Biochemical Health Profiling: Antioxidants
Charles A. Thomas, Jr., Ph.D.
In our laboratories in San Diego, we have developed assays to monitor blood levels of many substances that influence health and disease. These substances include fat-soluble antioxidants, such as vitamin E, coenzyme Q10 (CoQ10), lycopene, beta- and alpha-carotene, and water-soluble antioxidants, including vitamin C, uric acid and albumin. Such monitoring may allow us to make dietary suggestions that may reduce an individualís risk of contracting age-related degenerative disease.
Coenzyme Q10 - Ubiquinol
CoQ10 is a very easily oxidized lipid-soluble molecule that is made by the body and also derived from food. It is found mainly in the inner membrane of mitochondria (the cellís "power plant") where it helps generate usable biochemical energy in the form of adenosine triphosphate. However, it is also found in other cell membranes, where is helps to maintain vitamin E in its active (reduced) from and may function in other biochemical pathways that are still poorly understood. CoQ10 can also function directly as a lipid-soluble antioxidant and, in fact, is more efficient than vitamin E in protecting low-density lipoprotein (LDL) from oxidation in vitro, although vitamin E is more important physiologically because its serum concentration is about 30-fold higher. Most of the bodyís pool of CoQ10 is made endogenously, as demonstrated by the fact that cholesterol-lowering "statin" drugs, which interfere with CoQ10 synthesis, typically decrease serum and tissue levels of this cofactor. Despite the poor absorption of CoQ10 from supplements, clinical studies have documented the efficacy of high-dose supplemental CoQ10 (60-300 mg daily) in congestive heart failure and essential hypertension. CoQ10 may also be useful in treating or preventing angina, periodontal disease, and adriamycin-mediated cardiotoxicity. Although CoQ10 has immunostimulatory effects in animals, its clinical potential in this regard has received little evaluation. CoQ10 supplementation appears to be safe and without side effects at all doses studied.
Vitamin E is the most abundant lipid-soluble antioxidant in the body. It is embedded in the various lipoprotein particles, where it is chiefly responsible for the protection of LDL particles from oxidation. Vitamin C helps maintain vitamin E in its reduced active form, which may be why, in epidemiological studies, vitamin C supplements appear to be most beneficial to those who concurrently take vitamin E. Vitamin E also provides vital antioxidant protection for cell membranes, where it works together with both vitamin C and CoQ10. Supplemental intakes of vitamin E increase the vitamin E content of LDL particles and have been found to increase the resistance of these particles to oxidative damage, which may explain why long-term use of supplemental vitamin E has been associated with substantially reduced risk for coronary heart disease. Recent clinical studies have demonstrated the slowing of coronary stenosis and the prevention of non-fatal heart attacks in subjects taking vitamin E (400-800 IU daily). Although vitamin E--unlike selenium or tea polyphenols--does not show anticancer activity in animals, a recent clinical chemoprevention study suggests that supplemental vitamin E might decrease risk for prostate cancer, and epidemiological studies support a protective role against colon cancer.
Gamma-tocopherol, a close chemical relative of the more abundant alpha-tocopherol, is present in serum at concentrations about ten-fold lower than the latter compound and is less effective as a chain-breaking lipid antioxidant. However, it may be more effective for quenching dangerous radicals derived from peroxynitrite, a product of inflammation. One recent study found decreased serum levels of gamma-tocopherol in coronary heart disease patients compared to healthy controls. Interestingly, residents of Fiji display relatively high serum levels of this antioxidant and have an anomalously low risk for lung cancer. Gamma-tocopherol is not commercially available as a separate supplement, although it is present in "mixed tocopherol" supplements derived from soy oil. So far, there are no experimental or clinical studies showing that mixed tocopherol supplements are more protective than alpha-tocopherol. While it is premature to conclude that gamma-tocopherol has any special health-protective merits, further research is clearly warranted.
Lycopene, a prominent member of the pigmented carotenoid family, is more effective than other dietary carotenoids for quenching singlet oxygen (a strong pro-oxidant generated by exposure of tissues to UV light). It also scavenges free radicals in cell membranes and lipoproteins. Although it has the potential to protect LDL, normal serum levels correspond to only about one molecule of lycopene per five LDL particles. Epidemiological studies reveal significant protection of increased dietary intakes or serum levels of lycopene against cancers of the stomach, colon, rectum, prostate and cervix. Some of these studies focus specifically on tomato products, the most significant dietary source of bioavailable lycopene. Prostate cancer has received particular attention in light of the discovery that prostate tissue contains more lycopene than other carotenoids. Some animal studies demonstrate anticarcinogenic or cancer-retardant effects of high-dose lycopene. Lycopene has also inhibited the growth of certain cancer cell lines. In a large European study, increased concentrations of lycopene in adipocytes (fat cells) correlated with decreased risk for heart attack. Whether dietary lycopene is truly significantly protective remains to be established in controlled supplementation trials, but current epidemiological evidence strongly suggests that a high intake of tomato products may be beneficial. The bioavailability of lycopene from raw tomatoes or raw tomato juice appears to be relatively poor, but tomato paste or sauce, heated with small amounts of oil, is a good source of absorbable lycopene.
Like other carotenoids, beta-carotene is potentially important as a scavenger of several aggressive oxygen species, including singlet oxygen. It is usually the most abundant carotenoid in serum and is found in carrots, orange and yellow fruits, and green leafy vegetables. Supplemental beta-carotene accumulates preferentially in arterial plaque, suggesting that it may provide useful antioxidant protection for damaged arteries. Indeed, beta-carotene is antiatherogenic in cholesterol-fed rabbits. In cell culture studies, beta-carotene and other carotenoids can retard the carcinogen-mediated transformation of cells, and some anticancer effects have been reported in animal studies. Despite these studies and encouraging epidemiological reports that link increased dietary or serum beta-carotene levels with reduced risk for heart disease and certain cancers, three large long-term beta-carotene supplementation studies have failed to demonstrate protection against cancer or heart disease. A recent Finnish study linked supplemental beta-carotene to a modest but significant increase of lung cancer incidence in long-time smokers, though not in ex-smokers or non-smokers. The risk was greatest among smokers who were also drinkers, and some experts have speculated that ethanol and beta-carotene may cooperate in the induction of lung enzymes that activate smoke-derived carcinogens. The apparent protection observed in epidemiological studies may primarily reflect the function of beta-carotene as a marker for fruit and vegetable intake. However, supplemental beta-carotene has been shown to reverse pre-neoplastic lesions (leukoplakia) in the oral cavity. Claims that high-dose beta-carotene supplementation decreases the bioavailability of other carotenoids have not been borne out in more recent work. The only evident side-effect of high carotene intake is a harmless yellowing of the skin (carotoderma) that clinically is differentiated from jaundice by the fact that the sclera (the whites of the eyes) remain white. Both beta- and alpha-carotene are precursors to vitamin A.
Alpha-carotene is very similar in structure to beta-carotene, but less abundant. It is equivalent to beta-carotene in function, although one report indicates that alpha-carotene is more effective than beta-carotene in preventing lung and skin cancer in mice. Very little animal or clinical research has focused on alpha-carotene. Since most people obtain little if any alpha-carotene from supplements or food additives (in contrast to beta-carotene), serum levels of alpha-carotene, along with those of its fellow carotenoids lutein and lycopene, can serve as useful markers for fruit and vegetable consumption. Among 156 studies that have correlated fruit and vegetable intake with risk for various cancers, 128 revealed significant protection associated with higher intakes of these foods. Thus, a relatively low serum level of alpha-carotene may mean that the intake of fruits and vegetables has been less than optimal.
Vitamin C is the premier water-soluble antioxidant in serum and protects lipoproteins against oxidation by quenching aqueous radicals, as well as by restoring the reduced active forms of vitamin E and other lipid-soluble antioxidants. Dehydroascorbate, which is the oxidized from of vitamin C, is readily converted to ascorbate in cells by enzymatic mechanisms. Ascorbate can then exit the cell, quench radicals and re-arm other antioxidants in the serum and extracellular space. However, in the presence of free iron ions, ascorbate can generate the dangerous ferrous ion, a crucial catalyst of oxidant damage. Fortunately, supplementation studies demonstrate that, at least under ordinary circumstances in which iron is properly sequestered in storage and transport proteins, vitamin C exerts a net antioxidant effect. When dietary ascorbate intake is fairly good, supplements produce only transient elevations of serum vitamin C levels. Thus, high-dose therapeutic applications require numerous doses daily. Serum vitamin C can act as a marker for fruit and vegetable intake, which makes it difficult to interpret the many epidemiological studies correlating higher vitamin C status with reduced risk of cardiovascular diseases or cancer. Vitamin C deficiency exacerbates atherogenesis in animal models. High vitamin C intakes usually lack anticancer activity in carcinogen-treated animals. However, oral vitamin C suppresses the endogenous production of carcinogenic nitrosamines, which may reduce the risk for gastric cancer. Risks for esophageal, pancreatic and lung cancer also appear to be lower in those with ample intakes of vitamin C and/or fruit. In epidemiological studies examining the impact of supplement use on total mortality or disease risk, vitamin C appears less strikingly and consistently protective than vitamin E. The greatest benefits are seen in those concurrently taking vitamin E, which is consistent with vitamin Cís ability to potentiate the antioxidant activity of vitamin E. The versatility and prominence of vitamin C as a physiological antioxidant, as well as its other manifold physiological and biochemical functions, suggest that it is wise to maintain serum levels in the high-normal range, which can be achieved with supplements or by eating abundant amounts of fruits and vegetables high in vitamin C.
Uric acid, a metabolic breakdown product of nucleic acids in DNA (purines), is found in serum at concentrations ten-fold higher than those of vitamin C and recently has been shown to offer significant antioxidant activity. Its concentration can be increased by eating nucleic acid-rich foods, such as yeast or sardines, or by accelerating purine breakdown by drinking alcoholic beverages. While moderate alcohol consumption appears to be highly cardioprotective, it is not clear whether increased serum urate plays a role in this effect. The health impact of increased nucleic acid ingestion has so far received little study. However, it is well known that, in susceptible individuals, high serum or tissue levels of uric acid can result in the precipitation of uric acid crystals, which can cause gouty arthritis or nephropathy. One study suggests that high uric acid levels may protect against multiple sclerosis.
Albumin is the most abundant protein in serum. Recent evidence indicates that albumin may provide antioxidant protection by functioning as a serum peroxidase in the presence of reduced glutathione, which is an intracellular antioxidant. Albumin is a superb binder of metals of all sorts, and one of its chief roles is to bind and carry serum free fatty acids (FFAs). The pathogenic impacts of high levels of FFAs are undoubtedly greater when the FFA/albumin ratio is high. When the levels of gamma globulin increase, reflecting infection, for instance, the blood level of albumin decreases. Thus, the most effective way to achieve high albumin levels is to avoid infection or inflammation. High albumin levels are correlated with lean mass in the elderly, suggesting that exercise might favorably influence albumin levels. Epidemiological studies have demonstrated that low albumin levels are associated with an increased risk for mortality from both cardiovascular disease and cancer, whereas life expectancy is highest at high-normal albumin levels. Low albumin may be serving as a marker for other pathogenic processes or factors--infection, inflammation, loss of lean mass associated with illness, undernutrition or lack of activity--but may also reflect a serum antioxidant deficit that contributes to risk. (References for cited studies are available on request.)
Last updated May, 1999
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