Turmeric is a spice derived from the rhizomes of Curcuma longa, which is a member of the ginger family (Zingiberaceae) (1). Rhizomes are horizontal underground stems that send out shoots as well as roots. The bright yellow color of turmeric comes mainly from polyphenolic pigments, known as curcuminoids (Figure 1). Curcumin is the principal curcuminoid found in turmeric, and is generally considered its most active constituent (2). Other curcuminoids found in turmeric include demethoxycurcumin and bisdemethoxycurcumin. In addition to its use as a spice and a pigment, turmeric has been used in India for medicinal purposes for centuries. More recently, evidence that curcumin may have anti-inflammatory and anticancer activities has renewed scientific interest in its potential to prevent and treat disease.
Metabolism and Bioavailability
Clinical trials in humans indicate that the systemic bioavailability of orally administered curcumin is relatively low (2). Curcumin is readily conjugated in the intestine and liver to form curcumin glucuronides and curcumin sulfates or reduced to hexahydrocurcumin (Figure 2) (3). Curcumin metabolites may not have the same biological activity as the parent compound. In one study, conjugated or reduced metabolites of curcumin were less effective inhibitors of inflammatory enzyme expression in cultured human colon cells than curcumin itself (4) . In a clinical trial conducted in Taiwan, serum curcumin concentrations peaked 1-2 hours after an oral dose, and peak serum concentrations were 0.5, 0.6 and 1.8 micromoles/liter at doses of 4, 6 and 8 g/day, respectively (5). Curcumin could not be detected in serum at lower doses than 4 g/day. More recently, a clinical trial conducted in the UK, found that plasma curcumin, curcumin sulfate and curcumin glucuronide concentrations were in the range of 10 nanomoles/liter (0.01 micromole/liter) one hour after a 3.6 g dose of oral curcumin (6). Curcumin and its metabolites could not be detected in plasma at lower doses than 3.6 g/day. Curcumin and its glucuronidated and sulfated metabolites were also measured in urine at a dose of 3.6 g/day. There is some evidence that orally administered curcumin accumulates in gastrointestinal tissues. When colorectal cancer patients took 3.6 g/d of curcumin orally for 7 days prior to surgery, curcumin was detected in malignant and normal colorectal tissue (7). In contrast, curcumin was not detected in the liver tissue of patients with liver metastases of colorectal cancer after the same dose of oral curcumin (8), suggesting that oral curcumin administration may not effectively deliver curcumin to tissues outside the gastrointestinal tract.
Antioxidant Activity
Curcumin is an effective scavenger of reactive oxygen species and reactive nitrogen species in the test tube (in vitro) (9, 10). However, it is not clear whether curcumin acts directly as an antioxidant in vivo. Due to its limited oral bioavailability in humans (see Metabolism and Bioavailability above), plasma and tissue curcumin concentrations are likely to be much lower than that of other fat-soluble antioxidants, such as alpha-tocopherol (vitamin E). However, the finding that 7 days of oral curcumin supplementation (3.6 g/day) decreased the number of oxidative DNA adducts in malignant colorectal tissue suggests that curcumin taken orally may reach sufficient concentrations in the gastrointestinal tract to inhibit oxidative DNA damage (7). In addition to direct antioxidant activity, curcumin may function indirectly as an antioxidant by inhibiting the activity of inflammatory enzymes or by enhancing the synthesis of glutathione, an important intracellular antioxidant (see below).
Anti-inflammatory Activity
The metabolism of arachidonic acid in cell membranes plays an important role in the inflammatory response by generating potent chemical messengers known as eicosanoids (11). Membrane phospholipids are hydrolyzed by phospholipase A2 (PLA2), releasing arachidonic acid, which may be metabolized by cyclooxygenases (COX) to form prostaglandins and thromboxanes, or lipoxygenases (LOX) to form leukotrienes. Curcumin has been found to inhibit PLA2, COX-2 and 5-LOX activity in cultured cells (12). Although curcumin inhibited the catalytic activity of 5-LOX directly, it inhibited PLA2 by preventing its phosphorylation and COX-2 mainly by inhibiting its transcription. Nuclear factor-kappa B (NF-kB) is a transcription factor that binds DNA and enhances the transcription of the COX-2 gene and other pro-inflammatory genes, such as inducible nitric oxide synthase (iNOS). In inflammatory cells, such as macrophages, iNOS catalyzes the synthesis of nitric oxide, which can react with superoxide to form peroxynitrite, a reactive nitrogen species that can damage proteins and DNA. Curcumin has been found to inhibit NF-kB-dependent gene transcription (13), and to inhibit the induction of COX-2 and iNOS in cell culture and animal studies (14, 15).
Glutathione Synthesis
Glutathione is an important intracellular antioxidant that plays a critical role in cellular adaptation to stress (16). Stress-related increases in cellular glutathione levels result from increased expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Studies in cell culture suggest that curcumin can increase cellular glutathione levels by enhancing the transcription of the genes for GCL (17).
Effects on Biotransformation Enzymes Involved in Carcinogen Metabolism
Biotransformation enzymes play important roles in the metabolism and elimination of a variety of biologically active compounds, including drugs and carcinogens. In general, phase I biotransformation enzymes, including those of the cytochrome P450 (CYP) family, 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 these compounds (18). Although increasing biotransformation enzyme activity may enhance the elimination of potential carcinogens, some carcinogen precursors (procarcinogens) are metabolized to active carcinogens by phase I enzymes (19). CYP1A1 is involved in the metabolic activation of several chemical carcinogens. Curcumin has been found to inhibit increases in CYP1A1 activity induced by procarcinogens in cell culture and animal studies (20-23). Increasing phase II biotransformation enzyme activity is generally thought to enhance the elimination of potential carcinogens. Several studies in animals have found that dietary curcumin increased the activity of phase II enzymes, such as glutathione S-transferases (GSTs) (22, 24, 25). However, curcumin intakes ranging from 0.45-3.6 g/day for up to 4 months did not increase leukocyte GST activity in humans (6).
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 it can divide again. Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage cannot be repaired (26). Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Curcumin has been found to induce cell cycle arrest and apoptosis in a variety of cancer cell lines grown in culture (2, 27). The mechanisms by which curcumin induces apoptosis are varied but may include inhibitory effects on several cell signaling pathways. However, not all studies have found that curcumin induces apoptosis in cancer cells. Curcumin inhibited apoptosis induced by the tumor suppressor protein p53 in cultured human colon cancer cells (28, 29), and one study found that curcumin inhibited apoptosis induced by several chemotherapeutic agents in cultured breast cancer cells at concentrations of 1-10 micromoles/liter (30).
Inhibition of Tumor Invasion and Angiogenesis
Cancerous cells invade normal tissue aided by enzymes called matrix metalloproteinases. Curcumin has been found to inhibit the activity of several matrix metalloproteinases in cell culture studies (31-33). Invasive tumors must also develop new blood vessels to fuel their rapid growth by a process known as angiogenesis. Curcumin has been found to inhibit angiogenesis in cultured vascular endothelial cells (34) and in an animal model (35).
Note: It is important to keep in mind that that many of the biological activities discussed above were observed in cells cultured in the presence of curcumin at higher concentrations than are likely to be achieved in humans consuming curcumin orally (see Metabolism and Bioavailability above).
The ability of curcumin to induce apoptosis in cultured cancer cells by several different mechanisms has generated scientific interest in the potential for curcumin to prevent some types of cancer (2). Oral curcumin administration has been found to inhibit the development of chemically-induced cancer in animal models of oral (36, 37), stomach (38, 39), liver (40), and colon (41-43) 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 that is 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 (44, 45). In contrast, oral curcumin administration has not consistently been found to inhibit the development of mammary (breast) cancer in animal models (41, 46, 47).
Although the results of animal studies are promising, particularly with respect to colorectal cancer, there is presently little evidence that high intakes of curcumin or turmeric are associated with decreased cancer risk in humans. A phase I clinical trial in Taiwan, examined the effects of oral curcumin supplementation up to 8 g/day for 3 months in patients with precancerous lesions of the mouth (oral leukoplakia), cervix (high grade cervical intraepithelial neoplasia), skin (squamous carcinoma in situ) or stomach (intestinal metaplasia) (5). Histologic improvement on biopsy was observed in 2 out of 7 patients with oral leukoplakia, 1 out of 4 patients with cervical intraepithelial neoplasia, 2 out of 6 patients with squamous carcinoma in situ and 1 out of 6 patients with intestinal metaplasia. However, cancer developed in 1 out of 7 patients with oral leukoplakia and 1 out of 4 patients with cervical intraepithelial neoplasia by the end of the treatment period. This study was designed mainly to examine the bioavailability and safety of oral curcumin, and interpretation of its results is limited by the lack of a control group for comparison. As a result of the promising findings in animal studies, 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 (48).
In Alzheimer’s disease, a peptide called amyloid beta forms aggregates (oligomers), which accumulate in the brain and form deposits known as amyloid plaques (49). Inflammation and oxidative damage are also associated with the progession of Alzheimer’s disease (50). Curcumin has been found to inhibit amyloid beta oligomer formation in vitro (51). When injected peripherally, curcumin was found to cross the blood brain barrier in an animal model of Alzheimer’s disease (51). Dietary curcumin has been found to decrease biomarkers of inflammation and oxidative damage and to decrease amyloid plaque burden in the brain and amyloid beta-induced memory deficits in animal models of Alzheimer’s disease (51-53). It is not known whether curcumin taken orally can cross the blood brain barrier or inhibit the progression of Alzheimer’s disease in humans. As a result of the promising findings in animal models, several clinical trials of oral curcumin supplementation in patients with early Alzheimer’s disease are under way (48).
The ability of curcumin to induce apoptosis in a variety of cancer cell lines in culture and its low toxicity have led to scientific interest in its potential for cancer therapy as well as cancer prevention (54). To date, most of the controlled clinical trials of curcumin supplementation in cancer patients have been Phase I trials. Phase I trials are clinical trials in small groups of people, aimed at determining bioavailability, optimal dose, safety and early evidence of the efficacy of a new therapy (55). A phase I clinical trial in patients with advanced colorectal cancer found that doses up to 3.6 g/day for 4 months were well tolerated, although the systemic bioavailability of oral curcumin was low (60). When colorectal cancer patients with liver metastases took 3.6 g/day of curcumin orally for 7 days, trace levels of curcumin metabolites were measured in liver tissue, but curcumin itself was not detected (8). In contrast, curcumin was measured in normal and malignant colorectal tissue after patients with advanced colorectal cancer took 3.6 g/day of curcumin orally for 7 days (7) These findings suggest that oral curcumin is more likely to be effective as a therapeutic agent in cancers of the gastrointestinal tract than other tissues. Phase II trials are clinical trials designed to investigate the effectiveness of a new therapy in larger numbers of people, and to further evaluate short-term side effects and safety of the new therapy. Phase II clinical trials of curcumin in patients with advanced pancreatic cancer are currently under way (48), and phase II trials of curcumin for colorectal cancer have been recommended (2).
Although the anti-inflammatory activity of curcumin has been demonstrated in cell culture and animal studies, few controlled clinical trials have examined the efficacy of curcumin in the treatment of inflammatory conditions. A preliminary intervention trial that compared curcumin with a nonsteroidal anti-inflammatory drug (NSAID) in 18 rheumatoid arthritis patients found that improvements in morning stiffness, walking time and joint swelling after 2 weeks of curcumin supplementation (1200 mg/day) were comparable to those experienced after 2 weeks of phenylbutazone (NSAID) therapy (300 mg/day) (56). A placebo-controlled trial in 40 men who had surgery to repair an inguinal hernia or hydrocele found that 5 days of oral curcumin supplementation (1200 mg/day) was more effective than placebo in reducing post surgical edema, tenderness and pain, and was comparable to phenylbutazone therapy (300 mg/day) (57). Two uncontrolled studies found that oral curcumin (1125 mg/day) for 12 weeks or longer improved anterior uveitis and idiopathic inflammatory orbital pseudotumor, inflammatory conditions of the eye (58, 59). However, without a control group, it is difficult to draw conclusions regarding the anti-inflammatory effects of curcumin in these conditions. Larger randomized controlled trials are needed to determine whether oral curcumin supplementation is effective in the treatment of inflammatory diseases, such as rheumatoid arthritis.
Cystic fibrosis is a hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTCR) gene (60). CFTCR is a transmembrane protein that acts as a chloride channel and plays a critical role in ion and fluid transport. In the lungs, CFTCR mutations ultimately result in increased mucus concentration and decreased clearance, which leads to progressive lung disease. The most common CFTCR mutation contributing to the development of cystic fibrosis is the delta F508 mutation, which results in CFTCR protein misfolding and degradation before the protein can be targeted to the cell membrane. However, the mutated protein retains some ability to function as a chloride channel if it can be inserted in the cell membrane. In 2004, a study in mice with the delta F508 mutation found that oral curcumin administration corrected abnormal ion transport and improved the survival of these mice (61). However, unlike humans, mice with the delta F508 mutation experience only the digestive complications of cystic fibrosis without the lung complications, and treatment benefits in the mouse model are not always realized in humans (60) More recently, another group of scientists was unable to duplicate the beneficial effects of curcumin in the same mouse model given the same dose of curcumin (62). It is unclear whether curcumin supplementation will be of benefit to humans with cystic fibrosis. The Cystic Fibrosis Foundation is funding a phase I clinical trial to determine the safety of curcumin supplementation in cystic fibrosis patients (63). Until the safety and efficacy of curcumin in individuals with cystic fibrosis has been evaluated in clinical trials, the Cystic Fibrosis Foundation does not recommend the use of curcumin as a therapy for cystic fibrosis (64).
Food Sources
Tumeric, is the dried ground rhizome of Curcuma longa Linn (65). It is used as a spice in Indian, Southeast Asian and Middle Eastern cuisines. Curcuminoids comprise about 2-9% of turmeric (66). Curcumin is the most abundant curcuminoid in turmeric, providing about 75% of the total curcuminoids, while demethoxycurcumin provides 10-20% and bisdemethoxycurcumin generally provides < 5%. Curry powder contains turmeric along with other spices, but the amount of curcumin in curry powders is variable and often relatively low (67). Curcumin extracts are also used as food coloring agents (68).
Supplements
Curcumin 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. However, piperine may also affect the metabolism of drugs (see Drug Interactions below). 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 above).
Adverse Effects
In the US, turmeric is generally recognized as safe (GRAS) as a food additive by the FDA (68). Serious adverse effects have not been reported in humans taking high doses of curcumin. In a phase I trial in Taiwan, curcumin supplementation up to 8 g/day for 3 months was reported to be well-tolerated in patients with precancerous conditions or noninvasive cancer (5). In another clinical trial in the UK, curcumin supplementation ranging from 0.45-3.6 g/day for 4 months was generally well tolerated by people with advanced colorectal cancer, although two participants experienced diarrhea and another reported nausea (6). 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 (2). Curcumin supplementation of 20-40 mg has been reported to increase gallbladder contractions in healthy people (69, 70). Although increasing gallbladder contractions could decrease the risk of gallstone formation by promoting gallbladder emptying, it could potentially increase the risk of symptoms in people who already have gallstones.
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.
Curcumin has been found to inhibit platelet aggregation in vitro (71, 72), 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 campothecin, mechlorethamine and doxorubicin at concentrations of 1-10 micromolesl/liter (30). In an animal model of breast cancer, dietary curcumin inhibited cyclophosphamide-induced tumor regression. Although 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 (8). it may be advisable for women undergoing chemotherapy for breast cancer to avoid curcumin supplements (30). Some curcumin supplements also contain piperine, for the purpose of increasing the bioavailability of curcumin. However, piperine may also increase the bioavailability and slow the elimination of a number of drugs, including phenytoin (Dilantin), propranolol (Inderal) and theophylline (73, 74).
Written by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed by:
Chung S. Yang, Ph.D.
Professor II and Chair
Department of Chemical Biology
Ernest Mario School of Pharmacy
Rutgers, The State University of NJ
Last updated 11/07/2005 Copyright 2005-2008 Linus Pauling Institute
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