The preceding Part I of this article outlined the causative role of cigarette smoking-generated oxygen free radicals in the pathogenesis of chronic degenerative diseases like emphysema, lung cancer and coronary artery disease. Furthermore, evidence was presented that smoking causes a huge oxidative stress load,1 and that antioxidant supplements are helpful in preventing or mitigating oxidative damage.

Despite (1) this overwhelming evidence of smoking-induced oxidative stress, (2) the known causative role of smoking in the development of chronic degenerative disease, and (3) the frequently demonstrated benefits of antioxidants in preventing these diseases, recent findings by the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group in Finland appear to contradict what are believed to be the established benefits of antioxidant supplements in smokers. In the Finnish study, investigators performed a randomized, double-blind, placebo-controlled trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 men were randomly assigned to one of four regimens: (1) alpha-tocopherol, vitamin E, (50 mg per day) alone; (2) beta carotene (20 mg per day) alone; (3) both alpha-tocopherol and beta carotene; or (4) placebo. The study participants receiving these different supplement regimens were followed for five to eight years, unless death occurred earlier during the follow-up.

At the conclusion of the trial, the researchers found 876 new cases of cancer (3% incidence). Surprisingly, they found no difference in the incidence of lung cancer between the two groups who received either alpha-tocopherol or placebo. Equally unexpected were their findings of a higher incidence of lung cancer among the men who received beta carotene compared to those who received the placebo. Additionally, there was no apparent benefit of combining alpha-tocopherol and beta carotene. They did find, however, fewer cases of prostate cancer among those who received alpha-tocopherol compared to those who did not. The investigators concluded that "antioxidant supplements may have both harmful as well as beneficial effects."2

The Flawed Finnish Study
The questions aroused by this Finnish study warrant a critical evaluation of both the study design and interpretation of its data, both of which I believe are flawed, and which probably account for the surprising paradoxical conclusions of the authors. First, the investigators chose very heavy smokers (mean age sixty years) who had been smoking for nearly 40 years. Although it has been shown that oxidative damage increases with age, independent of cigarette smoking,3,4 the investigators did not evaluate the baseline antioxidant status nor degree of oxidative damage in these individuals prior to their enrollment in the study despite the availability of a number of valid tests.  

Because of the relatively advanced age of the study participants and the extended period in which they had been subjected to the smoking-induced oxidative load, it is likely that the paltry 50 mg of vitamin E that was administered was simply an inadequate dose. Indeed, it has been suggested that the minimum dose of alpha-tocopherol required to produce beneficial effects against oxidative stress is in excess of 200 IU (or mg) per day.5 It is therefore not surprising that 50 mg/day of this antioxidant was without effect.

Interestingly, in contrast to the Finnish study, it has recently been shown that red blood cells obtained from younger smokers (mean age 30 years) who received 70 to 1050 mg/day alpha-tocopherol for twenty weeks were significantly less susceptible to oxidative damage after taking vitamin E than they were before taking vitamin E.6

Furthermore, whereas beta carotene may contribute to the overall antioxidant defense of the body, the mechanism of its action does not appear to be through the free radical chain-breaking reactions which involve vitamin C (ascorbate), vitamin E (tocopherol), glutathione, selenium and the associated antioxidant enzymes.7,8 In addition, it is believed that over-consumption of only one carotenoid (like beta carotene) may inhibit the effectiveness of other carotenoids (like alpha and gamma carotene, lutein, and lycopene). This is of particular significance in view of the recent findings that subjects with the lowest blood levels of lycopene (a carotenoid found in high levels in tomatoes) had a cancer risk about three times higher than subjects with the highest lycopene levels.9 Consequently, it is not surprising that no positive interaction was observed between the low doses of alpha-tocopherol and beta carotene as an isolated nutrient as used in this study.

In summary, the findings from the Finnish study created an unwarranted controversy due to its poor design and the erroneous conclusions arrived at by the authors. What the authors did prove, however (but which they failed to clearly state), was that a dose of 50 mg of vitamin E per day is clearly inadequate to impart any significant benefit to those with a significant oxidative stress load.

BENEFITS OF ANTIOXIDANT SUPPLEMENTS
The evidence supporting the beneficial role of antioxidant supplements in disease prevention among smokers and other populations is overwhelming.1,10,11 Antioxidant supplementation in smokers is necessary to raise tissue antioxidant levels that have been depleted both by increased age12,13 and by the direct destruction of antioxidants by cigarette smoke.14 I have heard vitamin E described as the 'Michael Jordan' of antioxidant supplements. This probably comes from the fact that this vitamin has been one of the most thoroughly-investigated antioxidants and has generally been shown to be efficacious in the prevention or delay of a variety of diseases, including those frequently associated with cigarette smoking as has been highlighted in this review article.

I have already alluded to the recent study, in which it was found that the use of 70-1050 mg/day of alpha-tocopherol by young smokers (mean age 30 years) increased the resistance of their red blood cells to oxidative damage.5 Furthermore, as already pointed out, there are synergistic biochemical interactions among certain antioxidants which participate in the chain-breaking reactions for free radical destruction.8 Therefore, it seems advisable to use appropriate combinations and doses of specific antioxidants, such as 400-800 IU of vitamin E, combined with 500-5,000 mg of vitamin C per day. It is pertinent to point out that the use of ascorbate (vitamin C) alone at the dose of 1,000 mg per day for four weeks, has been found to be effective in reducing oxidative damage in smokers.11

Another promising supplement which appears to have a potent role in health promotion and disease prevention is N-acetylcysteine (NAC). This supplement is an analog of the amino acid, cysteine, which is critically important for the formation of glutathione, the major intra-cellular antioxidant in the body. Indeed, NAC has emerged as a leading cancer protective agent. It has been used since 1988 in a large trial in Europe (Euro-scan) designed to evaluate its efficacy in preventing second primary cancers in high-risk individuals. The results of this and other studies show that long-term daily use of 600 mg of NAC is safe and has been highly recommended for clinical chemopreventive trials.15 Other antioxidant supplements that have demonstrated effectiveness in reducing the damage from smoking-associated diseases, particularly, cardiovascular disease, include lipoic acid, fish oil, coenzyme Q10 and green tea (see part 1 of this article for references).

CONCLUSION
Given the apparent flaws in the design of the Finnish study, it is clear that the investigators arrived at erroneous conclusions. This resulted in an unwarranted controversy about the benefits of antioxidant supplements. I believe the true significance of the Finnish study is that it confirmed that low doses of antioxidants are of little use in disease prevention. I believe that much higher doses are certainly warranted, as confirmed by many other studies. I also believe combinations of antioxidant supplements may work better than large doses of only one supplement taken alone. Furthermore, it appears that older smokers may have to use higher doses of antioxidants in order to derive maximum benefits. For individuals who are unable to quit smoking, it thus appears that an appropriate antioxidant regimen offers the next best option for disease prevention.

Highly recommended source of nutrients and supplements.

How did we qualify them ?

Dr. Opara is a research professor in the departments of Surgery and Cell Biology and a member of the Sara W. Stedman Center for Nutritional Studies at Duke University Medical Center in Durham, NC. He received his Ph.D. degree in Medical Biochemistry from the University of London in England and did his postdoctoral training in Endocrinology and Metabolism at the Mayo Clinic in Rochester, MN. He subsequently worked as an investigator at the National Institutes of Health in Bethesda, M.D., before his present employment at Duke. Dr. Opara has written well over 100 scientific publications.

References:

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2. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Eng J Med. 1994, 330:1029-1035.

3. Lang CA, Naryshkin S, Schneider DL, Mills BJ, Lindeman RD. Low blood glutathione levels in healthy aging adults. J Lab Clin Med, 1992, 120: 720-725.

4. Vega JA, Cavallotti C, Collier WL, De Vincentis G, Rossodivita I, Amenta F. Changes in glutathione content and localization in rat heart as a function of age. Mechanisms of Aging and Dev, 1992, 64: 37-48.

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8. Machlin LJ, Bendich A. Free radical tissue damage: protective role of antioxidant nutrients. FASEB J, 1987, 1: 441-445.

9. Ford, J.G. Nutrient in tomatoes is found to lower an individual's risk of lung cancer. Presentation at 1997 Annual meeting of the American Association for Cancer Research, reported in:

10. Reilly M, Delanty N, Lawson JA, Fitzgerald GA. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation, 1996, 94: 19-25.

11. Fuller CJ, Grundy SM, Norkus EP, Jialal I. Effect of ascorbate supplementation on low density lipoprotein oxidation in smokers. Atherosclerosis, 1996, 119: 139-150.

12. Lane JD, Opara EC, Rose JE, Behm F. Quitting smoking raises whole blood glutathione. Physiol Behav, 1996, 60: 1379-1381.

13. Brown AJ. Acute effects of smoking cessation on antioxidant status. J Nutr Biochem, 1996, 7: 29-39.

14. Handelman GJ, Packer L, Cross CE. Destruction of tocopherols, carotenoids, and retinol in human plasma by cigarette smoke. Am J Clin Nutr, 1996, 63: 559-565.

15. van Zandwijk N. N-Acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer. J Cell Biochem, 1995, Suppl 22: 24-32.

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