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The Role of Antioxidants in Exercise and Disease Prevention

Alexandra K. Adams, MD, PhD
Thomas M. Best, MD, PhD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO. 5 - MAY 2002

In Brief: Excess free-radical formation has been hypothesized to contribute to cancer, atherosclerosis, aging, and exercise-associated muscle damage. Antioxidant supplements such as vitamin C, vitamin E, and beta-carotene have been touted as beneficial for enhancing exercise performance and for preventing certain diseases. Before physicians routinely recommend supplements to prevent exercise-associated damage, more study will be required. Recommendations for the prevention of cardiovascular disease and cancer are more complex. Because study results have been contradictory, individual supplement recommendations must be offered with caution. Physicians must be cognizant of which supplements patients are taking and be prepared to discuss risks and benefits. The most beneficial prescription is probably a daily diet containing five to seven servings of fruits and vegetables.

Many claims have been made for the benefits of antioxidants in enhancing exercise performance, preventing illnesses such as heart disease and cancer, and even mitigating the effects of aging. Patients often take various supplements, sometimes based on confusing and conflicting reports. Physicians need to be aware of what supplements patients are taking and be prepared to discuss the risks and benefits of these treatment strategies with patients interested in health promotion through exercise and supplement use.

Pathophysiology of Oxidation

Tissue damage and disease processes. The adverse effects of excess free-radical formation have been hypothesized to lead to cancer, atherosclerosis, aging, and even exercise-associated oxidative damage. Free radicals are generated from normal oxidative processes in the body and can damage DNA and RNA and inactivate enzymes and other proteins. Free radicals also facilitate oxidation of fatty acids in cell membranes, producing destructive chain reactions that cause cell damage and cell death. Excess levels of free radicals in plasma and the arterial wall increase low-density lipoprotein (LDL) oxidation,1 leading to cytotoxicity and enhanced plaque formation.

Protective mechanisms. Aerobic organisms would not survive without mechanisms that counteract the detrimental effects of free radicals. The system includes the fat-soluble antioxidants such as vitamin E and beta-carotene (a vitamin A precursor); the major water-soluble antioxidant, vitamin C; antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and selenium-dependent glutathione peroxidase (GPX); and low-molecular-weight compounds such as glutathione. These components preserve homeostasis during most normal cell function and mild oxidative stress. When free-radical production is excessive, however, or when the antioxidant system is overwhelmed, such as during nutritional deficiencies or exhaustive exercise, such imbalances may favor an "oxidative stress" environment (figure 1).

Antioxidant Basics

Vitamin E. This fat-soluble vitamin is incorporated into lipoproteins and cell membranes and prevents oxidation of polyunsaturated fatty-acids in cell membranes. Vitamin E also inhibits platelet activation and monocyte adhesion1 and is the predominant antioxidant in LDL.2,3 The most active and most common commercial form of vitamin E is alpha-tocopherol.

Vitamin E is found in vegetable and seed oils, wheat germ, and (in lower quantities) meats, fish, fruits, and vegetables. The recommended dietary allowance (RDA) for both men and women is 15 mg/day of alpha-tocopherol.4 Obtaining sufficient vitamin E from the average diet is difficult; supplements can make up the difference. Multivitamins usually contain 30 to 50 IU (30 to 50 mg) of vitamin E.

Vitamin C. This water-soluble vitamin is the predominant plasma antioxidant that scavenges plasma free radicals and prevents their entry into LDL.3 Vitamin C regenerates oxidized vitamin E and increases cholesterol excretion. Some studies5-7 have demonstrated that vitamin C can improve arterial vasoreactivity. A single dose (2 g) of vitamin C improved vasoreactivity in patients who were chronic smokers,5 had hypercholesterolemia,6 or had cardiovascular disease (CVD).7

Sources of vitamin C include citrus fruits, strawberries, cantaloupe, tomatoes, cabbage, and green leafy vegetables. Cooking can destroy the vitamin, so the best sources are obtained from raw foods or supplements. The RDA is 90 mg/day for men, 75 mg/day for women, with an additional 35 mg/day for smokers.4

Beta-carotene. Carotenoids form a class of more than 600 compounds normally found in fruits and vegetables.8 Beta-carotene is a vitamin A precursor carried in plasma and LDL.9 Both beta-carotene and vitamin A have antioxidant and immunoenhancement properties. Because of previous animal, dietary, and epidemiologic studies, beta-carotene has been the focus of several large chemoprevention clinical trials.8

Carotenoids are found in fruits, yellow-orange vegetables such as carrots, squash, and sweet potatoes, and deep green vegetables such as spinach and broccoli. No RDA has been established.

Selenium. This essential trace element functions through selenoproteins, several of which have antioxidant functions, and includes enzymes such as glutathione peroxidase, a potent free-radical scavenger.

Sources include meat and seafood, and low levels are present in fruits and vegetables. The major forms of dietary selenium are highly bioavailable.4 Selenium levels in plant foods and grains vary with soil content. Certain areas of the world have soils with a low selenium content, and populations in these areas manifest lower plasma levels of the element.10 The RDA is 55 mg/day for both men and women.4

Free-Radical Generation in Exercise

In the past two decades, accumulating evidence has shown that unaccustomed and strenuous exercise induces an imbalance between free-radical production and the body's antioxidant defense systems. However, it remains unknown whether increased free-radical production is an unwanted consequence of exercise that promotes further inflammation and tissue damage, or if the body regulates oxidant production to control inflammation and repair.11 Resistance exercise may also increase free-radical production, although the evidence is less convincing.12

Three main potential pathways exist for increased free-radical generation with exercise. Oxygen consumption increases up to 20 times greater than the resting level, resulting in an elevated flow of oxygen through the mitochondrial electron-transport chain. Superoxide radical may leak from this pathway and be reduced to hydrogen peroxide by mitochondrial SOD. Cytosolic SOD is also available to perform this function. Hydrogen peroxide can then be reduced by CAT and GPX.

Although both enzymes share the primary function of reducing hydrogen peroxide, their substrate specificity and cellular location are different. CAT is found primarily in peroxisomes, organelles involved in nonmitochondrial oxidation of fatty acids and amino acids, and they generate hydrogen peroxide. GPX, a mitochondrial enzyme, uses glutathione, a low-molecular-weight thiol, to reduce hydrogen to water and organic peroxides to alcohol. Thus, GPX plays an important role in inhibiting lipid peroxidation and preventing damage to DNA and RNA.

A second pathway is in organs, such as the liver, kidneys, and gut, that experience a hypoxic environment with blood-flow redistribution to the working muscles. This relative ischemia-reperfusion of the splanchnic region may trigger activation of xanthine oxidase, a membrane-bound enzyme that produces both superoxide and hydrogen peroxide. Finally, neutrophil and macrophage involvement in inflammation and repair may be a potent source of free-radical production.

Antioxidant Supplementation and Exercise

Given that high-intensity exercise can increase free-radical production, antioxidant supplements may offer benefit during prolonged aerobic activity.12-15

Vitamin E. This vitamin is essential for normal cell function during exercise. Animals depleted of vitamin E demonstrate significant free-radical generation, lipid peroxidative damage, and a 40% decline in endurance capacity.16 Endurance performance also decreases in rats fed a vitamin E-deficient diet,16,17 thus implicating vitamin E in protecting against exercise-induced free-radical generation and injury.

At least two animal studies18,19 have shown promising results: Vitamin E supplementation at supraphysiologic doses for a minimum of 5 weeks can decrease lipid peroxide levels with exhaustive exercise. To be effective at all, vitamin E must be given for at least 2 weeks before exercise, and five times the RDA for vitamin E may be necessary to prevent free-radical damage.20 These findings should be balanced against human studies that have not demonstrated convincing evidence for exercise-induced oxidative stress damage. Duthie et al21 found no difference in levels of plasma alpha- or beta-tocopherol in runners following a half marathon. Lovlin et al14 actually noted a decrease in plasma malondialdehyde levels, a marker for lipid peroxidation, in cyclists exercising at 40% to 70% VO2max.

Vitamin C. Less convincing is the evidence for vitamin C supplement-mediated protection against exercise-induced oxidative damage. One study22 demonstrated that ascorbate is an effective antioxidant in human plasma. Improved musculoskeletal healing has been reported in patients who took 500 to 1,000 mg of ascorbic acid two to four times a day.23 A recent review24 notes that although large doses of vitamin C are claimed to reduce fatigue and muscle damage, none of the studies examined specific oxidative stress markers, and therefore such large-dose strategies must be interpreted with some caution. Furthermore, high doses of vitamin C in the presence of iron can have pro-oxidant effects.25 High-dose vitamin C (>2 g/day) can cause diarrhea, bloating, and false-negative occult blood tests but does not increase levels of urinary oxalic acid.26

Coenzyme Q10. Supplementation with coenzyme Q10 (CoQ10) has also been suggested to be beneficial for endurance athletes. Rats given CoQ10 had reduced creatinine kinase and lactate dehydrogenase enzyme activities after downhill running,27 but similar effects were not seen in human subjects after cycling to exhaustion.28 Finally, one study29 in unsupplemented rats showed that SOD attenuated lipid peroxidative damage from acute bouts of exercise.

Enzymes, exercise, and training. No evidence shows that long-term physical activity leads to any permanent detrimental effects on skeletal muscle (table 1). This observation suggests that regular exercise might enhance the enzymatic defense systems against free-radical activity. For example, mitochondrial enzymes GPX and manganese-dependent SOD play a major role in free-radical production and are consistently upregulated with chronic exercise training (see table 1).30,31 In addition, some animal studies32,33 demonstrate that acute exercise stimulates antioxidant enzyme activity in skeletal muscle and to a lesser extent in cardiac tissue and the liver. The degree of change depends on both the training status and the muscle fiber type studied.

TABLE 1. Enzyme Responses to Acute and Chronic Exercise

Acute Exercise
EnzymeLocationResponse
Superoxide dismutase
Catalase
Glutathione peroxidase
   (selenium dependent)
Glutathione reductase		Heart, liver, lungs, skeletal muscle
Heart, liver, skeletal muscle
Heart, platelets

Muscle		Studies show no consensus
Most studies reveal increased activity
Most studies reveal increased activity

Studies show no consensus
Chronic Exercise
EnzymeResponse
Superoxide dismutase
   (manganese dependent)
Catalase
Glutathione peroxidase
   (selenium dependent)		Increased activity

No significant change
Increased activity

Antioxidants and eccentric muscle damage. Investigators have speculated that free radicals may play a role in muscle damage associated with eccentric muscle activity.11,34 Recent studies35,36 in animal models have provided some evidence to support the assertion that vitamin E deficiency is associated with certain types of muscular dystrophy.37 Because of the possible link between eccentric muscle activity and oxidative stress damage, some studies36,38,39 have examined the effects of antioxidant vitamin supplementation or depletion. The results, however, are conflicting and make it difficult to make an unequivocal antioxidant recommendation to prevent such damage.

Antioxidants and Disease Prevention

Before the interest in antioxidants and intensive exercise arose, many epidemiologic studies showed that diets high in antioxidants were associated with a decreased risk of chronic disease, especially CVD and cancer.40-49 In addition, a number of important clinical trials have been conducted (table 2).

TABLE 2. The Effect of Intervention Trials of Antioxidants on Cardiovascular Disease and Cancer

StudyNo. of Subjects  Duration  Daily Antioxidant Dosage  Results
ATBC40-42:
primary prevention
in smokers		29,133
(pooled)		6 yr50 mg vitamin E and/or
20 mg beta-carotene		Nonfatal MI 32% lower for vitamin E
users; no effect of vitamin E on lung
cancer; reduction in prostate cancer

Beta-carotene group had 11% higher
CVD and 18% more lung cancer
deaths; beta-carotene-only and
combination-therapy groups had
significantly higher rates of fatal CHD
CARET43:
primary prevention
in smokers and those
with asbestos exposure		18,3144 yr30 mg beta-carotene and
25,000 IU vitamin A		28% increase in lung cancer
incidence; 26% (nonsignificant)
increase in CVD for treatment group
Physicians Health Study44:
primary prevention in
nonsmokers and smokers		22,07112 yr50 mg beta-carotene
(alternate days)		No effects on CVD (nonfatal MI,
stroke) or cancer even among
smokers
Linxian Cancer Prevention
Study45: primary
prevention in poorly
nourished Chinese		29,5845 yr15 mg beta-carotene,
30 mg vitamin E, and
50 mg selenium or
125 mg vitamin C and
30 mg molybdenum		9% lower total mortality; 13%
reduction in cancer mortality; 21%
decrease in stomach cancer
mortality; no significant
reduction in total or CV mortality
CHAOS46: secondary
prevention in patients
with atherosclerosis		2,0021 yr or
until MI		400 or 800 IU
(268 or 537 mg)
vitamin E		Nonfatal MI reduced 77%; 47%
overall reduction in fatal and
nonfatal CVD events; no effect
on overall mortality
GISSI47: secondary
prevention in patients
with recent MI		11,3243.5 yr300 mg vitamin E
or 1 g fish oil		Vitamin E group had no benefit;
fish oil group had 15% decreased
risk of death, nonfatal MI, and stroke
HOPE48: secondary
prevention in patients at
high risk for CV events		9,5414.5 yr400 IU (268 mg)
vitamin E and ACE
inhibitor or placebo		No benefit from vitamin E for
incidence of MI, stroke, or CV
death; ongoing to determine effects
on cancer
Women's Health Study49:
primary prevention in
healthy women		39,8764.1 yr50 mg beta-carotene
(alternate days)		No effect on cancer incidence, CVD,
or total deaths
MI = myocardial infarction; CVD = cardiovascular disease; CHD = coronary heart disease; CV = cardiovascular;
ACE = angiotensin-converting enzyme

European and US studies revealed that the risks of CVD and cancer were inversely correlated with fruit and vegetable consumption.50-54 Plasma levels of vitamins E, C, beta-carotene, and selenium are inversely correlated with cross-cultural CVD mortality.50,51,55,56 However, epidemiologic studies cannot prove causality for a number of reasons, including selection bias. In addition, other food components such as flavonoids may be responsible for the beneficial health effects seen.

Cardiovascular disease. Many prospective cohort studies have shown a relationship between intakes of vitamins E, beta-carotene, and vitamin C and CVD. The Health Professionals Study57 (41,910 male physicians) noted a 40% risk reduction for coronary heart disease (CHD) among individuals in the upper quintile of vitamin E intake (about 400 IU/day) compared with men in the lowest quintile (6 IU/day). After adjustment for other additional factors and other vitamins, physicians in the highest quintile of beta-carotene intake (19,034 IU/day) had a 29% CHD risk reduction compared with those in the lowest quintile (3,969 IU/day), with the benefit only for smokers. The study noted no vitamin C benefits.

In a study58 of supplement use in 11,178 elderly people, vitamin E consumption reduced the risk of all-cause mortality by 34% and CHD by 47%. Vitamins E and C together caused a reduction in total mortality by 42% and coronary mortality by 53%. Vitamin E supplements averaged greater than 100 IU/day. The Scottish Heart Health study59 (10,349 participants) found lower CHD risk among patients in the highest quintile of dietary vitamin E intake, but not significantly so for those with CHD.

In a study60 of more than 121,000 female nurses between the ages of 30 and 55, women in the highest quintile of vitamin E intake (>100 IU/day) had a 31% lower CHD risk compared with women in the lowest quintile. No effects were found with multivitamins, vitamin C, or beta-carotene. The National Health and Nutrition Examination Survey-1 cohort study61 revealed an inverse relationship between those with the highest vitamin C intake (diet and supplements) and CHD risk among 11,349 US men and women between the ages of 25 and 74 in a 10-year study. Selenium levels were inversely correlated to CHD mortality in one study,62 but others provide conflicting data.3 Ubiquinone, a reduced form of CoQ10, has been reported to decrease LDL oxidation and improve ejection fraction.63-65 However, two small randomized controlled trials66,67 evaluated the effects of CoQ10 on patients with class 3 and 4 heart failure and found no significant benefit.

Cancer. Recent reviews of the existing epidemiologic studies have found a strong effect of fruit and vegetable consumption to lower all types of cancer risks.52,54 Persons in the lowest quartiles of fruit and vegetable consumption have 1.5 to 2 times the risk of cancer compared with people who have higher intakes.52

For vitamin A, more than 100 case-control and cohort studies have examined the relationship between carotenoid-containing fruits and vegetables and cancer risk.68 The relationship between carotenoid intake and lowered risk of lung and stomach cancers has been the most consistent, with risk reductions of 10% to 90% seen in people with the highest dietary intakes.68 For lung cancer, risk reduction was primarily seen after controlling for smoking.

Many studies have also shown an inverse relationship between lung cancer risk and vitamin C intake. Dietary vitamin C has also been shown to lower the risk of breast cancer (8 studies), colon cancer (10 studies), stomach cancer (9 studies), and oral and esophageal cancers (5 studies).52

Studies of the relationship between selenium intake or plasma selenium levels and cancer have been less conclusive. Ten prospective studies have shown an inverse relationship of plasma selenium levels and cancer risk, but in only 6 was the relationship statistically significant.52 Observational studies of vitamin E intake showed lower risks of stomach cancer (3 studies), lung cancer (2 studies), breast cancer (5 studies), and colon cancer (2 studies).52

Mortality and Antioxidant Supplementation

Although many epidemiologic studies have implicated consumption of fruits, vegetables, and antioxidant supplements in preventing disease, these studies cannot prove causality. To date, there have been five large, randomized, controlled trials looking at the effects of vitamin supplementation on mortality due to CVD and cancer (see table 2).58-68

CVD and cancer. Many studies present conflicting results about vitamin E for primary and secondary CVD prevention. The Cambridge Heart Antioxidant Study (CHAOS),46 a double-blind, placebo-controlled trial, was designed to test whether high-dose vitamin E (400 IU or 800 IU) would reduce risk in CVD patients. Vitamin E significantly reduced overall fatal and nonfatal CVD events by 47%, and nonfatal MI by 77%, but it did not produce a significant effect on overall mortality (relative risk, 1.18). These results strongly support evidence that vitamin E at doses greater than 100 IU/day reduces CVD events.

Two more recent trials47,48 do not support these results. In patients who had a recent myocardial infarction (MI), fish oil or vitamin E (300 IU/day) was given to assess secondary outcomes of MI, stroke, and cardiovascular (CV) death. Vitamin E supplementation offered no benefit.47 The Heart Outcomes Prevention Evaluation (HOPE) trial48 evaluated the effect of 4.5 years of supplemental vitamin E (400 IU/day) against a placebo and either the angiotensin-converting enzyme inhibitor ramipril or matching placebo in patients at high risk for CV events. Primary outcomes of MI, stroke, and death from CV causes showed no significant benefit of vitamin E compared with placebo. Both trials are ongoing to assess longer-term effects on cancer.

In the Women's Health Study,49 an ongoing trial of antioxidant supplements and prevention of cancer and CVD, 50 mg of beta-carotene given on alternate days had no effect on cancer, CVD, or overall mortality in healthy women age 45 or older. Results of supplementation with vitamin E (600 IU on alternate days) are pending.

A recent small 3-year study69 examined the effects of simvastatin with or without niacin and a combination of antioxidants (Vitamins E, C, selenium, and beta-carotene) or placebos on CVD protection in 160 patients with CVD. No clinical or angiographically measurable benefit from antioxidants was found. Other primary and secondary prevention trials have considered the combined outcomes of CVD, cancer, and mortality (see table 2). Many other supplementation trials are ongoing, and the results should be available soon.

Cancer studies. Many clinical trials of antioxidants for cancer prevention have been done, and most have focused on vitamin A and its derivatives. Supplemental beta-carotene has failed to reduce cancer risk in randomized trials and showed increased risk of lung cancer in the Alpha Tocopherol Beta Carotene (ATBC) trial42 (see table 2). However, a lower incidence of prostate cancer was found with vitamin E supplementation. Three double-blind, randomized, controlled trials assessed the effect of beta-carotene and/or vitamin E and C supplements on the recurrence of colon adenomas in patients who had resected adenomas; supplementation showed no significant effect.8 In a randomized controlled trial70 among patients receiving bacillus Calmette-Guerin immunotherapy, bladder tumor recurrence decreased from 80% to 40% in patients who took megadoses of vitamins A, B6, C, E, and zinc.

Selenium supplementation in patients with a history of basal cell or squamous cell skin cancer was examined in a large randomized, controlled trial; mean follow-up was 6.4 years.71,72 Recurrence rate of skin cancer did not change, but total cancer incidence and mortality, as well as incidences of lung, colorectal, and prostate cancers were significantly reduced in patients who received selenium. Several ongoing research trials may shed light on the effectiveness of combinations of antioxidant vitamins on cancer prevention.52,53

Lingering Questions and Preliminary Answers

Antioxidants are vital dietary requirements that play a major role in protecting us from our environment, and they probably play a role in preventing CVD and cancer. Available evidence points to the benefits of food-derived antioxidants, but more evidence is needed before antioxidant or enzyme supplementation can be routinely recommended for people engaging in prolonged exercise. Because of conflicting study results of antioxidants in preventing CVD and cancer, more conclusive studies will be required. In general, routine antioxidant supplementation for preventing exercise-induced oxidative stress damage is still questionable, because the inflammation and associated oxidative stress damage may be important in healing.

Future studies should focus on assessing the value of antioxidant supplementation for attenuating postexercise tissue damage. Recommendations of individual nutrients to patients must be done with caution, but a diet that contains five to seven servings of fruits and vegetable daily is probably the most beneficial prescription. A daily multiple vitamin may also be needed to meet nutritional needs since the benefit outweighs any possible harm.73,74 Combinations of supplements may prove to be more beneficial than individual nutrients, especially in preventing cancer.

References

  1. Diaz MN, Frei B, Vita JA, et al: Antioxidants and atherosclerotic heart disease. N Engl J Med 1997;337(6):408-416
  2. Odeh RM, Cornish LA: Natural antioxidants for the prevention of atherosclerosis. Pharmacotherapy 1995;15(5):648-659
  3. Kwiterovich PO: The effect of dietary fat, antioxidants, and pro-oxidants on blood lipids, lipoproteins, and atherosclerosis. J Am Diet Assoc 1997;97(7 suppl):S31-S41
  4. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids: a Report of the Panel on Dietary Antioxidants and Related Compounds. Washington DC, National Academy Press, 2000
  5. Heitzer T, Just H, Munzel T: Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996;94(1):6-9
  6. Ting HH, Timimi FK, Haley EA, et al: Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 1997;95(12):2617-2622
  7. Levine GN, Frei B, Koulouris SN, et al: Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996;93(6):1107-1113
  8. Singh D, Lippman S: Cancer chemoprevention, part 1: retinoids and carotenoids and other classic antioxidants. Oncology (Huntingt) 1998;12(11):1643-1660
  9. Jialal I, Grundy SM: Influence of antioxidant vitamins on LDL oxidation. Ann N Y Acad Sci 1992;669:237-248
  10. Linder MC (ed): Nutritional Biochemistry and Metabolism: With Clinical Applications, New York City, Elsevier, 1985, pp 176-178
  11. Tidball JG: Inflammatory cell response to acute muscle injury. Med Sci Sports Exerc 1995;27(7):1022-1032
  12. McBride JM, Kraemer WJ, Triplett-McBride T, et al: The effect of resistance exercise on free radical production. Med Sci Sports Exerc 1998;30(1):67-72
  13. Kanter MM, Nolte LA, Holloszy JO: Effects of an antioxidant vitamin mixture on lipid peroxidation at rest and postexercise. J Appl Physiol 1993;74(2):965-969
  14. Lovlin R, Cottle W, Pyke I, et al: Are indices of free radical damage related to exercise intensity? Eur J Appl Physiol Occup Physiol 1987;56(3):313-316
  15. Pyke S, Lew H, Quintanilha A: Severe depletion in liver glutathione during physical exercise. Biochem Biophys Res Commun 1986;139(3):926-931
  16. Davies KJ, Quintanilha AT, Brooks GA, et al: Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun 1982;107(4):1198-1205
  17. Gohil K, Packer L, de Lumen B, et al: Vitamin E deficiency and vitamin C supplements: exercise and mitochondrial oxidation. J Appl Physiol 1986;60(6):1986-1991
  18. Goldfarb AH, McIntosh MK, Boyer BT, et al: Vitamin E effects on indexes of lipid peroxidation in muscle from DHEA-treated and exercised rats. J Appl Physiol 1994;76(4):1630-1635
  19. Sumida S, Tanaka K, Kitao H, et al: Exercise-induced lipid peroxidation and leakage of enzymes before and after vitamin E supplementation. Int J Biochem 1989;21(8):835-838
  20. Diplock AT: Dietary supplementation with antioxidants: is there a case for exceeding the recommended dietary allowances? Free Radic Biol Med 1987;3(3):199-201
  21. Duthie GG, Robertson JD, Maughan RJ, et al: Blood antioxidant status and erythrocyte lipid peroxidation following distance running. Arch Biochem Biophys 1990;282(1):78-83
  22. Frei B, England L, Ames BN: Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 1989;86(16):6377-6381
  23. Bucci L: Nutrition Applied to Injury Rehabilitation and Sports Medicine. Boca Raton, FL, CRC Press, 1995
  24. Kanter M: Free radicals and exercise: effects of nutritional antioxidant supplementation. Exerc Sport Sci Rev 1995;23:375-397
  25. Yu BP: Cellular defenses against damage from reactive oxygen species. Physiol Rev 1994;74(1):139-162
  26. Meyers DG, Maloley PA, Weeks D: Safety of antioxidant vitamins. Arch Intern Med 1996;156(9):925-935
  27. Shimomura Y, Suzuki M, Sugiyama S, et al: Protective effect of coenzyme Q10 on exercise-induced muscular injury. Biochem Biophys Res Commun 1991;176(1):349-355
  28. Zuliani U, Bonetti A, Campana M, et al: The influence of ubiquinone (Co Q10) on the metabolic response to work. J Sports Med Phys Fitness 1989;29(1):57-62
  29. Radak Z, Asano K, Inoue M, et al: Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during exhaustive exercise. J Appl Physiol 1995;79(1):129-135
  30. Sen CK, Marin E, Kretzschmar M, et al: Skeletal muscle and liver glutathione homeostasis in response to training, exercise, and immobilization. J Appl Physiol 1992;73(4):1265-1272
  31. Leeuwenburgh C, Fiebig R, Chandwaney R, et al: Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems. Am J Physiol 1994;267(2 pt 2):R439-R445
  32. Ji LL: Antioxidant enzyme response to exercise and aging. Med Sci Sports Exerc 1993;25(2):225-231
  33. Ji LL, Fu R: Responses of glutathione systems and antioxidant enzymes to exhaustive exercise and hydroperoxide. J Appl Physiol 1992;72(2):549-554
  34. Armstrong RB: Mechanisms of exercise-induced delayed onset muscular soreness: a brief review. Med Sci Sports Exerc 1984;16(6):529-538
  35. Best TM, Fiebig R, Corr DT, et al: Free radical activity, antioxidant enzyme, and glutathione changes with muscle stretch injury in rabbits. J Appl Physiol 1999;87(1):74-82
  36. Zerba E, Komorowski TE, Faulkner JA: Free radical injury to skeletal muscles of young, adult, and old mice. Am J Physiol 1990;258(3 pt 1):C429-C435
  37. Bicknell F: Vitamin E in the treatment of muscular dystrophies and nervous diseases. Lancet 1940;1:10-13
  38. Warren JA, Jenkins RR, Packer L, et al: Elevated muscle vitamin E does not attenuate eccentric exercise-induced muscle injury. J Appl Physiol 1992:72(6):2168-2175
  39. Saxton JM, Donnelly AE, Roper HP: Indices of free-radical-mediated damage following maximum voluntary eccentric and concentric muscular work. Eur J Appl Physiol Occup Physiol 1994;68(3):189-193
  40. Virtamo J, Rapola JM, Ripatti S, et al: Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med 1998;158(6):668-675
  41. Rapola JM, Virtamo J, Ripatti S, et al: Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 1997;349(9067):1715-1720
  42. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330(15):1029-1035
  43. Omenn GS, Goodman GE, Thornquist MD, et al: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334(18):1150-1155
  44. Hennekens CH, Buring JE, Manson JE, et al: Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334(18):1145-1149
  45. Blot WJ, Li JY, 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(18):1483-1492
  46. Stephens NG, Parsons A, Schofield PM, et al: Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347(9004):781-786
  47. GISSI-Prevenzione Investigators: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354(9177):447-455
  48. Yusuf S, Dagenais G, Pogue J, et al: Vitamin E supplementation and cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3):154-160
  49. Lee IM, Cook NR, Manson JE, et al: Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst 1999;91(24):2102-2106
  50. Riemersma RA, Wood DA, Macintyre CC, et al: Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet 1991;337(8732):1-5
  51. Gey KF, Puska P, Jordan P, et al: Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 1991;53(1 suppl):326S-334S
  52. Hercberg S, Galan P, Preziosi P, et al: Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers: SUpplementation en VItamines et Mineraux AntioXydants Study. Int J Vitam Nutr Res 1998;68(1)3-20
  53. Buring JE, Hennekens CH: The Women's Health Study: rationale and background. J Myocard Ischemia 1992;4(5):30-40
  54. Block G: Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr 1991;53(1 suppl):270S-282S
  55. Verlangieri AJ, Kapeghian JC, el-Dean S, et al: Fruit and vegetable consumption and cardiovascular mortality. Med Hypotheses 1985;16(1):7-15
  56. Luoma PV, Nayha S, Sikkila K, et al: High serum alpha-tocopherol, albumin, selenium and cholesterol, and low mortality from coronary heart disease in northern Finland. J Intern Med 1995;237(1):49-54
  57. Knekt P, Reunanen A, Jarvinen R, et al: Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139(12):1180-1189
  58. Losonczy KG, Harris TB, Havlik RJ: Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64(2):190-196
  59. Bolton-Smith C, Woodward M, Tunstall-Pedoe H: The Scottish Heart Health Study: dietary intake by food frequency questionnaire and odds ratios for coronary heart disease risk. 2: the antioxidant vitamins and fibre. Eur J Clin Nutr 1992;46(2):85-93
  60. Stampfer MJ, Hennekens CH, Manson JE, et al: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328(20):1444-1449
  61. Enstrom JE, Kanim LE, Klein MA: Vitamin C intake and mortality among a sample of the United States population. Epidemiology 1992;3(3):194-202
  62. Salonen JT, Alfthan G, Huttunen JK, et al: Association between cardiovascular death and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982;2(8291):175-179
  63. Jialal I: Micronutrient modulation of nonconventional risk factors for CAD: LDL oxidation and hyperhomocysteinemia. Postgrad Med Special Report, June 1997, pp 13-20
  64. Sinatra ST: Refractory congestive heart failure successfully managed with high dose coenzyme Q10 administration. Mol Aspects Med 1997;18(suppl):S299-S305
  65. Soja AM, Mortensen SA: Treatment of congestive heart failure with coenzyme Q10 illuminated by meta-analyses of clinical trials. Mol Aspects Med 1997;18(suppl):S159-S168
  66. Watson PS, Scalia GM, Galbraith A, et al: Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure. J Am Coll Cardiol 1999;33(6):1549-1552
  67. Khatta M, Alexander BS, Krichten CM, et al: The effect of coenzyme Q10 in patients with congestive heart failure. Ann Int Med 2000;132(8):636-640
  68. Lee IM: Antioxidant vitamins in the prevention of cancer. Proc Assoc Am Physicians 1999;111(1):10-15
  69. Brown BG, Zhao XQ, Chait A, et al: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583-1592
  70. Lamm DL, Riggs DR, Shriver JS, et al: Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 1994;151(1):21-26
  71. Colditz GA: Selenium and cancer prevention: promising results indicate further trails required. JAMA 1996;276(24):1984-1985
  72. Clark LC, Combs GF, Turnbull BW, et al: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. Nutritional Prevention of Cancer Study. JAMA 1996;276(24):1957-1963 [erratum in JAMA 1997;227(19):1520]
  73. Position of the American Dietetic Association: food fortification and dietary supplements. J Am Diet Assoc 2001;101(1):115-25
  74. Willet WC, Stampfer MJ: What vitamins should I be taking, doctor? N Engl J Med 2001;345(25):1819-1824

Dr Adams is an assistant professor in the department of family medicine, and Dr Best is an assistant professor in the departments of family medicine and orthopedic surgery at the University of Wisconsin at Madison. Dr Best is an editorial board member of The Physician and Sportsmedicine. Address correspondence to Thomas M. Best, MD, PhD, Depts of Family Medicine and Orthopedic Surgery, UW Medical School, 621 Science Dr, Madison, WI 53711; e-mail to tm.best@hosp.wisc.edu.

Disclosure information: Dr Best discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.

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