum enterolactone levels in men (10), it is not clear whether this effect was related to enterolactone or other antioxidants present in lignan-rich foods.

Disease Prevention

Cardiovascular disease

Diets rich in foods containing plant lignans (whole grains, nuts and seeds, legumes, fruit, and vegetables) have been consistently associated with reductions in risk of cardiovascular disease. However, it is likely that numerous nutrients and phytochemicals found in these foods contribute to their cardioprotective effects. In a prospective cohort study of 1,889 Finnish men followed for an average of 12 years, those with the highest serum enterolactone levels (a marker of plant lignan intake) were significantly less likely to die from coronary heart disease (CHD) or cardiovascular disease than those with the lowest levels (11). However, a recent study in male smokers did not find strong support for an association between serum enterolactone levels and CHD (12). Flaxseeds are among the richest sources of plant lignans in the human diet, but they are also good sources of other nutrients and phytochemicals with cardioprotective effects, such as omega-3 fatty acids and fiber. Four small clinical trials found that adding 30 to 50 g/day of flaxseed to the usual diet for 4 to 12 weeks resulted in modest 8%-14% decreases in LDL cholesterol levels (13-16), while four other trials did not observe significant reductions in LDL cholesterol after adding 30 to 40 g/day of flaxseed to the diet (17-20). More recently, a double-blind, randomized controlled trial in adults aged 44 to 75 found that supplementation with 40 g/day of flaxseed led to significant reductions in LDL cholesterol after five weeks, but cholesterol reductions were not statistically significant following ten weeks of supplementation (21). Additionally, a one-year clinical trial in menopausal women reported that supplementation with 40 g/day of flaxseed did not lower LDL cholesterol compared to a placebo containing wheat germ (22). Most of these trials used ground or crushed flaxseed, which much more bioavailable than whole flaxseed (23). Although the results of prospective cohort studies consistently indicate that diets rich in whole grains, nuts, fruit, and vegetables are associated with significant reductions in cardiovascular disease risk, it is not yet clear whether lignans themselves are cardioprotective.

Hormone-associated cancers

Breast cancer

Overall, there is little evidence that dietary intake of plant lignans is significantly associated with breast cancer risk; studies to date have reported conflicting results. Two prospective cohort studies examining plant lignan intake and breast cancer found no association (24, 25). A more recent prospective study reported no association between total lignan intake and breast cancer in premenopausal women (26). In another prospective analysis, the same group of authors found postmenopausal women in the highest quartile of dietary lignan intake had a 17% lower risk of breast cancer compared to women in the lowest quartile, but this protective association was only observed in women with estrogen-positive and progesterone-positive tumors (27). A recent meta-analysis did not find an overall association between dietary lignan intake and breast cancer, but when the analysis was limited to postmenopausal women, the authors reported a 15% reduction in risk of breast cancer with high lignan intake (28). Several studies, mainly case-control studies, have examined the relationship between blood or urine levels of enterolactone and breast cancer; results of these studies are conflicting (29-31). Moreover, a recent meta-analysis did not find an association between blood levels of enterolactone and breast cancer (28). At present, it is not clear whether high intakes of plant lignans or high circulating levels of enterolignans offer significant protective effects against breast cancer.

Endometrial and ovarian cancer

In a case-control study of lignans and endometrial cancer, US women with the highest intakes of plant lignans had the lowest risk of endometrial cancer, but the reduction in risk was statistically significant in postmenopausal women only (32). Yet, a recent prospective case-control study in three different countries (US, Sweden, and Italy) did not find an association between circulating enterolactone, a marker of lignan intake, and endometrial cancer in premenopausal or in postmenopausal women (33). In the only case-control study of lignans and ovarian cancer, US women with the highest intakes of plant lignans had the lowest risk of ovarian cancer (34). However, high intakes of other phytochemicals associated with plant-based diets like fiber, carotenoids, and phytosterols were also associated with decreased ovarian cancer risk. Although these studies support the hypothesis that diets rich in plant foods may be helpful in decreasing the risk of hormone-associated cancers, they do not provide strong evidence that lignans are protective against endometrial or ovarian cancer.

Prostate cancer

Although dietary lignans are the principal source of phytoestrogens in the typical Western diet, relationships between dietary lignan intake and prostate cancer risk have not been well-studied. Three prospective case-control studies examined the relationship between circulating enterolactone concentrations, a marker of lignan intake, and the subsequent development of prostate cancer in Scandinavian men (35-37). In all three studies, initial serum enterolactone concentrations in men who were diagnosed with prostate cancer five to 14 years later were not significantly different from serum enterolactone levels in matched control groups of men who did not develop prostate cancer. In a retrospective case-control study, recalled dietary lignan intake did not differ between US men diagnosed with prostate cancer and a matched control group (38). More recently, serum enterolactone levels were not significantly associated with risk of prostate cancer in a case-control study in Swedish men (39). Additionally, two prospective, European case-control studies did not find an association between serum enterolactone and prostate cancer (40, 41). However, a case-control study conducted in Scotland found that higher serum enterolactone concentrations were associated with a lower risk of prostate cancer (42). At present, limited data from epidemiological studies do not support a relationship between dietary lignan intake and prostate cancer risk.

Osteoporosis

Research on the effects of dietary lignan intake on osteoporosis risk is very limited. In two small observational studies, urinary enterolactone excretion was used as a marker of dietary lignan intake. One study of 75 postmenopausal Korean women, who were classified as osteoporotic, osteopenic, or normal on the basis of bone mineral density (BMD) measurements, found that urinary enterolactone excretion was positively associated with BMD of the lumbar spine and hip (43). However, a study of 50 postmenopausal Dutch women found that higher levels of urinary enterolactone excretion were associated with higher rates of bone loss (44). In two separate placebo controlled trials, supplementation of postmenopausal women with 25 to 40 g/day of ground flaxseed for 3 to 4 months did not significantly alter biochemical markers of bone formation or bone resorption (loss) (19, 45). More research is necessary to determine whether high dietary intakes of plant lignans can decrease the risk or severity of osteoporosis.

Sources

Food sources

Lignans are present in a wide variety of plant foods, including seeds (flax, pumpkin, sunflower, poppy, sesame), whole grains (rye, oats, barley), bran (wheat, oat, rye), beans, fruit (particularly berries), and vegetables (30, 46). Secoisolariciresinol and matairesinol were the first plant lignans identified in foods (47). Pinoresinol and laricresinol, two recently identified plant lignans, contribute substantially to total dietary lignan intakes. A survey of 4,660 Dutch men and women during 1997-1998 found that the median total lignan intake was 0.98 mg/day (48). Lariciresinol and pinoresinol contributed about 75% to the total lignan intake, while secoisolariciresinol and matairesinol contributed only about 25%. Plant lignans are the principal source of phytoestrogens in the diets of people who do not typically consume soy foods. The daily phytoestrogen intake of postmenopausal women in the US was estimated to be less than 1 mg/day, with 80% from lignans and 20% from isoflavones (49).

Flaxseed is by far the richest dietary source of plant lignans (50), and lignan bioavailability can be improved by crushing or milling flaxseed (23). Lignans are not associated with the oil fraction of foods, so flaxseed oils do not typically provide lignans unless ground flaxseed has been added to the oil. A variety of factors may affect the lignan contents of plants, including geographic location, climate, maturity, and storage conditions. Table 1 provides the total lignan (secoisolariciresinol, matairesinol, pinoresinol, and lariciresinol) contents of selected lignan-rich foods (51).

Table 1. Total Lignan Content of Selected Foods
Food Serving Total Lignans (mg)
Flaxseeds 1 oz
85.5
Sesame seeds 1 oz
11.2
Curly kale ½ cup, chopped
0.8
Broccoli ½ cup, chopped
0.6
Apricots ½ cup, sliced
0.4
Cabbage ½ cup, chopped
0.3
Brussels sprouts ½ cup, chopped
0.3
Strawberries ½ cup
0.2
Tofu ¼ block (4 oz)
0.2
Dark rye bread 1 slice
0.1

Supplements

Dietary supplements containing lignans derived from flaxseed are available in the US without a prescription. One such supplement provides 50 mg of secoisolariciresinol diglycoside per capsule.

Safety

Adverse effects

Lignan precursors in foods are not known to have any adverse effects. Flaxseeds, which are rich in lignan precursors as well as fiber, may increase stool frequency or cause diarrhea in doses of 45 to 50 g/day in adults (13, 52). The safety of lignan supplements in pregnant or lactating women has not been established. Therefore, lignan supplements should be avoided by women who are pregnant, breast-feeding, or trying to conceive.


Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2010 by:
Johanna W. Lampe, Ph.D., R.D.
Full Member, Fred Hutchinson Cancer Research Center
Research Professor, Epidemiology
School of Public Health and Community Medicine, University of Washington
Seattle, WA

Copyright 2004-2017  Linus Pauling Institute 


References

1.  Lampe JW. Isoflavonoid and lignan phytoestrogens as dietary biomarkers. J Nutr. 2003;133 Suppl 3:956S-964S.  (PubMed)

2.  de Kleijn MJ, van der Schouw YT, Wilson PW, Grobbee DE, Jacques PF. Dietary intake of phytoestrogens is associated with a favorable metabolic cardiovascular risk profile in postmenopausal U.S. women: the Framingham study. J Nutr. 2002;132(2):276-282.  (PubMed)

3.  Valsta LM, Kilkkinen A, Mazur W, et al. Phyto-oestrogen database of foods and average intake in Finland. Br J Nutr. 2003;89 Suppl 1:S31-38.  (PubMed)

4.  Rowland I, Faughnan M, Hoey L, Wahala K, Williamson G, Cassidy A. Bioavailability of phyto-oestrogens. Br J Nutr. 2003;89 Suppl 1:S45-58.  (PubMed)

5.  Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonen P, Adlercreutz H. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol. 2002;155(5):472-477.  (PubMed)

6.  Kuijsten A, Arts IC, Vree TB, Hollman PC. Pharmacokinetics of enterolignans in healthy men and women consuming a single dose of secoisolariciresinol diglucoside. J Nutr. 2005;135(4):795-801.  (PubMed)

7.  National Cancer Institute. Understanding Estrogen Receptors/SERMs. National Cancer Institute. January, 2005. http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors. Accessed 1/15/10.

8.  Wang LQ. Mammalian phytoestrogens: enterodiol and enterolactone. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;777(1-2):289-309.  (PubMed)

9.  Brooks JD, Thompson LU. Mammalian lignans and genistein decrease the activities of aromatase and 17beta-hydroxysteroid dehydrogenase in MCF-7 cells. J Steroid Biochem Mol Biol. 2005;94(5):461-467.  (PubMed)

10.  Vanharanta M, Voutilainen S, Nurmi T, et al. Association between low serum enterolactone and increased plasma F2-isoprostanes, a measure of lipid peroxidation. Atherosclerosis. 2002;160(2):465-469.  (PubMed)

11.  Vanharanta M, Voutilainen S, Rissanen TH, Adlercreutz H, Salonen JT. Risk of cardiovascular disease-related and all-cause death according to serum concentrations of enterolactone: Kuopio Ischaemic Heart Disease Risk Factor Study. Arch Intern Med. 2003;163(9):1099-1104.  (PubMed)

12.  Kilkkinen A, Erlund I, Virtanen MJ, Alfthan G, Ariniemi K, Virtamo J. Serum enterolactone concentration and the risk of coronary heart disease in a case-cohort study of Finnish male smokers. Am J Epidemiol. 2006;163(8):687-693.  (PubMed)

13.  Cunnane SC, Hamadeh MJ, Liede AC, Thompson LU, Wolever TM, Jenkins DJ. Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr. 1995;61(1):62-68.  (PubMed)

14.  Arjmandi BH, Khan DA, Jurna S. Whole flaxseed consumption lowers serum LDL-cholesterol and lipoprotein(a) concentrations in postmenopausal women. Nutr Res. 1998;18:1203-1214.

15.  Jenkins DJ, Kendall CW, Vidgen E, et al. Health aspects of partially defatted flaxseed, including effects on serum lipids, oxidative measures, and ex vivo androgen and progestin activity: a controlled crossover trial. Am J Clin Nutr. 1999;69(3):395-402.  (PubMed)

16.  Patade A, Devareddy L, Lucas EA, Korlagunta K, Daggy BP, Arjmandi BH. Flaxseed reduces total and LDL cholesterol concentrations in Native American postmenopausal women. J Womens Health (Larchmt). 2008;17(3):355-366.  (PubMed)

17.  Clark WF, Kortas C, Heidenheim AP, Garland J, Spanner E, Parbtani A. Flaxseed in lupus nephritis: a two-year nonplacebo-controlled crossover study. J Am Coll Nutr. 2001;20(2 Suppl):143-148.  (PubMed)

18.  Lemay A, Dodin S, Kadri N, Jacques H, Forest JC. Flaxseed dietary supplement versus hormone replacement therapy in hypercholesterolemic menopausal women. Obstet Gynecol. 2002;100(3):495-504.  (PubMed)

19.  Lucas EA, Wild RD, Hammond LJ, et al. Flaxseed improves lipid profile without altering biomarkers of bone metabolism in postmenopausal women. J Clin Endocrinol Metab. 2002;87(4):1527-1532.  (PubMed)

20.  Stuglin C, Prasad K. Effect of flaxseed consumption on blood pressure, serum lipids, hemopoietic system and liver and kidney enzymes in healthy humans. J Cardiovasc Pharmacol Ther. 2005;10(1):23-27.  (PubMed)

21.  Bloedon LT, Balikai S, Chittams J, et al. Flaxseed and cardiovascular risk factors: results from a double blind, randomized, controlled clinical trial. J Am Coll Nutr. 2008;27(1):65-74.  (PubMed)

22.  Dodin S, Lemay A, Jacques H, Legare F, Forest JC, Masse B. The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial. J Clin Endocrinol Metab. 2005;90(3):1390-1397.  (PubMed)

23.  Kuijsten A, Arts IC, van't Veer P, Hollman PC. The relative bioavailability of enterolignans in humans is enhanced by milling and crushing of flaxseed. J Nutr. 2005;135(12):2812-2816.  (PubMed)

24.  Horn-Ross PL, Hoggatt KJ, West DW, et al. Recent diet and breast cancer risk: the California Teachers Study (USA). Cancer Causes Control. 2002;13(5):407-415.  (PubMed)

25.  Keinan-Boker L, van Der Schouw YT, Grobbee DE, Peeters PH. Dietary phytoestrogens and breast cancer risk. Am J Clin Nutr. 2004;79(2):282-288.  (PubMed)

26.  Touillaud MS, Thiebaut AC, Niravong M, Boutron-Ruault MC, Clavel-Chapelon F. No association between dietary phytoestrogens and risk of premenopausal breast cancer in a French cohort study. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2574-2576.  (PubMed)

27.  Touillaud MS, Thiebaut AC, Fournier A, Niravong M, Boutron-Ruault MC, Clavel-Chapelon F. Dietary lignan intake and postmenopausal breast cancer risk by estrogen and progesterone receptor status. J Natl Cancer Inst. 2007;99(6):475-486.  (PubMed)

28.  Velentzis LS, Cantwell MM, Cardwell C, Keshtgar MR, Leathem AJ, Woodside JV. Lignans and breast cancer risk in pre- and post-menopausal women: meta-analyses of observational studies. Br J Cancer. 2009;100(9):1492-1498.  (PubMed)

29.  Velentzis LS, Woodside JV, Cantwell MM, Leathem AJ, Keshtgar MR. Do phytoestrogens reduce the risk of breast cancer and breast cancer recurrence? What clinicians need to know. Eur J Cancer. 2008;44(13):1799-1806.  (PubMed)

30.  Adlercreutz H. Lignans and human health. Crit Rev Clin Lab Sci. 2007;44(5-6):483-525.  (PubMed)

31.  Boccardo F, Puntoni M, Guglielmini P, Rubagotti A. Enterolactone as a risk factor for breast cancer: a review of the published evidence. Clin Chim Acta. 2006;365(1-2):58-67.  (PubMed)

32.  Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst. 2003;95(15):1158-1164.  (PubMed)

33.  Zeleniuch-Jacquotte A, Lundin E, Micheli A, et al. Circulating enterolactone and risk of endometrial cancer. Int J Cancer. 2006;119(10):2376-2381.  (PubMed)

34.  McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. J Nutr. 2003;133(6):1937-1942.  (PubMed)

35.  Kilkkinen A, Virtamo J, Virtanen MJ, Adlercreutz H, Albanes D, Pietinen P. Serum enterolactone concentration is not associated with prostate cancer risk in a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2003;12(11 Pt 1):1209-1212.  (PubMed)

36.  Stattin P, Adlercreutz H, Tenkanen L, et al. Circulating enterolactone and prostate cancer risk: a Nordic nested case-control study. Int J Cancer. 2002;99(1):124-129.  (PubMed)

37.  Stattin P, Bylund A, Biessy C, Kaaks R, Hallmans G, Adlercreutz H. Prospective study of plasma enterolactone and prostate cancer risk (Sweden). Cancer Causes Control. 2004;15(10):1095-1102.  (PubMed)

38.  Strom SS, Yamamura Y, Duphorne CM, et al. Phytoestrogen intake and prostate cancer: a case-control study using a new database. Nutr Cancer. 1999;33(1):20-25.  (PubMed)

39.  Hedelin M, Klint A, Chang ET, et al. Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden). Cancer Causes Control. 2006;17(2):169-180.  (PubMed)

40.  Travis RC, Spencer EA, Allen NE, et al. Plasma phyto-oestrogens and prostate cancer in the European Prospective Investigation into Cancer and Nutrition. Br J Cancer. 2009;100(11):1817-1823.  (PubMed)

41.  Ward H, Chapelais G, Kuhnle GG, Luben R, Khaw KT, Bingham S. Lack of prospective associations between plasma and urinary phytoestrogens and risk of prostate or colorectal cancer in the European Prospective into Cancer-Norfolk study. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2891-2894.  (PubMed)

42.  Heald CL, Ritchie MR, Bolton-Smith C, Morton MS, Alexander FE. Phyto-oestrogens and risk of prostate cancer in Scottish men. Br J Nutr. 2007;98(2):388-396.  (PubMed)

43.  Kim MK, Chung BC, Yu VY, et al. Relationships of urinary phyto-oestrogen excretion to BMD in postmenopausal women. Clin Endocrinol (Oxf). 2002;56(3):321-328.  (PubMed)

44.  Kardinaal AF, Morton MS, Bruggemann-Rotgans IE, van Beresteijn EC. Phyto-oestrogen excretion and rate of bone loss in postmenopausal women. Eur J Clin Nutr. 1998;52(11):850-855.  (PubMed)

45.  Brooks JD, Ward WE, Lewis JE, et al. Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004;79(2):318-325.  (PubMed)

46.  Meagher LP, Beecher GR. Assessment of data on the lignan content of foods. J Food Compos Anal. 2000;13(6):935-947.

47.  Ososki AL, Kennelly EJ. Phytoestrogens: a review of the present state of research. Phytother Res. 2003;17(8):845-869.  (PubMed)

48.  Milder IE, Feskens EJ, Arts IC, de Mesquita HB, Hollman PC, Kromhout D. Intake of the plant lignans secoisolariciresinol, matairesinol, lariciresinol, and pinoresinol in Dutch men and women. J Nutr. 2005;135(5):1202-1207.  (PubMed)

49.  de Kleijn MJ, van der Schouw YT, Wilson PW, et al. Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study(1-4). J Nutr. 2001;131(6):1826-1832.  (PubMed)

50.  Thompson LU. Experimental studies on lignans and cancer. Baillieres Clin Endocrinol Metab. 1998;12(4):691-705.  (PubMed)

51.  Milder IE, Arts IC, van de Putte B, Venema DP, Hollman PC. Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol. Br J Nutr. 2005;93(3):393-402.  (PubMed)

52.  Clark WF, Parbtani A, Huff MW, et al. Flaxseed: a potential treatment for lupus nephritis. Kidney Int. 1995;48(2):475-480.  (PubMed) 

Phytosterols

Summary

  • Plant sterols and plant stanols, known commonly as phytosterols, are plant-derived compounds that are structurally related to cholesterol. (More information)
  • Early human diets were likely rich in phytosterols, providing as much as 1 g/day; however, the typical Western diet today is relatively low in phytosterols. (More information)
  • Although phytosterols are present in the diet in amounts similar to cholesterol, they are poorly absorbed and blood concentrations tend to be low. After absorption into enterocytes, phytosterols are actively excreted back into the intestinal lumen by the ATP-binding cassette transporter, ABCG5/G8. (More information)
  • Phytosterols interfere with the intestinal absorption of dietary cholesterol by displacing cholesterol from micelles; they also facilitate the excretion of biliary cholesterol in the feces. (More information)
  • Numerous clinical trials have demonstrated that daily consumption of phytosterols from phytosterol-enriched foods can significantly lower serum low-density lipoprotein (LDL)-cholesterol. An average phytosterol intake of 2 g/day lowers serum LDL-cholesterol by 8%-10%. (More information)
  • The effect of long-term use of foods enriched with phytosterols on cardiovascular risk is not known. (More information) 
  • The results of a few clinical trials suggested that phytosterol supplementation at relatively low doses can improve urinary tract symptoms related to benign prostatic hyperplasia, but further research is needed to confirm these findings. (More information)
  • Good food sources of phytosterols include unrefined vegetable oils, whole grains, nuts, seeds, and legumes(More information)
  • Foods and beverages with added phytosterols are now available in many countries throughout the world, and some countries allow health claims on such commercial products. (More information)
  • Consumption of phytosterol-enriched foods may have undesirable effects, such as a reduction in plasma carotenoid concentrations. (More information)

Introduction

Throughout much of human evolution, it is likely that large amounts of plant foods were consumed (1). In addition to being rich in fiber and plant protein, the diets of our ancestors were also rich in phytosterols — plant-derived compounds that are structurally very similar to cholesterol (Figure 1). There is increasing evidence to suggest that the reintroduction of plant foods providing phytosterols into the modern diet could improve serum lipid (cholesterol) profiles and help reduce the risk of cardiovascular disease (1).

Cholesterol in human blood and tissues is derived from the diet, as well as from endogenous cholesterol synthesis. In contrast, all phytosterols in human blood and tissues are derived from the diet because humans cannot synthesize phytosterols (2). While cholesterol is the predominant sterol in animals, including humans, a variety of sterols are found in plants (3). Nutritionists recognize two classes of phytosterols:

(1) Plant sterols have a double bond in the sterol ring. The most abundant sterols in plants and the human diet are β-sitosterol, campesterol, and stigmasterol (Figure 2).

(2) Plant stanols lack a double bond in the sterol ring. Stanols, especially sitostanol and campestanol, comprise only about 10% of total dietary phytosterols (Figure 3).

   Figure 1. Chemical Structure of Cholesterol.

[Figure 1 - Click to Enlarge]

Figure 2. Chemical Structures of Plant-derived Sterols, beta-sitosterol, campesterol, and stigmasterol.

[Figure 2 - Click to Enlarge]

Figure 3. Chemical Structures of Plant-derived Stanols, sitostanol and campestanol.

[Figure 3 - Click to Enlarge]

Definitions

Phytosterols: a collective term for plant-derived sterols and stanols.

Plant sterols or stanols: terms generally applied to plant-derived sterols or stanols; these phytochemicals are added to food or supplements.

Plant sterol or stanol esters: plant sterols or stanols that have been esterified by creating an ester bond between a fatty acid and the sterol or stanol. Esterification occurs in intestinal cells and is also an industrial process. Esterification makes plant sterols and stanols more fat-soluble so they are easily incorporated into fat-containing foods, including margarines and salad dressings. In this article, the weights of plant sterol and stanol esters are expressed as the equivalent weights of free (unesterified) sterols and stanols.

Metabolism and Bioavailability

Absorption and metabolism of dietary cholesterol

Dietary cholesterol must be incorporated into mixed micelles in order to be absorbed by the cells that line the intestine (enterocytes) (4). Mixed micelles are mixtures of bile salts, lipids, and sterols formed in the small intestine after a fat-containing meal is consumed. Transport across the apical membrane of enterocytes is mediated by intestinal cholesterol transporter, Niemann Pick C1-Like 1 (NPC1L1), which is also involved in the uptake of phytosterols (5). Inside the enterocyte, cholesterol is esterified in a reaction catalyzed by intestinal acyl-coenzyme A (CoA) cholesterol acyltransferases (ACATs; also present in the liver) and incorporated into triglyceride-rich lipoproteins known as chylomicrons, which are secreted into the intestinal lymphatics. The thoracic lymphatic duct then collects most of the lymph before draining into the systemic blood circulation (6). As circulating chylomicrons become depleted of triglycerides, they become chylomicron remnants, which are taken up by the liver. In the liver, cholesterol from chylomicron remnants may be repackaged into other lipoproteins for transport throughout the circulation or, alternatively, secreted into bile, which is released into the small intestine.

Absorption and metabolism of dietary phytosterols

Although varied diets typically contain similar amounts of phytosterols and cholesterol, serum phytosterol concentrations are usually several hundred times lower than serum cholesterol concentrations in humans (7). Less than 5% of dietary plant sterols and less than 0.5% of dietary plant stanols are systemically absorbed, in contrast to about 50%-60% of dietary cholesterol (8, 9). Like cholesterol, phytosterols must be incorporated into mixed micelles before they are taken up by enterocytes. Once inside the enterocyte, systemic absorption of phytosterols is inhibited by the activity of an efflux transporter, consisting of a pair of ATP-binding cassette (ABC) proteins known as ABCG5 and ABCG8. ABCG5 and ABCG8 each form one half of a transporter that secretes phytosterols and unesterified cholesterol from the enterocyte into the intestinal lumen. Phytosterols are secreted back into the intestine by ABCG5/G8 transporters at a much greater rate than cholesterol, resulting in much lower intestinal absorption of dietary phytosterols than cholesterol (10).

Within the enterocyte, phytosterols are not as readily esterified as cholesterol, so they are incorporated into chylomicrons at much lower concentrations. Those phytosterols that are incorporated into chylomicrons enter the circulation and are taken up by the liver. Once inside the liver, phytosterols are rapidly secreted into bile by hepatic ABCG5/G8 transporters. Although cholesterol is also secreted into bile, the rate of phytosterol secretion into bile is much greater than cholesterol secretion (11). Thus, the low serum concentrations of phytosterols relative to cholesterol can be explained by decreased intestinal absorption and increased excretion of phytosterols into bile.

Biological Activities

Effects on cholesterol absorption and excretion

It is well established that high intakes of plant sterols or stanols can lower serum total and low-density lipoprotein (LDL)-cholesterol concentrations in humans (see Cardiovascular disease). Different mechanisms appear to underlie the cholesterol-lowering effect of phytosterols (reviewed in 12). In the intestinal lumen, phytosterols displace cholesterol from mixed micelles and reduce cholesterol absorption (13). It is also suggested that phytosterols might interfere with the esterification and incorporation of cholesterol into chylomicrons inside the enterocytes (12). In a placebo-controlled, cross-over trial, the consumption of moderate (0.46 g/day) and high (2.1 g/day) phytosterol-enriched beverages reduced cholesterol absorption by about 10% and 25%, respectively (14). Moderate and high phytosterol intakes also significantly increased the excretion of biliary and dietary cholesterol in the feces by 36% and 74%, respectively (14). Although the mechanisms are currently not clear, phytosterols might facilitate cholesterol efflux from peripheral tissues and macrophages lining vessel walls. Cholesterol is then transported to the liver and incorporated into bile stored in the gallbladder. While plant sterols may promote the hepatobiliary secretion of cholesterol into the intestinal lumen, they are also hypothesized to facilitate the disposal of cholesterol via a nonbiliary route called transintestinal cholesterol efflux (TICE) (12).

Effects on cholesterol metabolism

A decrease in intestinal-derived cholesterol entering the circulation as chylomicrons triggers the endogenous production of cholesterol in order to maintain cholesterol homeostasis (14). Cell surface LDL-receptor expression is also up-regulated to enhance a receptor-mediated uptake of circulating LDL-cholesterol into cells (15). This process results in an increased clearance of circulating LDL from the blood. Within the cells, LDL particles are dismantled in lysosomes and cholesterol becomes available for metabolic needs. Through inhibiting the sterol regulatory element-binding protein (SREBP) pathway, LDL and LDL-derived cholesterol then suppress the transcription of the genes coding for 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and other enzymes involved in the synthesis of cholesterol and of the LDL-receptor (16). The net result is the maintenance of cellular cholesterol homeostasis within tissues (especially in the liver) and a reduction in serum LDL-cholesterol concentration.

Of note, some individuals with low intestinal cholesterol absorption efficiency (17) and/or high basal cholesterol synthesis rate (18) have been found to be poorly responsive to phytosterol therapy (reviewed in 19).

Other biological activities

Experiments in cell culture and animal models have suggested that phytosterols might have biological activities unrelated to cholesterol lowering. However, their significance in humans is not yet known.

Alterations in cell membrane properties

Cholesterol is an important structural component of mammalian cell membranes (20). Displacement of cholesterol with phytosterols has been found to alter the physical properties of cell membranes in vitro (21), which could potentially affect signal transduction or membrane-bound enzyme activity (22, 23). Limited evidence from an animal model of hemorrhagic stroke suggested that very high intakes of phytosterols could displace cholesterol in red blood cell membranes, resulting in decreased deformability and potentially increased fragility (24, 25). However, daily phytosterol supplementation (1 g/1,000 kcal) for four weeks did not alter red blood cell fragility in humans (26).

Alterations in testosterone metabolism

Limited evidence from animal studies suggests that very high phytosterol intake could alter testosterone metabolism by inhibiting 5-α-reductase, a membrane-bound enzyme that converts testosterone to dihydrotestosterone, a more potent metabolite (27, 28). It is not known whether phytosterol consumption alters testosterone metabolism in humans. No significant changes in free or total serum testosterone concentrations were observed in men who consumed 1.6 g/day of plant sterol esters for one year (29).

Anticancer effects

Phytosterols have been found to inhibit proliferation, induce apoptosis, and reduce invasiveness of cancer cells in culture (reviewed in 30). There is currently little evidence to suggest that phytosterol consumption could substantially contribute to lower the risk of cancer in humans (see Cancer).

Anti-inflammatory effects

Limited data from cell culture and animal studies suggest that phytosterols may attenuate the inflammatory activity of immune cells, including macrophages and neutrophils (31, 32). The result of a recent meta-analysis of 20 randomized controlled trials found that reductions in total cholesterol and LDL-cholesterol concentrations with phytosterol-enriched foods were not associated with changes in plasma concentration of C-reactive protein (CRP), a surrogate marker of chronic low-grade inflammation (33).

Disease Prevention

Cardiovascular disease

Typical diets across different populations have been estimated to provide 150 to 450 mg/day of naturally occurring phytosterols. Nevertheless, the consumption of vegetarian diets and of food products enriched with phytosterols can help achieve much greater intakes of phytosterols (see Food sources). Relatively few studies have considered the effects of naturally occurring dietary phytosterol intakes on serum LDL-cholesterol concentrations, while an abundance of studies have examined the lipid-lowering effect of phytosterol-enriched foods.

Foods enriched with plant sterols or stanols

Lipid-lowering effect: Elevated LDL-cholesterol concentration is a well-established risk factor in the development of atherosclerosis and coronary heart disease (34, 35). Numerous clinical trials have found that daily consumption of foods enriched with free or esterified forms of plant sterols or stanols lowers concentrations of serum total and LDL-cholesterol (36-40). This wealth of evidence has been summarized in several meta-analyses combining the results of randomized controlled trials (41-46). A dose-dependent relationship was reported between total phytosterol intake levels (from less than 1 g/day to 4 g/day) and LDL-cholesterol reduction in a recent meta-analysis of 124 human studies (47). When analyzed separately, plant sterols and stanols showed similar dose-response effects on LDL-cholesterol concentrations for average doses ranging from 0.6 g/day to 3.3 g/day. Average doses of phytosterols between 0.6 and 1.1 g/day were found to significantly lower LDL-cholesterol concentrations by at least 5%, while an average intake of 3.3 g/day resulted in reductions of about 12.4% (47).

Another meta-analysis that analyzed the results of 59 randomized controlled trials suggested that reductions in LDL-cholesterol were greater in those with higher baseline concentrations of LDL-cholesterol (41). Interestingly, a recent meta-analysis of 15 randomized controlled trials investigating the effects of phytosterol-enriched food intake (1.8 to 6 g/day of phytosterols) in patients treated with statins (drugs that inhibit endogenous cholesterol synthesis) found that co-administration of phytosterols and statins significantly reduced total cholesterol and LDL-cholesterol concentrations compared to statin therapy alone (48). The concentrations of HDL-cholesterol and triglycerides were unaffected by the combination of phytosterols and statins compared to statin alone. In subgroup analyses, the effect of combining phytosterols and statins on blood lipid profile was not found to be significantly influenced by lipid baseline values, phytosterol dosage, or study duration (48).

Effect on vascular health: Impairment of vascular endothelial function is considered to be an early step in the development of atherosclerosis and cardiovascular disease (49). A recent 12-week randomized, double-blind, placebo-controlled study in 240 subjects with hypercholesterolemia (serum cholesterol ≥5 mmol/L [≥193 mg/dL]) found no effect of consuming 3 g/day of phytosterols added to low-fat spread on brachial artery flow-mediated dilation (FMD), a surrogate marker of endothelial health (50). Assessment of arterial stiffness — using measures of aortic pulse wave velocity (PWV) and augmentation index (AI) — and blood pressure­­­ also showed no difference between supplemented and placebo groups, despite a significant 6.7% reduction in total and LDL-cholesterol. Other trials in individuals with hypercholesterolemia (51, 52) and type 1 diabetes mellitus (53) also failed to find an effect of phytosterol-enriched spread consumption on brachial artery diameter, FMD, and/or arterial stiffness. Nonetheless, the results of a randomized controlled trial in 92 individuals of whom 72% had serum cholesterol ≥5 mmol/L suggested beneficial effects of plant stanol-enriched spread consumption (corresponding to 3 g/day of stanols for six months) on arterial stiffness and endothelial function, as assessed by cardio-ankle vascular index (CAVI) and reactive hyperemia index (RHI) measures, respectively (54). Finally, a 21-month randomized controlled trial used retinal photography to examine the effect of phytosterol-enriched margarine consumption on retinal microcirculation in 43 statin-treated subjects (55). Reductions in LDL-cholesterol concentration by 9.7% and 11.2% with plant sterols (2.5 g/day) and plant stanols (2.5 g/day), respectively, were not accompanied by significant changes in the diameter of retinal arterioles and venules, a proxy measure to assess microvascular health (55). At present, whether phytosterols can improve vascular health in individuals with endothelial dysfunction is unclear. The lack of an effect of phytosterols in most of the abovementioned trials may be due to the inclusion of apparently healthy participants who may have normal endothelial function (50).

Effect on the risk of coronary heart disease: Elevated LDL-cholesterol is an established risk factor for coronary heart disease (CHD) (56). The pooled analysis of 27 randomized controlled trials of statin drug therapy found a 24% decrease in the risk of major coronary events and a 12% decrease in vascular mortality per 1 millimol/L (1 mM) reduction in LDL-cholesterol concentration, irrespective of gender and level of cardiovascular risk (57). Yet, at present, the effect of long-term use of foods enriched with plant sterols or stanols on CHD risk is not known.

The addition of plant sterol- or stanol-enriched foods to a heart-healthy diet that is low in saturated fat and rich in fruit and vegetables, whole grains, and fiber offers the potential for additive effects in CHD risk reduction. For example, following a diet that substituted monounsaturated and polyunsaturated fats for saturated fat resulted in a 9% reduction in serum LDL-cholesterol after 30 days, but the addition of 1.7 g/day of plant sterols to the same diet resulted in a 24% reduction (58). In addition, one-month adherence to a diet providing a portfolio of cholesterol-lowering foods, including plant sterols (1 g/1,000 kcal), soy protein, almonds, and viscous fibers, lowered serum LDL-cholesterol concentrations by an average of 30% — a decrease that was not significantly different from that induced by statin therapy (59).

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III included the use of plant sterol or stanol esters (2 g/day) as a component of maximal dietary therapy for elevated LDL-cholesterol (60). The 2013 report of the American College of Cardiology (ACC) task force advised clinicians to consider the use of phytosterol-enriched foods as dietary adjuncts for high-risk patients with insufficient LDL-cholesterol response to statin therapy (61). However, stepping back from a general recommendation, the ACC and American Heart Association (AHA) did not include phytosterols in their 2013 report on lifestyle management guidelines to reduce cardiovascular risk (62). Likewise, the 2015-2020 Dietary Guidelines for Americans — issued jointly by the US Department of Health and Human Services and the US Department of Agriculture — does not mention phytosterols in the composition of healthy eating patterns (63).

The US Food and Drug Administration (FDA) has authorized the use of health claims on food labels indicating that regular consumption of foods enriched with plant sterol or stanol esters, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease (see Foods enriched with plant sterols and plant stanols) (61, 64). In the EU, disease risk reduction claims for phytosterols are restricted to certain fortified food products and include a number of mandatory statements such as the fact that these products are not intended for people who do not need to control their blood cholesterol level (65).

Dietary phytosterols

Clinical trials finding daily consumption of foods enriched with plant sterols or stanols can significantly lower LDL-cholesterol concentrations do not account for naturally occurring phytosterols in the diet (66). Relatively few studies have considered the effects of dietary phytosterol intakes on serum LDL-cholesterol concentrations. Limited evidence, primarily from cross-sectional studies, suggests that dietary phytosterols may play an important role in decreasing cholesterol absorption. A cross-sectional study in the UK found that dietary phytosterol intakes were inversely related to serum total and LDL-cholesterol concentrations even after adjusting for saturated fat and fiber intake (67). Similarly, an analysis in a Swedish population found that dietary intake of phytosterols was inversely associated with total cholesterol in both men and women and with LDL-cholesterol in women (68). Dietary phytosterol intakes were also found to be inversely associated with LDL-cholesterol concentrations in another cross-sectional study in healthy Spanish participants (69). In single-meal tests, removal of 150 mg of phytosterols from corn oil increased cholesterol absorption by 38% (70), and removal of 328 mg of phytosterols from wheat germ increased cholesterol absorption by 43% (71). Although these findings suggest that moderate intakes of phytosterols could have an important impact on cardiovascular health, the intake of phytosterols (83 to 966 mg/day) from natural sources was not found to be associated with reduced risks of CHD, myocardial infarction, or total cardiovascular disease during the 12.2-year follow-up of 35,597 participants of the European Prospective Investigation into Cancer and Nutrition-The Netherlands (EPIC-NL) (72).

Cancer

Limited data from animal studies suggest that very high intakes of phytosterols, particularly sitosterol, may inhibit the growth of breast and prostate cancer (reviewed in 73). Only a few observational studies have examined associations between dietary phytosterol intakes and cancer risk in humans (30). A series of case-control studies in Uruguay found that dietary phytosterol intakes were lower in people diagnosed with stomach, lung, or breast cancer than in cancer-free control groups (74-76). Case-control studies in the US found that women diagnosed with breast or endometrial (uterine) cancer had lower dietary phytosterol intakes than women who did not have cancer (77, 78). In contrast, another case-control study in the US found that men diagnosed with prostate cancer had higher dietary campesterol intakes than cancer-free men, but total phytosterol consumption was not associated with prostate cancer risk (79). Although higher intakes of plant foods containing phytosterols may be associated with lower cancer risk, it is not clear whether potential anticancer health benefits can be attributed to phytosterols or to other compounds in plant foods (e.g., other phytochemicals, vitamins, minerals, and fiber).

Disease Treatment

Benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is the term used to describe a noncancerous enlargement of the prostate. The enlarged prostate may exert pressure on the urethra, resulting in difficulty urinating. Plant extracts that provide a mixture of phytosterols (marketed as β-sitosterol) are often included in herbal therapies for urinary symptoms related to BPH. However, relatively few controlled studies have examined the efficacy of phytosterol supplements in men with symptomatic BPH. In a six-month study of 200 men with symptomatic BPH, 60 mg/day of a β-sitosterol preparation improved symptom scores, increased peak urinary flow, and decreased post-void residual urine volume compared to placebo (80). A follow-up study reported that these improvements were maintained for up to 18 months in the 38 participants who continued β-sitosterol treatment (81). Similarly, in a six-month study of 177 men with symptomatic BPH, 130 mg/day of a different β-sitosterol preparation improved urinary symptom scores, increased peak urinary flow, and decreased post-void residual urine volume compared to placebo (82). A systematic review that combined the results of these and two other controlled clinical trials found that β-sitosterol extracts increased peak urinary flow by an average of 3.9 mL/second and decreased post-void residual volume by an average of 29 mL (83). Although the results of a few clinical trials suggest that relatively low doses of phytosterols can improve lower urinary tract symptoms related to BPH, further research is needed to confirm these findings (84).

Sources

Food

Unlike the typical diet in most developed countries today, the diets of our ancestors were rich in phytosterols, likely providing as much as 1 g/day (1). Present-day dietary phytosterol intakes have been estimated to vary from 150 to 450 mg/day in different populations (85). Vegetarians, particularly vegans, generally have the highest intakes of dietary phytosterols (86). Phytosterols are found in all plant foods, but the highest concentrations are found in unrefined plant oils, including vegetable, nut, and olive oils (3). Nuts, seeds, whole grains, and legumes are also good dietary sources of phytosterols (4). The phytosterol content of selected foods are presented in Table 1. For information on the nutrient content of specific foods, search the USDA food composition database.

Table 1. Total Phytosterol Content of Selected Foods
Food Serving Phytosterols* (mg)
Soybeans, mature seeds, raw ½ cup 149
Peas, green, mature seeds, raw ½ cup 133
Sesame oil 1 tablespoon (14 g) 118
Kidney beans, mature seeds, raw ½ cup 117
Pistachio nuts 1 ounce (49 kernels) 61
Safflower oil 1 tablespoon (14 g) 60
Lentils, pink or red, mature seeds, raw ½ cup 54
Cashew nuts 1 ounce 45
Soybeans, green, cooked, boiled ½ cup 45
Cottonseed oil 1 tablespoon (14 g) 44
Orange, raw 1 fruit 34
Macadamia nuts 1 ounce (10-12 kernels) 33
Almonds, blanched  1 ounce 32
Olive oil  1 tablespoon (14 g) 30
Banana, raw 1 large 24
Brussels sprouts, raw  1 cup 21

*In the USDA food composition database, the values of phytosterol content of foods are likely to be underestimates since they account only for major sterols (sitosterol, campesterol, and stigmasterol). In addition, the values correspond to the amounts of free and esterified phytosterols in foods, because phytosterol glycosides are not quantified by the current method unless glycosides (sugars) are removed before quantification (87).

Food enriched with plant sterols and plant stanols

Clinical trials that demonstrated a cholesterol-lowering effect have primarily used plant sterol or stanol esters solubilized in fat-containing foods, such as margarine or mayonnaise (44). Additional studies indicate that low-fat or even nonfat foods can effectively deliver plant sterols or stanols if they are adequately solubilized (37, 66). Plant sterols or stanols added to low-fat yogurt (88-91), low-fat milk (92-94), low-fat cheese (95), dark chocolate (96), and orange juice (97, 98) have been reported to lower LDL-cholesterol in randomized controlled trials. A variety of foods containing added plant sterols or stanols, including margarines, mayonnaises, vegetable oils, salad dressings, yogurt, milk, soy milk, orange juice, snack bars, and meats, are available in the US, Europe, Asia, Australia, and New Zealand (37). A 2008 meta-analysis found that phytosterols added to fat spreads, mayonnaise, salad dressings, milk, or yogurt more effectively reduced LDL-cholesterol concentrations compared to phytosterols incorporated into chocolate, orange juice, cheese, meats, and cereal bars (41). In most clinical trials, dividing the daily dose of phytosterols among two or three meals appeared to effectively lower LDL-cholesterol (41). Nevertheless, consumption of the daily dose of plant sterols or stanols with a single meal has also been found to lower LDL-cholesterol in a few clinical trials (89-91, 99, 100).

In the US, FDA-authorized health claims on food labels specify that the daily dietary intake of plant sterol (≥1.3 g/day) or stanol esters (≥3.4 g/day) that has been associated with a reduced risk of heart disease should be consumed in two servings eaten at different times of the day with other foods, as part of a diet low in saturated fat and cholesterol (61, 64). In the EU, food labels must indicate that the beneficial effect of phytosterols is obtained with a daily intake of 1.5 to 3 g of plant sterols/stanols in order to use the following European Food Safety Authority (EFSA)-approved statement: "Plant sterol and stanol esters have been shown to lower blood cholesterol. High cholesterol is a risk factor in the development of coronary heart disease" (65).

Supplements

Available without a prescription in the US, β-sitosterol supplements typically contain a mixture of β-sitosterol with other phytosterols and/or with substances like pumpkin seed oil and saw palmetto extract (101). Doses of 60 to 130 mg/day of β-sitosterol have been found to alleviate the symptoms of benign prostatic hyperplasia in a few clinical trials (see Benign prostatic hyperplasia). Phytosterol and phytostanol supplements should be taken with a meal that contains fat.

Safety

In the US, plant sterols and stanols added to a variety of food products are generally recognized as safe (GRAS) by the FDA (102). Additionally, the Scientific Committee on Foods of the EU concluded that plant sterols and stanols added to various food products are safe for human use (103). However, the Committee recommended that intakes of plant sterols and stanols from food products should not exceed 3 g/day because there is no evidence of health benefits at higher intakes and there might be undesirable effects at high intakes (65).

Adverse effects

Few adverse effects have been associated with regular consumption of plant sterols or stanols for up to one year. People who consumed a plant sterol-enriched spread providing 1.6 g/day did not report any more adverse effects than those consuming a control spread for up to one year (29), and people consuming a plant stanol-enriched spread providing 1.8 to 2.6 g/day for one year did not report any adverse effects (104). Consumption of up to 8.6 g/day of phytosterols in margarine for three to four weeks was well tolerated by healthy men and women and did not adversely affect intestinal bacteria or female hormone levels (105). Although phytosterols are usually well tolerated, nausea, indigestion, diarrhea, and constipation have occasionally been reported (106).

Sitosterolemia

Sitosterolemia, also known as phytosterolemia, is a very rare hereditary disease that results from inheriting a mutation in both copies of the ABCG5 or ABCG8 gene (107). Individuals who are homozygous for a mutation in either transporter protein have dramatically elevated serum phytosterol concentrations due to increased intestinal absorption and decreased biliary excretion of phytosterols. Although serum cholesterol concentrations may be normal or only mildly elevated, individuals with sitosterolemia are at high risk for premature atherosclerosis. Other clinical symptoms include tuberous and tendon xanthomas (i.e., cutaneous lipid depositions), hematological abnormalities, and sometimes joint pain and arthritis.

People with sitosterolemia should avoid foods or supplements with added plant sterols (37). Two studies have examined the effect of plant sterol consumption in heterozygous carriers of sitosterolemia, a more common condition. Consumption of 3 g/day of plant sterols for four weeks by two heterozygous carriers (108) and consumption of 2.2 g/day of plant sterols for 6 to 12 weeks by 12 heterozygous carriers did not result in abnormally elevated serum phytosterols (109). Because atherosclerosis has been reported in subjects with sitosterolemia, phytosterols have been attributed atherogenic effects. However, no relationship between serum concentrations of sitosterol and campesterol and risk of cardiovascular disease has been identified in a recent meta-analysis of 17 observational studies in 11,182 participants (110).

Pregnancy and lactation

Phytosterol-enriched foods and supplements are not recommended for pregnant or breast-feeding women because their safety has not been studied (106). At present, there is no evidence that high dietary intakes of naturally occurring phytosterols, such as those consumed by vegetarian women, adversely affects pregnancy or lactation.

Drug interactions

Statins

There is some evidence showing that statin administration initially reduces plant sterol concentrations in blood. This might be attributed to the reduction of circulating LDL, the major transport lipoprotein of plant sterols, due to enhanced hepatic uptake of LDL. However, statin therapy appears to increase the absorption of plant sterols that can be then transported by the remaining LDL particles (111). Further, the LDL-cholesterol-lowering effect of plant sterols or stanols may be additive to that of statins. The result of a recent meta-analysis of controlled clinical trials suggested that consumption of 2 to 3 g/day of plant sterols or stanols by individuals on statin therapy may lower both total cholesterol and LDL-cholesterol by an additional 0.30 mmol/L (11.6 mg/dL), compared to statin alone (48).

Ezetimibe

Ezetimibe (marketed as Zetia) is another cholesterol-lowering drug that may interfere with the intestinal absorption of phytosterols, thus significantly reducing phytosterol concentration in blood (112).

Nutrient interactions

Fat-soluble vitamins (vitamins A, D, E, and K)

Because plant sterols and stanols decrease cholesterol absorption and serum LDL-cholesterol concentrations, their effects on fat-soluble vitamin status have also been studied in clinical trials. Plasma vitamin A (retinol) concentrations were not affected by plant stanol or sterol ester consumption for up to one year (29, 44). Although the majority of studies found no changes in plasma vitamin D (25-hydroxyvitamin D3) concentrations, one placebo-controlled study in individuals consuming 1.6 g/day of sterol esters for one year observed a small (7%) but statistically significant decrease in plasma 25-hydroxyvitamin D3 concentrations (29). There is little evidence that plant sterol or stanol consumption adversely affects vitamin K status. Consumption of 1.6 g/day of sterol esters for six months was associated with a nonsignificant, 14% decrease in plasma vitamin K1 (phylloquinone) concentrations, and the level of carboxylated osteocalcin, a functional indicator of vitamin K status, was unchanged (29). Other studies of shorter duration also found no change in plasma concentrations of phylloquinone (113, 114) or vitamin K-dependent clotting factors with the consumption of plant sterol and stanol esters (115). Consumption of phytosterol-enriched foods has been found to decrease plasma vitamin E (α-tocopherol) concentration in a number of studies (44, 114). However, those decreases generally do not persist when plasma α-tocopherol concentrations are standardized to LDL-cholesterol concentrations, suggesting that observed reductions in plasma α-tocopherol are due in part to reductions in its lipoprotein carrier, LDL.

A recent meta-analysis of intervention studies found no adverse effects of phytosterol-enriched food consumption (average dose of 2.5 g/day) on fat-soluble vitamin status in well-nourished people (116).

Carotenoids

Dietary carotenoids are fat-soluble phytochemicals that circulate in lipoproteins. A recent meta-analysis of randomized controlled studies reported about 5 to 20% reductions in plasma hydrocarbon carotenoids after consumption of plant sterol- or stanol-enriched foods for one month to one year (116). Even when standardized to serum total cholesterol concentrations, decreases in α-carotene, β-carotene, and lycopene may persist, suggesting that phytosterols could inhibit the absorption of these carotenoids. Total cholesterol-standardized concentrations of xanthophyll carotenoids, zeaxanthin and β-cryptoxanthin, but not lutein, were also found to be significantly reduced by 5 to 15% with the consumption of phytosterol-enriched foods (116).

Although it is not clear whether reductions in plasma carotenoid concentrations confer any health risks (see the article on Carotenoids), a few studies showed that increasing intakes of carotenoid-rich fruit and vegetables would prevent phytosterol-induced decreases in plasma concentrations of carotenoids (117). In one randomized controlled study, advice to consume five daily servings of fruit and vegetables, including one serving of carotenoid-rich vegetables, was enough to maintain plasma carotenoid levels in people consuming 2.5 g/day of plant sterol or stanol esters (118).


Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2017 by:
Susan B. Racette, Ph.D.
Professor, Program in Physical Therapy
and Department of Medicine
Washington University in St. Louis

Copyright 2005-2017  Linus Pauling Institute 


References

1.  Jew S, AbuMweis SS, Jones PJ. Evolution of the human diet: linking our ancestral diet to modern functional foods as a means of chronic disease prevention. J Med Food. 2009;12(5):925-934.  (PubMed)

2.  Sudhop T, Lutjohann D, von Bergmann K. Sterol transporters: targets of natural sterols and new lipid lowering drugs. Pharmacol Ther. 2005;105(3):333-341.  (PubMed)

3.  Ostlund RE, Jr. Phytosterols in human nutrition. Annu Rev Nutr. 2002;22:533-549.  (PubMed)

4.  de Jong A, Plat J, Mensink RP. Metabolic effects of plant sterols and stanols (Review). J Nutr Biochem. 2003;14(7):362-369.  (PubMed)

5.  Davis HR, Zhu LJ, Hoos LM, et al. Niemann-Pick C1 like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. Journal of Biological Chemistry. 2004;279(32):33586-33592.  (PubMed)

6.  Howles PN. Cholesterol absorption and metabolism. Methods Mol Biol. 2016;1438:177-197.  (PubMed)

7.  von Bergmann K, Sudhop T, Lutjohann D. Cholesterol and plant sterol absorption: recent insights. Am J Cardiol. 2005;96(1A):10D-14D.  (PubMed)

8.  Ostlund RE, Jr., McGill JB, Zeng CM, et al. Gastrointestinal absorption and plasma kinetics of soy Delta(5)-phytosterols and phytostanols in humans. Am J Physiol Endocrinol Metab. 2002;282(4):E911-916.  (PubMed)

9.  Weingartner O, Bohm M, Laufs U. Controversial role of plant sterol esters in the management of hypercholesterolaemia. Eur Heart J. 2009;30(4):404-409.  (PubMed)

10.  Jones PJ, Rideout T. Lipids, sterols, and their metabolites. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease: Lippincott Williams & Wilkins; 2014:65-87.

11.  Sudhop T, Sahin Y, Lindenthal B, et al. Comparison of the hepatic clearances of campesterol, sitosterol, and cholesterol in healthy subjects suggests that efflux transporters controlling intestinal sterol absorption also regulate biliary secretion. Gut. 2002;51(6):860-863.  (PubMed)

12.  De Smet E, Mensink RP, Plat J. Effects of plant sterols and stanols on intestinal cholesterol metabolism: suggested mechanisms from past to present. Mol Nutr Food Res. 2012;56(7):1058-1072.  (PubMed)

13.  Nissinen M, Gylling H, Vuoristo M, Miettinen TA. Micellar distribution of cholesterol and phytosterols after duodenal plant stanol ester infusion. Am J Physiol Gastrointest Liver Physiol. 2002;282(6):G1009-1015.  (PubMed)

14.  Racette SB, Lin X, Lefevre M, et al. Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study. Am J Clin Nutr. 2010;91(1):32-38.  (PubMed)

15.  Plat J, Mensink RP. Plant stanol and sterol esters in the control of blood cholesterol levels: mechanism and safety aspects. Am J Cardiol. 2005;96(Suppl):15D-22D.  (PubMed)

16.  Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431-438.  (PubMed)

17.  Zhao HL, Houweling AH, Vanstone CA, et al. Genetic variation in ABC G5/G8 and NPC1L1 impact cholesterol response to plant sterols in hypercholesterolemic men. Lipids. 2008;43(12):1155-1164.  (PubMed)

18.  Rideout TC, Harding SV, Mackay D, Abumweis SS, Jones PJ. High basal fractional cholesterol synthesis is associated with nonresponse of plasma LDL cholesterol to plant sterol therapy. Am J Clin Nutr. 2010;92(1):41-46.  (PubMed)

19.  Rideout TC, Harding SV, Mackay DS. Metabolic and genetic factors modulating subject specific LDL-C responses to plant sterol therapy. Can J Physiol Pharmacol. 2012;90(5):509-514.  (PubMed)

20.  Mouritsen OG, Zuckermann MJ. What's so special about cholesterol? Lipids. 2004;39(11):1101-1113.  (PubMed)

21.  Halling KK, Slotte JP. Membrane properties of plant sterols in phospholipid bilayers as determined by differential scanning calorimetry, resonance energy transfer and detergent-induced solubilization. Biochim Biophys Acta. 2004;1664(2):161-171.  (PubMed)

22.  Awad AB, Chen YC, Fink CS, Hennessey T. beta-Sitosterol inhibits HT-29 human colon cancer cell growth and alters membrane lipids. Anticancer Res. 1996;16(5A):2797-2804.  (PubMed)

23.  Leikin AI, Brenner RR. Fatty acid desaturase activities are modulated by phytosterol incorporation in microsomes. Biochim Biophys Acta. 1989;1005(2):187-191.  (PubMed)

24.  Ratnayake WM, L'Abbe MR, Mueller R, et al. Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr. 2000;130(5):1166-1178.  (PubMed)

25.  Ratnayake WM, Plouffe L, L'Abbe MR, Trick K, Mueller R, Hayward S. Comparative health effects of margarines fortified with plant sterols and stanols on a rat model for hemorrhagic stroke. Lipids. 2003;38(12):1237-1247.  (PubMed)

26.  Jones PJ, Raeini-Sarjaz M, Jenkins DJ, et al. Effects of a diet high in plant sterols, vegetable proteins, and viscous fibers (dietary portfolio) on circulating sterol levels and red cell fragility in hypercholesterolemic subjects. Lipids. 2005;40(2):169-174.  (PubMed)

27.  Awad AB, Hartati MS, Fink CS. Phytosterol feeding induces alteration in testosterone metabolism in rat tissues. J Nutr Biochem. 1998;9(12):712-717.

28.  Cabeza M, Bratoeff E, Heuze I, Ramirez E, Sanchez M, Flores E. Effect of beta-sitosterol as inhibitor of 5 alpha-reductase in hamster prostate. Proc West Pharmacol Soc. 2003;46:153-155.  (PubMed)

29.  Hendriks HF, Brink EJ, Meijer GW, Princen HM, Ntanios FY. Safety of long-term consumption of plant sterol esters-enriched spread. Eur J Clin Nutr. 2003;57(5):681-692.  (PubMed)

30.  Woyengo TA, Ramprasath VR, Jones PJ. Anticancer effects of phytosterols. Eur J Clin Nutr. 2009;63(7):813-820.  (PubMed)

31.  Awad AB, Toczek J, Fink CS. Phytosterols decrease prostaglandin release in cultured P388D1/MAB macrophages. Prostaglandins Leukot Essent Fatty Acids. 2004;70(6):511-520.  (PubMed)

32.  Navarro A, De las Heras B, Villar A. Anti-inflammatory and immunomodulating properties of a sterol fraction from Sideritis foetens Clem. Biol Pharm Bull. 2001;24(5):470-473.  (PubMed)

33.  Rocha VZ, Ras RT, Gagliardi AC, Mangili LC, Trautwein EA, Santos RD. Effects of phytosterols on markers of inflammation: A systematic review and meta-analysis. Atherosclerosis. 2016;248:76-83.  (PubMed)

34.  Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(39):2999-3058.  (PubMed)

35.  Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45.  (PubMed)

36.  St-Onge MP, Jones PJ. Phytosterols and human lipid metabolism: efficacy, safety, and novel foods. Lipids. 2003;38(4):367-375.  (PubMed)

37.  Berger A, Jones PJ, Abumweis SS. Plant sterols: factors affecting their efficacy and safety as functional food ingredients. Lipids Health Dis. 2004;3:5.  (PubMed)

38.  Moruisi KG, Oosthuizen W, Opperman AM. Phytosterols/stanols lower cholesterol concentrations in familial hypercholesterolemic subjects: a systematic review with meta-analysis. J Am Coll Nutr. 2006;25(1):41-48.  (PubMed)

39.  Ellegard LH, Andersson SW, Normen AL, Andersson HA. Dietary plant sterols and cholesterol metabolism. Nutr Rev. 2007;65(1):39-45.  (PubMed)

40.  Van Horn L, McCoin M, Kris-Etherton PM, et al. The evidence for dietary prevention and treatment of cardiovascular disease. J Am Diet Assoc. 2008;108(2):287-331.  (PubMed)

41.  AbuMweis SS, Barake R, Jones P. Plant sterols/stanols as cholesterol lowering agents: A meta-analysis of randomized controlled trials. Food & Nutrition Research. 2008; 52. doi: 10.3402/fnr.v52i0.1811.  (PubMed)

42.  Chen JT, Wesley R, Shamburek RD, Pucino F, Csako G. Meta-analysis of natural therapies for hyperlipidemia: plant sterols and stanols versus policosanol. Pharmacotherapy. 2005;25(2):171-183.  (PubMed)

43.  Demonty I, Ras RT, van der Knaap HC, et al. Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake. J Nutr. 2009;139(2):271-284.  (PubMed)

44.  Katan MB, Grundy SM, Jones P, Law M, Miettinen T, Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc. 2003;78(8):965-978.  (PubMed)

45.  Law M. Plant sterol and stanol margarines and health. BMJ. 2000;320(7238):861-864.  (PubMed)

46.  Musa-Veloso K, Poon TH, Elliot JA, Chung C. A comparison of the LDL-cholesterol lowering efficacy of plant stanols and plant sterols over a continuous dose range: results of a meta-analysis of randomized, placebo-controlled trials. Prostaglandins Leukot Essent Fatty Acids. 2011;85(1):9-28.  (PubMed)

47.  Ras RT, Geleijnse JM, Trautwein EA. LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta-analysis of randomised controlled studies. Br J Nutr. 2014;112(2):214-219.  (PubMed)

48.  Han S, Jiao J, Xu J, et al. Effects of plant stanol or sterol-enriched diets on lipid profiles in patients treated with statins: systematic review and meta-analysis. Sci Rep. 2016;6:31337.  (PubMed)

49.  Landmesser U, Drexler H. The clinical significance of endothelial dysfunction. Curr Opin Cardiol. 2005;20(6):547-551.  (PubMed)

50.  Ras RT, Fuchs D, Koppenol WP, et al. The effect of a low-fat spread with added plant sterols on vascular function markers: results of the Investigating Vascular Function Effects of Plant Sterols (INVEST) study. Am J Clin Nutr. 2015;101(4):733-741.  (PubMed)

51.  Hallikainen M, Lyyra-Laitinen T, Laitinen T, et al. Endothelial function in hypercholesterolemic subjects: Effects of plant stanol and sterol esters. Atherosclerosis. 2006;188(2):425-432.  (PubMed)

52.  Raitakari OT, Salo P, Gylling H, Miettinen TA. Plant stanol ester consumption and arterial elasticity and endothelial function. Br J Nutr. 2008;100(3):603-608.  (PubMed)

53.  Hallikainen M, Lyyra-Laitinen T, Laitinen T, Moilanen L, Miettinen TA, Gylling H. Effects of plant stanol esters on serum cholesterol concentrations, relative markers of cholesterol metabolism and endothelial function in type 1 diabetes. Atherosclerosis. 2008;199(2):432-439.  (PubMed)

54.  Gylling H, Halonen J, Lindholm H, et al. The effects of plant stanol ester consumption on arterial stiffness and endothelial function in adults: a randomised controlled clinical trial. BMC Cardiovasc Disord. 2013;13:50.  (PubMed)

55.  Kelly ER, Plat J, Mensink RP, Berendschot TT. Effects of long term plant sterol and -stanol consumption on the retinal vasculature: a randomized controlled trial in statin users. Atherosclerosis. 2011;214(1):225-230.  (PubMed)

56.  McCormack T, Dent R, Blagden M. Very low LDL-C levels may safely provide additional clinical cardiovascular benefit: the evidence to date. Int J Clin Pract. 2016;70(11):886-897.  (PubMed)

57.  Cholesterol Treatment Trialists Collaboration. Fulcher J, O'Connell R, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397-1405.  (PubMed)

58.  Jones PJ, Ntanios FY, Raeini-Sarjaz M, Vanstone CA. Cholesterol-lowering efficacy of a sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men. Am J Clin Nutr. 1999;69(6):1144-1150.  (PubMed)

59.  Jenkins DJ, Kendall CW, Marchie A, et al. Direct comparison of a dietary portfolio of cholesterol-lowering foods with a statin in hypercholesterolemic participants. Am J Clin Nutr. 2005;81(2):380-387.  (PubMed)

60.  Grundy SM. Stanol esters as a component of maximal dietary therapy in the National Cholesterol Education Program Adult Treatment Panel III Report. Am J Cardiol. 2005;96(1A):47D-50D.  (PubMed)

61.  Writing C, Lloyd-Jones DM, Morris PB, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92-125.  (PubMed)

62.  Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S76-99.  (PubMed)

63.  US Department of Health and Human Services and US Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans; 2015. Available at: https://health.gov/dietaryguidelines/2015/guidelines/.

64.  Food and Drug Administration. Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD). U. S. Government Printing Office [Code of Federal Regulations]. April 1, 2002. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.83. Accessed 6/29/05.

65.  Shortt C. Authorised EU h