Antioxidants - The Latest Weapon in the War on Smoking and Free Radicals Part I

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: [1] cardiovascular disease; [2] chronic emphysema; and [3] 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: [1] difficulties in measuring certain indices of oxidative damage; [2] enrollment of inappropriate and ineligible subjects; [3] insufficient duration of the study; and [4] 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 superoxide dismutase).

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 Partner
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 cigarettes.

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 system
  • Generation of chemotactic peptides
  • 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.

Furthermore, free 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 Antioxidant Combinations
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.

Specifically, alpha-tocopherol (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 article

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References:

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) 89-8411; 1989.
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: 709.
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: 562-563.
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: 496-502.
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: 387-391.
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: 311-315.
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.
© Vitamin Research Products Inc. 2001

 

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