Roger Clemens

Dietary Antioxidants—Risk or Relief?
Nutritional antioxidants have come under close scrutiny of late and are the subject of escalating debate. The alphabet soup of flavonoids, such as catechins (tea)and anthocyanins (wine and bilberries), occur naturally in virtually all foods and appear to be particularly abundant in fruits and vegetables. Notable examples and their sources include beta-carotene (sweet potatoes, squash, apricots, and pumpkin), lycopene (tomatoes, papaya, and blood oranges), lutein (spinach, kale, collard greens), vitamin C (citrus fruits), and vitamin E (almonds and other nuts, and corn and soybean oils).

An excellent recent study by Wu et al. (2004) indicated that the total antioxidant capacity of pecans, walnuts, and hazelnuts was very high, based in part on an in-vitro assessment of oxygen radical absorbance capacity (ORAC) and polyphenol content. Their results also suggested that grain-based foods, including some ready-to-eat breakfast cereals, are among the best sources of antioxidants, based on this assessment. Part of the challenge is to translate these in-vitro assessments into clinical relevance.

These antioxidants may have a role in protecting cells from molecules known as reactive oxygen species (ROS) or free radicals, which have been implicated in the etiology of various malignancies, coronary artery disease, diabetic vasculopathy, and aging. The National Cancer Institute has reviewed a number of completed and clinical trials in progress (NCI, 2004) and concluded, in essence, that inconsistent data preclude anything but the recommendation that a healthy diet should include a variety of fruits and vegetables in moderate quantities.

The American Heart Association (www.americanheart.org/presenter) similarly finds no evidence to support antioxidant supplements, and continues to recommend a balanced diet including five daily servings of fruits and vegetables. Omenn et al. (1996a, b) reported that beta-carotene and vitamin A supplements were associated with a higher incidence of lung cancer in relatively high-intensity smokers than in controls. There have also been at least two studies that have found that antioxidant supplements, specifically vitamins E (400 IU twice a day, BID) and C (500 mg BID), beta-carotene (12.5 mg BID), and selenium (50 g BID), and selenium may interfere with the protective effect of statin agents, such as Zocor, and HDL levels (Cheung et al., 2001; Brown et al., 2001).

In-vitro evidence and observational studies to date underscore the benefits derived from food-derived antioxidants and undermine the role of some antioxidant-laden dietary supplements. Some relatively small clinical studies among high-risk individuals, however, such as those recently described by Richer et al. (2004), Sesso et al. (2004), and Block et al. (2004) are clinically provocative. For example, the evidence by Richer et al. suggests that visual function in patients with age-related macular degeneration may be improved by supplementation with 10 mg of lutein/day over a 12-month period. Sesso et al. described data from the Women’s Health Study that indicated that higher plasma lycopene concentrations were associated with a lower risk of cardiovascular disease in women. Block et al. noted that when active smokers supplemented their diet with vitamin C (515 mg/day) during a 2-month study period, one of the plasma indicators of inflammation, namely C-reactive protein, decreased significantly.

Despite these potential benefits associated with a reduction in health risks, all of the investigators stipulated the need for additional clinical research to understand mechanisms of action, assess long-term effects, and validate these potential benefits in the general population. This is particularly important when considering the large number of middle-aged, those more senior in age, and the overweight/obese individuals who are consuming multiple medications, including statins to reduce their blood cholesterol levels.

Clearly, more rigorous study is indicated before antioxidant supplements can be recommended for those at risk for chronic disease such as cancer, vascular disease, and age-related conditions. The recent meta-analysis by Bjelakovic et al. (2004) suggests that pharmacological doses of beta-carotene, vitamins A, C, and E, and selenium supplements may not decrease one’s risk of gastrointestinal cancers. On the other hand, the accompanying editorial by Forman and Altman (2004) asserts that the apparently negative impact of these nutrients is not convincing.

One of the key findings of the Dietary Guidelines Advisory Committee (2005) is that Americans should increase their daily intake of fruits and vegetables, whole grains, and nonfat or low-fat milk and milk products, so that we can increase our consumption of vitamins A, C, and E, as well as calcium, potassium, magnesium, and fiber. This recommendation incorporates the Advisory Committee’s recognition that these foods provide physiological doses of diverse micronutrients as part of a balanced diet, and that the lifelong practice of balance, moderation, and variety beginning at childhood can contribute to a reduced risk of chronic disease. This finding also emphasizes that the specific roles of antioxidant compounds remains largely unknown from a clinical perspective, and that the doses and forms of these antioxidants that may reduce or even exacerbate one’s risk of disease remain to be determined.

by ROGER CLEMENS, Dr.P.H.
Director, Analytical Research
Professor, Molecular Pharmacology & Toxicology
USC School of Pharmacy, Los Angeles, Calif.
[email protected]

by PETER PRESSMAN, M.D.
Internal Medicine
Geller, Rudnick, Bush & Bamberger
Beverly Hills, Calif.
[email protected]

References

Bjelakovic, G., Nikolova, D., Simonetti, R.G., and Gluud, C. 2004. Antioxidant supplements for prevention of gastrointestinal cancers: A systematic review and meta-analysis. Lancet 364: 1219-1228.

Block, G., Jensen, C., Dietrich, M., Norkus, E.P., Hudes, M., and Packer, L. 2004. Plasma C-reative protein concentrations in active and passive smokers: Influence of antioxidant supplementation. J. Am. Coll. Nutr. 23(2): 141-147.

Brown, B.G., Zhao, X.Q., Chait, A., Fisher, L.D., Cheung, M.C., Morse, J.S., Dowdy, A.A., Marino E.K., Bolson, E.L., Alaupovic, P., Frohlich, J., and Albers, J.J. 2001. Simvastatin and niacin, antioxidant vitamins, or the combination in the prevention of coronary disease. New Eng. J. Med. 345: 1583-1592.

Cheung, M.C., Zhao, X.Q., Chait, A., Albers, J.J., and Brown, B.G. 2001. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arteriosclerosis, Thrombosis, Vascular Biol. 21: 1320-1326.

Dietary Guidelines Advisory Committee. 2005. Nutrition and your health: Dietary guidelines for Americans. U.S. Dept. of Agriculture, www.health.gov/dietaryguidelines/dga2005/report

Forman, D. and Altman, D. 2004. Vitamins to prevent cancer: Supplementary problems. Lancet 364: 1193-1194.

NCI. 2004. NCI fact sheet. Natl. Cancer Inst., www.cancer.gov/newscenter/pressreleases/antioxidants.

Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Valanis, B., Williams, J.H., Barnhart, S., and Hammar, S. 1996a. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New Eng. J. Med. 334: 1150 1155.

Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L Jr., Valanis, B., Williams, J.H Jr., Barnhart, S., Cherniack, M.G., Bordkin, C.A., and Hammar, S. 1996b. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl. Cancer Inst. 88: 1550-1559.

Richer, S., Stiles, W., Statkute, L., Pulido, J., Frankowski, J., Rudy, D., Pei, K., Tsipursky, M., and Nyland, J. 2004. 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 75(4): 216-230.

Sesso, H.D., Buring, J.E., Norkus, E.P., and Gaziano, J.M. 2004. Plasma lycopene, other carotenoids, and retinol and the risk of cardiovascular disease in women. Am. J. Clin. Nutr. 79: 47-53.

Wu, X., Beecher, G.R., Holden, J.M., Haytowitz, D.B., Gebhardt, S.E., and Prior, R.L. 2004. Lipophilic and hydrophilic antioxidant capacities of common foods in the United States. J. Agric. Food Chem. 52: 4026-4037.