Antioxidants - The
Latest Weapon in the War on Smoking and Free Radicals Part 2
Vitamin Research Products Inc. 2001
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
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
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
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
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.
source of nutrients and supplements.
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.
|1. Cross CE, Traber MG.
Cigarette smoking and antioxidant vitamins: the smoke screen continues
to clear but has a way to go. Am J Clin Nutr, 1997, 65:562-563.
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,
|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.
|5. Jialal I, Fuller CJ,
Huet BA. The effect of alpha-tocopherol supplementation on LDL
oxidation. A dose-response study. Arterioscler Thromb Vasc Biol,
1995, 15: 190-198.
|6. Brown KM, Morrice PC,
Duthie GD. Erythrocyte vitamin E and ascorbate concentrations in
relation to erythrocyte peroxidation in smokers and nonsmokers: dose
response to vitamin E supplementation. Am J Clin Nutr, 1997,
|7. Halliwell B. Free
radicals, antioxidants, and human disease: curiosity, cause, or
consequence? Lancet, 1994, 344: 721-724.
|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:
|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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