Antioxidant Supplement Myth

The nutrition buzzword for 1994 is ìantioxidant.î Every supplement so labeled is seen as having only an upside and no down‚side. This is a myth. No supplement is a pure antioxidant.

At the November 1ó3, 1993 Food and Drug Administration (FDA) Conference on Antioxidant Vitamins in Cancer and Cardiovascular Disease (1), there was essentially unanimous agreement that vitamins C, E, and b-carotene are mischaracterized by describing them solely as ìantioxidantsî (fighters against harm‚ful free radicals). They in fact are redox agents, antioxidant in some circumstances (often so in the physiologic quantities found in food), and prooxidant (producing billions of harmful free radicals) in other circumstances (often so in the pharmacologic quantities found in supplements).

Excessive antioxidant action can adversely affect key physiological processes (1). Pharmacologic amounts of ìantioxidantî vitamins have chemical actions that are neither antioxidant nor prooxidant (1, 2). For example, protection by pharmacologic amounts of vitamin E against heart attacks may have more to do with the prohemorrhagic action of megadoses of vitamin E and, being prohemorrhagic, in some circumstances vitamin E may promote excessive bleeding (2, 3, 4).

Large doses of vitamin E enhance immune activity and thus may promote progression of immune and autoimmune diseases (eg, asthma, food allergy, diabetes, rheumatoid arthritis, multiple sclerosis, and lupus) (5). Large doses of vitamin C can promote kidney stones (2).

Vitamin C is especially dangerous in the presence of high body iron stores, which make vitamin C violently prooxidant (1, 6, 7). For genetic reasons (7), more than 10% of American whites and perhaps as many as 30% of American blacks have high body iron.

For consumer protection, every advertisement and label for vitamin C and/or iron supplements should warn: Do not take this product until your blood iron status has been determined. Six percent of Americans are in negative iron balance, and this product may help them. Twelve percent of Americans are in positive iron balance and this product may hurt them.

Iron status is determined by measuring serum ferritin and, if it is high, also measuring serum iron. Alternatively, it is measured by determining percent saturation of the serum iron-binding capacity. Measuring serum ferritin alone is inadequate, because each molecule of serum ferritin may have anywhere from no iron to 4500 atoms of iron on it (6).

In 1963, we demonstrated in a patient with scurvy and folic acid deficiency that 1 g of vitamin C mobilized into his blood enough iron from high body stores to saturate his iron-binding capacity (8). In iron overload due to transfusion therapy of patients with thalassemia or sickle cell disease, vitamin C can mobilize enough iron from body stores to overwhelm the iron-binding capacity of iron-binding proteins, with the resultant free iron producing death within minutes to hours from iron-induced cardiac failure (9).

The 1993 report of a group of 29,584 vegetarian Chinese with a high frequency of esophageal cancer (10) has been represented as evidence that ìantioxidantî supplements protect against cancer. This is not so. The study showed three things, none of them new: 1) their vegetarianism did not protect the Chinese against cancer, 2) nutrient deficiencies promote the development of some cancers, and 3) correcting those nutrient deficiencies reduces the frequency of those cancers.

It has been known for many years that nutrient deficiencies promote cancers. The Plummer-Vinson syndrome, caused by iron deficiency, has been known for more than half a century to promote the development of esophageal cancer (10). The Chinese study subjects were deficient (ie, their intakes were below minimal daily vitamin requirements to sustain normal metabolism) in so-called ìantioxidantî vitamins A, b-carotene, and E. Supplements containing b-carotene and vitamin E, by raising intakes above the minimum daily requirement, eliminated the deficiencies that promoted the cancers, thereby reducing the frequency of those cancers. Interestingly, vitamin C supplements were worthless against cancer (11), just as they (and b-carotene) proved worthless against heart disease (12, 13).

Our own group (14) reported that in the area in China with the highest frequency of folic acid deficiency (caused by cooking the nutrients out of food), vitamin B-12 deficiency (caused by vegetarianism), and esophageal carcinoma, we could reverse toward normal precancerous esophageal dysplasia, by either improving the diets (by less prolonged cooking of food plus adding a few ounces of animal protein three to four times a week), or keeping the bad diet and administering supplements of vitamin B-12 and folic acid. Those esophageal dysplasia cells not yet committed to be cancer cells reversed to normal; the committed cells did not.

We recently reported that in the presence of iron, not only does vitamin C appear to be worthless against cancer (15), but it increased lipoxidation of relatively harmless low-density-lipoprotein (LDL) cholesterol to coronary-artery-damaging oxidized LDL cholesterol (16). Vitamin C is so potent a redox agent in the presence of iron that vitamin E researchers use a vitamin Có iron mixture to inactivate vitamin E in the test tube (17).

Strong support for this position is provided by a randomized, double-blind, placebo-controlled primary-prevention trial comparing daily supplementation with a-tocopherol, b-carotene, both, or placebo. In 29 133 male smokers in Finland (18), neither vitamin prevented lung cancer. In fact, lung cancer rates were 18% higher with b-carotene than with placebo, and there were more heart disease deaths. As we predicted because of the pro-hemorrhagic action of vitamin E supplements, men taking vitamin E had more hemorrhagic strokes. They did have less prostate cancer. Total (all-cause) mortality was 8% higher among those who took b-carotene than among those taking placebo.

A study showing that b-carotene supplements produced 18% more lung cancer than a placebo in smokers (18) was to be expected. ìAntioxidantî vitamin supplements are unbalanced biochemistry, ie, only in the reduced form, which can drive free radical generation by catalytic iron (16, 19). A second reason vitamin C supplements would be expected to increase lung cancer and mortality in smokers is that vitamin C supplements drive nicotine out of the blood into the urine (19), causing smokers to reach for that next cigarette (more carcinogens) that much faster to sustain their nicotine ìhigh.î We are now investigating whether b-carotene supplements also drive nicotine into the urine. Vitamin C supplements can double cardiac risk (16, 19).

American diets average 120% of the recommended dietary allowances (RDAs) for vitamin A, b-carotene, and vitamin C (2). Dietary vitamin E deficiency has never been reported in the United States (2). Thus, has 1994 research confirmed the wisdom of 10th Recommended Dietary Allowance Committee authors Olson and Hodges (20, 21) in lowering the recommended dietary allowance (RDA) for vitamins A and C, and rejected that of the Subcommittee editors (22) to not only have a high vitamin C RDA of 60 mg, but to raise it to 100 mg for smokers.

The answer to the question, ìIf I drink orange juice for vitamin C, why not take a vitamin C pill for the same effect?î is that the effect is entirely different. ìAntioxidantî vitamins as naturally present in food are balanced biochemistry, ie, part of a mixture of redox agents half in oxidized form and half in reduced form. Every supplement pill, including those containing vitamin C, is unbalanced biochemistry.

Insun Kim and her coworkers at the Centers for Disease Control and Prevention reported in 1993 (23) that supplements were worthless to increase longevity. Supplements help some, harm some, and do nothing for most, so the bottom line is a wash. For truth in advertising, all supplements should be labeled: ìSupplements can help some people, harm others, and have no effect on most." (2) Apparently not comprehending the meaning of all the adverse facts, including those from us (19), presented at the FDA conference (1) which she attended, Bonnie Liebman of the Center for Science in the Public Interest continued to promote ìanti‚oxidantî b-carotene and vitamin E supplements in Nutrition Action Healthletter, finally retracting (24) only after publication of the New England Journal study (18).

References

1. Food and Drug Administration. November 1ó3. 1993. FDA Conference on Antioxidant Vitamins and Cancer and Cardiovascular Disease. Washington. DC: Office of Special Nutritionals. 1993 (transcript).

2. Herbert V. Subak-Sharpe G. Hammock DA. eds. The Mount Sinai School of Medicine Complete Book of Nutrition. New York: St Martinís Press. 1990.

3. Horwitt M. In reference 1 above.

4. Marshall C. Vitamins and minerals: help or harm? Philadelphia: George F Stickley Co, 1985.

5. Herbert V. Vitamin E supplementation of elderly people. Am J Clin Nutr 1991:53:976.

6. Herbert V. Dangers of iron and vitamin C supplements. J Am Diet Assoc 1993;93:526ó7.

7. Simopoulos AP, Herbert V, Jacobson B. Genetic nutrition: designing a diet based on your family medical history. New York: Macmillan, 1993.

8. Herbert V. Megaloblastic anemia. N EngI J Med 1963:268:201ó3, 368ó71.

9. Herbert V. Does mega-C do more good than harm, or more harm than good? Nutr Today 1993;28(I):28ó32.

10. Wynder EL, Hultberg S. Jacobson F, Bross IJ. Environmental factors in cancer of the upper alimentary tract; Swedish study with special reference to Plummer-Vinson (Paterson-Kelly) syndrome. Cancer 1957; 10:470ó87.

11. Blot WJ. Li J-Y, Taylor PR. et al. Nutrition intervention trials in Linxian, China:, supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:1483ó92.

12. Steinberg D. Antioxidant vitamins and coronary heart disease. N Engl J Med 1993;328:1487ó9.

13. Jialal I, Grundy SM. Effect of combined supplementation with a‚tocopherol, ascorbate, and b-carotene on low-density lipoprotein oxidation. Circulation 1993;88:2780ó6.

14. Ran JY, Dou P. Wang LY, et al. Correlation of low serum folate and total B₁₂with high incidence of esophageal carcinoma (EC) in Shanxi, China. In a high-frequency esophageal carcinoma (EC) area, folate and B₁₂deficient subjects with esophageal dysplasia (ED) im‚prove with added folate and B₁₂. Blood 1993;82(suppl l):532a.

15. Shaw S, Jayatilleke E, Herbert V. Evidence against antioxidant‚prooxidant vitamin C supplements protecting against cancer. Clin Res 1994;42:172 A (abstr).

16. Herbert V, Shaw S. Jayatilleke E. Vitamin C supplements are hann‚ful to lethal for the over 10% of Americans with high iron stores. FASEB J 1994;8:A678 (abstr).

17. Herbert V. Diet and cancer prevention. NCAHF (National Council Against Health Fraud) Newsletter 1992; 15(3): 1.

18. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effects of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029ó35.

19. Herbert V, Shaw S, Jayatilleke E, Stopler-Kasdan T. Most free-radical injury is iron-related: it is promoted by iron, hemin, holoferritin and vitamin C, and inhibited by Desferoxamine and apoferritin. Stem Cells 1994;12:289ó303.

20. Olson JA, Hodges RE. Recommended dietary intakes (RDI) of vita‚min C in humans. Am J Clin Nutr 1987;45:693ó703.

21. Olson JA. Recommended dietary intakes (RDI) of vitamin A in hu‚mans. Am J Clin Nutr 1987;45:704ó16.

22. Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press, 1989.

23. Kim I, Williamson DF, Byers T, Koplan JP. Vitamin and mineral supplement use and mortality in a US cohort. Am J Public Health I 993;83:546ó50.

24. Liebman B. Antioxidants: surprise, surprise. Nutrition Action Healthletter 1994; 21 (5): 4.