There is a preponderance of
evidence that shows a causal association between cigarette smoking and
increased risk of developing certain diseases. The diseases most clearly
associated with cigarette smoking are:  cardiovascular disease;  chronic
emphysema; and  lung cancer. Clearly, the best strategy to prevent
smoking-related diseases is to quit smoking. However, the success of smoking
cessation programs is notoriously poor, even in those who are highly motivated
to stop smoking. Consequently, I believe that we need to explore other ways to
minimize smoking-related damage and diseases.
Every puff of cigarette smoke
is bristling with disease-generating free radicals. Since the role of
oxidative damage in the pathogenesis of these diseases is well-known, one
attractive and simple option is to use antioxidant supplements. However, there
is a raging debate among physicians and scientists about the usefulness of
antioxidant supplements in this regard. Results in antioxidant supplement
trials have been equivocal for a variety of reasons. In particular, a recent
report in the New England Journal of Medicine (NEJM) concluded that
antioxidant supplements were not helpful and may even be harmful for cigarette
smokers. The conclusions in the NEJM article are erroneous for a number of
reasons, including:  difficulties in measuring certain indices of oxidative
damage;  enrollment of inappropriate and ineligible subjects; 
insufficient duration of the study; and  use of inadequate and poorly
-designed antioxidant regimens.
In this article, I will
summarize the role of free radical pathology in smoking-related diseases and
make suggestions for what I believe is a more optimum selection of
antioxidants and their doses for maximum disease prevention. I believe that
the evidence in support of appropriate antioxidant supplementation to protect
smokers is very strong.
There is overwhelming evidence
from epidemiological and experimental studies showing the direct link between
smoking and chronic emphysema, lung cancer and cardiovascular disease. This
also easily translates to increased mortality of smokers from these diseases.
Deaths from cardiovascular disease attributable to cigarette smoking in the
United States are estimated to be more than 150,000 per year. 1 The death rate
from bronchitis and emphysema in men aged 45-65 years is five times higher in
smokers than non-smokers. 2 Other studies have also shown an increased
incidence of lung cancer and cardiovascular disease in cigarette smokers. 3
Deadly Clouds of Free Radicals
The role of free radicals in the pathogenesis of these smoking-related
diseases has been substantiated by detailed descriptions of the biochemical
mechanisms involved.4 A free radical is a reactive molecule that contains one
or more unpaired electrons. Free radical formation is a normal consequence of
a variety of essential biochemical reactions, without which we could not live.
However, free radicals are relatively unstable and have a tremendous potential
to damage cells and tissues. Consequently, these highly reactive molecules
require antioxidants in the form of enzymes and small molecular weight
substances for detoxification.
The major antioxidant defenses
against free radical damage include alpha-tocopherol (vitamin E),
ascorbic acid (vitamin C), glutathione, and several
metalloenzymes (such as selenium-containing
glutathione-peroxidase, iron-containing catalase and copper-containing
Under normal circumstances,
there is a delicate balance between tissue concentrations of antioxidants and
the production of reactive oxygen species (free radicals) in the body. When
there is an excessive addition of free radicals from exogenous (outside the
body) sources, added to the endogenous (within the body) production of these
reactive oxygen species, the available tissue antioxidant systems may become
overwhelmed, leading to oxidative damage to tissues.
A major exogenous source of
free radicals is cigarette smoke.4,5 Cigarette smoke is a complex mixture of
approximately 5,000 chemical compounds, including high concentrations of free
radicals and other reactive oxygen species.5 These oxidants are contained in
both the tar and gas phases of cigarette smoke. The gas-phase reactive
oxidants are both inorganic and organic in nature, and include epoxides,
peroxides, nitric oxide (NO), nitrogen dioxide, peroxynitrite (ONOO-),
perinitrates and a myriad of other free radicals. Indeed, it has been reported
that gas-phase cigarette smoke contains approximately one quadrillion radicals
per puff!5 This represents an enormous oxidant load to body tissues.
The reactive oxygen species in
the tar phase are stable and predominantly organic. These include the hydroxyl radical, hydrogen peroxide and semiquinone, which can react with oxygen
to produce the superoxide radical. The obligatory use of the body reserve of
antioxidants to detoxify the humongous levels of these free radicals in
smokers, therefore, results in a deficiency of different antioxidants. 6
Furthermore, the antioxidant deficiency in smokers may be enhanced by their
generally lower intake of both supplemental and dietary antioxidants.7
The Short Cut to Emphysema
The mechanism by which cigarette smoke causes emphysema through oxidative
reactions is apparent. The lung seems to be particularly susceptible to damage
by oxygen free radicals.4 Furthermore, cigarette smoke contains other
substances that activate the resident phagocytes and recruit polymorphonuclear
cells into the lung. These activated phagocyte recruits exacerbate damage to
the lung tissue through oxygen free radical generation and pro teolytic
(protein-destroying) systems.4 It has been shown that cigarette smoke can
inactivate the alpha1-antiprotease inhibitor through oxidative mechanisms,
thus promoting proteolytic injury to lung tissue. 4
Cancer: Smoking's Silent
Since reactive oxygen species are capable of degrading mucus glycoproteins, it
is quite possible that oxidants in cigarette smoke react with respiratory
tract secretory glycoproteins. The role played by oxygen free radicals and
oxidative reactions in carcino-genesis is well established. The reaction of
free radicals with DNA accounts for most of the DNA strand breaks, and this
represents a major reaction leading to carcinogenesis. 4 In addition,
oxidative stress induces functional changes in gene expression, and reactive
oxygen species produced by activated polymorphonuclear cells can induce DNA
changes in neighboring cells.4 Also, nitric oxide in cigarette smoke can be in
concentrations greater than 500 parts per million, thus representing one of
the most significant exogenous sources of nitric oxide to humans. 5 Therefore,
the formation of toxic nitrosamine and nitrosamide reactions promoted by this
free radical may augment the con tents of these carcinogenic compounds in
A Cardiovascular Catastrophe
Oxygen free radicals also play a role in the development of cardiovascular
abnormalities, and there is considerable evidence to show that oxidant injury
may contribute to the production of ischemic myocardial injury. 4 Oxygen free
radicals may cause myocardial injury by ischemia-reperfusion through various
processes that include:
- Activation of the complement
- Generation of chemotactic
- Migration of polymorphonuclear cells
- Membrane lipid alterations4
Ischemia-induced disease has
been reported to be the single greatest cause of death in the United States. 4
When vital organs such as the heart and brain are exposed to reduced blood
flow and cannot continue to function, death becomes inevitable. It is
important to understand that ischemia, or reduced blood flow, per se, is not
the entire problem. Reperfusion or reoxygenation following resumption of blood
flow and oxygen supply is a major cause of injury to the organs.
radical-mediated alteration of low-density lipoproteins (LDL), the major
carrier of circulating cholesterol, appears to be a critical episode in the
sequence of events le ading to coronary heart disease. LDL are readily
oxidized by oxygen free radicals, and the oxidized LDL are rapidly ingested by
macrophages in the artery wall to form cholesterol ester-filled foam cells
which represent an early manifestation of atherosclerotic lesions.4
Given the poor success rates of
smoking cessation programs, antioxidant supplements can minimize
smoking-related damage. Direct oral supplementation of antioxidant enzymes
like SOD and glutathione peroxidase is impractical, however, because enzymes
are proteins and are readily degraded by digestive enzymes.
The preceding portion of this
review article provides a valid scientific basis for antioxidant
supplementation. Fur her more, there is considerable evidence in support of
the efficacy of appropriate antioxidant regimens in smokers. 8,9
Mounting A Defense with
It is clear that the role of oxygen free radicals in the pathogenesis of
smoking-related diseases is well established. Cigarette smokers have an
enormous oxygen free radical load whose demand on tissue antioxidant systems
leads to a severe antioxidant deficiency state. This deficiency may be
exacerbated by the decrease in both supplemental and dietary intake of
antioxidants by smokers, thereby predisposing them to the development of
life-threatening diseases. Research in this area provides compelling evidence
for a beneficial role of specific antioxidant supplements in the prevention of
smoking-related oxidative damage.
(vitamin E) supplements in the dose range of 400 to 800 iu
per day have generally been found to be beneficial (although doses up to 3,200
iu per day have been reported to be safe). Also, ascorbic acid (vitamin
C) has been shown to be beneficial in the dose range of 500 to 2000
mg/day. Because of the biochemical interactions of antioxidants, it seems
advisable to use combined antioxidant supplements such as 500-1500 mg/day of
vitamin C (ascorbic acid) along with 400-800 mg/day of vitamin E (alpha-tocopherol).
10 It is particularly important to emphasize that high doses of antioxidants
work better when taken in combination, rather than as individual supplements.
It is worthy of note that fish
oil has a high content of fat-soluble antioxidants. In fact, fish oil
supplements have been shown to be efficacious in the prevention of
smoking-related diseases. For example, in one study of over 8,000 men between
45 and 68 years of age, it was found that smokers who consumed fish more than
twice/week sustained less smoking-related lung damage than did those who
consumed fish less often.11 Another study of nearly 9,000 current or former
smokers concluded that consumption of omega-3 fatty acid, found in fish, had a
protective role against chronic obstructive pulmonary disease and the
deterioration of lung function in cigarette smokers. 12
Glutathione is a major cellular
antioxidant which is critically important for the integrity of the lung as
well as its normal function. Consequently, the depletion of this antioxidant
which is a consequence of cigarette smoking 6 has been implicated in the
pathogenesis of smoking-related diseases including lung cancer. One supplement
which boosts the body stores of glutathione is N-Acetyl cysteine
(NAC). NAC has been shown to be effective as a cancer chemopreventive agent at
a daily dose of 600 mg.14 Another potential cancer-protective supplement
appears to be green tea extract, a powerful antioxidant, which was found to
stabilize sister-chromatid exchange in peripheral lymphocytes in smokers to a
level comparable to non-smokers.13
Some other naturally-occurring
compounds and their doses which have been found useful for antioxidant defense
against cardiovascular diseases and which may protect against smoking-induced
disease include lipoic acid (100 mg/day),20 taurine
(1.5 gm per day),15 coenzyme Q 10 (90 mg/day or higher)16, selenium
(200 mcg per day), garlic, 17 ginkgo biloba,18
and red wine polyphenols.19
Dr. Emmanuel C. Opara is a
research professor in the Departments of Surgery and Cell Biology and is a
member of the Sara W. Stedman Center for Nutritional Studies at Duke
University Medical Center in Durham, North Carolina.
Read Part II of this
source of nutrients and supplements.
did we qualify them ?
|1. U.S Department of
Health and Human Services. The Health Consequences of Smoking: 25
Years of Progress. A Report of the Surgeon General. U.S Department of
Health and Human Services, Public Health Service, Centers for Disease
Control, Center for Chronic Disease Prevention and Health Promotion,
Office of Smoking and Health. Washington DC: DHHS publication (CDC)
|2. Hammond, E.C. Smoking
in relation to the deaths of 1 million men and women. Moraph. 1966,
Jan, 19: 127-204.
|3. Phillips, A.N.,
Wannamethee, S.G., Walker, M., Thomson, A., Smith, G.D. Life
expectancy in men who have never smoked and those who have smoked
continuously: 15 year follow up of a large cohort of middle aged
British men. Br Med. 1996, 313: 907-90.
|4. Cross, C.E.,
Halliwell, B., Borish, E.T., Pryor, W.A. et al. Oxygen Radicals and
Human Disease. Ann Int Med. 1987, 107: 526-545.
|5. Rahman, I., MacNee,
W. Role of antioxidants in smoking- induced lung disease. Free Rad
Biol Med. 1996, 21: 669-681.
|6. Lane, J.D., Opara,
E.C., Rose, J.E., Behm, F. Quitting smoking raises whole blood
glutathione. Physiol Behav. 1996, 60: 1379-1381.
|7. Zondervan, K.T., Ocke,
M.C., Smit, H.A., Seidell, J.C. Do dietary and supplementary intakes
of antioxidants differ with smoking status. Int J Epidemiol. 1996, 25:
|8. Reilly, M., Delanty,
N., Lawson, J.A., Fitzgerald, G.A. Modulation of oxidant stress in
vivo in chronic cigarette smokers. Circulation. 1996, 94: 19-25.
|9. Cross, C.E., Traber,
M.G. Cigarette smoking and antioxidant vitamins: the smoke screen
continues to clear but has a way to go. Am J Clin Nutr. 1997, 65:
|10. Brown, K.M., Morrice,
P.C., Duthie. 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, 65:
|11. Sharp, D.S. Fish
consumption may limit the damage of smoking on the lung. American
Journal of Respiratory Critical Care Medicine, 1994, 150: 983-987.
|12. Shahar, E. Dietary
omega-3 polyunsaturated fatty acids in smoking-related chronic
obstructive pulmonary disease. The New England Journal of Medicine,
1994, 331 (4): 228-233.
|13. Shim, J.S.
Chemopreventive effect of green tea (Camellia sinesis) among cigarette
smokers. Cancer Epidemiology, Biomarkers and Prevention. 1995, 4:
|14. Zandwijk, N.
N-acetyl cysteine (NAC) and glutathione (GSH): Antioxidant and
chemopreventive properties, with special reference to lung cancer.
Journal of Cellular Biochemistry, 1995; Suppl. 22: 24-32.
|15. Franconi, F. Plama
and platelet taurine are reduced in subjects with insulin-dependent
diabetes mellitus: Effects of taurine supplementation. American
Journal of Clinical Nutrition, 1995, 61: 1115-1119.
|16. Weber, C.
Antioxidative effect of dietary Coenzyme Q10 in human plasma.
International Journal of Vitamin Nutrition Research, 1994, 624:
|17. Imai, J. Antioxidant
and radical scavenging effects of aged garlic extract and its
constituents. Planta Med, 1994, 60: 417-420.
|18. Marcocci, L.
Antioxidant action of ginkgo biloba extract Egb 761. Methods in
Enzymology, 1994, 234: 462-475.
|19. Fuhrman, B.
Consumption of red wine with meals reduces the susceptibility of human
plasma and low-density lipoprotein to lipid peroxidation. American
Journal of Clinical Nutrition, 1995, 61: 549-554.
|20. Kagan, V.E.
Dihydrolipoic acid, a universal antioxidant both in the membrane and
in the aqueous phase. Biochemical. 1992, 44: 1637-1649.