AJCN Tufts Nutrition Symposium, Boston & Online Sept 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jenkins, R. R
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jenkins, R. R
Agricola
Right arrow Articles by Jenkins, R. R
American Journal of Clinical Nutrition, Vol. 72, No. 2, 670S-674s, August 2000
© 2000 American Society for Clinical Nutrition

Article

Exercise and oxidative stress methodology: a critique1,2,3

Robert R Jenkins

1 From the Biology Department, Ithaca College, Ithaca, NY.

2 Presented at the workshop Role of Dietary Supplements for Physically Active People, held in Bethesda, MD, June 3–4, 1996.

3 Address reprint requests to RR Jenkins, Biology Department, Ithaca College, 953 Danby Road, Ithaca, NY 14850. E-mail: jenkins{at}ithaca.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 IS THERE A BEST...
 OTHER ISSUES
 SUMMARY
 REFERENCES
 
Historically, exercise physiologists' interest in oxygen has primarily centered on the problem of oxygen consumption. However, the interest of the general scientific community in oxygen-centered radicals has raised awareness of the oxygen paradox and has motivated investigators to question whether exercise-stimulated "overconsumption" of oxygen might induce an oxidative stress and pose some risk to biological systems. In recent years, a considerable amount of research has demonstrated that radicals are capable of damaging a vast array of biological targets. Unfortunately, the work related to oxidative stress and antioxidants subsequent to exercise has been narrow in scope. This paper provides a brief review of the shortcomings of the present state of knowledge in this discipline and outlines topics requiring attention.

Key Words: Oxidative stress • exercise • antioxidants • free radicals • free-radical research methodology


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
IS THERE A BEST...
 OTHER ISSUES
 SUMMARY
 REFERENCES
 
Approximately 3 billion y ago, blue-green algae appeared, and there went the environment, so to speak. Until that time, it is likely that oxygen existed only in oxides. The 21% oxygen diradical atmosphere in which we now live has presented living systems with an oxygen paradox. That is, oxygen is both essential and harmful to most life forms. From the time of Lavoisier, Priestly, and Scheele, a vast literature related to oxygen has emerged. For instance, nearly 131000 scientific, oxygen-related studies have been published since 1968, which was the year that McCord and Fridovich (1) demonstrated that certain enzymes liberated the superoxide radical. In the next decade, McCord (2) demonstrated that free radicals induce damage and that scavenging enzymes protect against such damage, Chance et al (3) published a seminal review on hydroperoxide metabolism, and Vladimirov et al (4) summarized their work on free-radical–induced membrane peroxidation. Such breakthroughs attracted persons from a wide array of disciplines to the emerging topic of oxidative stress and antioxidant protection.

Forster and Estabrook (5) suggested that it is proper to conceive of oxygen as an essential nutrient that can present problems of malnutrition and overnutrition. If oxygen overnutrition is truly a potential problem, then one would expect that exercise, which has the capacity to increase the body's total oxygen consumption by >10-fold over resting levels, might provide an exceptional model to demonstrate that fact. However, at the moment there are many inconsistencies in the exercise–oxidative stress (EXOS) literature. Haramaki and Packer (6) have attributed much of the lack of agreement to the diversity of exercise protocols, the analytic methodologies employed, and the tissues sampled. Progress in this area is slowed by the fact that only a few well-equipped laboratories have devoted continued attention to the question of EXOS. Much of the literature related to EXOS is the product of investigators with only a transient interest in the topic, which has resulted in a rather myopic approach because studies are primarily limited to measurements of flutathione and malondialdehyde (MDA) (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1.. Comparison of citations identified in scientific literature from 1985 to 1999 with use of the Medline Bibliographic Database to search for free-radical research method terms with and without exercise1
 
Excellent reviews exist on the biological sources of reactive oxygen species and endogenous defense systems (7), nutritional antioxidants (8), and the potential of antioxidant usage in disease intervention (9). Furthermore, a monograph provides a broad review of the potential role of exercise in oxidative stress (10). The purpose of this article is to attract the interest of new investigators by drawing attention to the rather narrow methodological approaches that are generally applied to the EXOS question, to note some of the potential pitfalls of the present methodologies, and to point out unexplored topics for investigation.


   IS THERE A BEST ASSAY METHOD?
TOP
 ABSTRACT
 INTRODUCTION
 IS THERE A BEST...
OTHER ISSUES
 SUMMARY
 REFERENCES
 
The principal difficulty in trying to study free-radical events in biological systems is the fleetingly short lifetimes of free radicals and even of some reactive species. Chance et al (3) quoted Warburg as saying, "Wieland has processed whole dogs and not found one drop of H2O2!". The problem was not the inability to detect H2O2, but the failure to realize how rapidly it was degraded in biological systems. It is essential to keep that point in mind when designing research related to oxidative stress.

Currently, direct observation and characterization of free radicals are limited to 2 special spectrometer techniques, which are discussed by Asmus and Bonifacic (11). The first method involves either pulse radiolysis or laser flash photolysis followed by time-resolved optical spectroscopy, which is not applicable to biological systems. The second method, involving electron spin resonance or electron paramagnetic resonance, is more friendly to biological applications but is also fraught with complications. For instance, aqueous solutions have a high dielectric absorption of microwave energy. Investigators have resorted to low-temperature techniques or the use of compounds known as "spin traps" in an attempt to overcome this problem. Furthermore, tissue preparation itself can generate free radicals. Such problems, added to the fact that the method is not applicable to in vivo systems, have resulted in infrequent use of this method in EXOS studies.

Lacking a suitable method for direct observation of free radicals, most investigators resort to various "fingerprint" assays to establish that oxidative stress reactions have occurred. Glutathione and its related enzyme systems have received the most extensive attention (Table 1Go). The influence of exercise on these compounds is the subject of several excellent reviews (12, 13). A decrease in reduced glutathione with a concomitant rise in the oxidized form of glutathione is widely accepted as evidence that a biological system has experienced a challenge by free radicals. However, the term oxidative stress is typically reserved for those circumstances in which the free-radical challenge can be shown to have resulted in tissue damage or to have produced compounds that are likely to be toxic or damaging to the tissue. Demonstration that these events have occurred necessitates using an assay for a suitable marker to provide evidence of damage.

Various factors, eg, interest in food preservation and relative ease of assay techniques, have motivated investigators to center their attention on lipid autoxidation or peroxidation. One of the most frequently used techniques in research related to free radicals and lipids involves reacting samples with thiobarbituric acid (TBA). A variety of fluorometric and spectrophotometric assays are used to determine the quality of TBA-reactive substances (TBARS) in biological samples. Some investigators refer to the products of this reaction as MDA, a reaction product of lipid peroxidation. This nomenclature is not correct, however, because it is known that TBA will react with molecules other than MDA. This has motivated some investigators to assay MDA directly by high-pressure liquid chromatography (HPLC) (14) or gas chromatography (15). However, not all lipid peroxidation products generate MDA, and MDA is produced by reactions other than lipid peroxidation (16).

Investigators have often failed to detect a rise in plasma TBARS subsequent to exercise and thus have concluded that oxidative stress did not occur. However, my laboratory has shown that TBARS are rapidly cleared from electrically stimulated muscle and that rats fatigued by running showed a significant increase in urinary TBARS (17). The failure of some investigators to detect a peroxidation product that actually was produced include such potential factors as an exclusive focus on MDA and a failure to look for a marker at the right time or place.

The use of a hydrocarbon breath test is underutilized in exercise research. The peroxidation of n–3 and n–6 fatty acids results in the production of the volatile alkanes ethane and pentane. The advantages of measuring breath samples of these alkanes include the ease of obtaining a noninvasive sample of compounds that are terminal products of lipid peroxidation and the ability to observe the same subject repeatedly over time. The problems with this method are that these markers cannot be attributed to a specific tissue and that atmospheric air is typically contaminated by hydrocarbons. Snider et al (18) found that the contamination problem can be overcome by including a washout period during which the subject breathes hydrocarbon-free air before the experimental period.

During free-radical reactions, an electron jump occurs from ground state to an excited state. When the electron falls back to ground state, a low level of light energy is emitted. This phenomenon is called chemiluminescence. Although chemiluminescent techniques are being used with greater frequency in a variety of biochemical investigations, they have rarely been used in exercise studies. Some investigators employ scintillation counters as a detector system. This technique is usually not suitable because scintillation counters are constructed with blue-sensitive photomultiplier tubes, whereas photons associated with radical events generally emit toward the red end of the spectrum. A single-photon counting system with a cooled phototube, similar to that described by Boveris et al (19), is recommended. A tissue can be challenged by various organic or inorganic hydroperoxides to test a tissue's antioxidant capacity (17, 20). When a variety of antioxidants are systematically added to the incubation mixture, the procedure may yield evidence to implicate the radical species involved. Additionally, single-photon counting may reveal evidence of electronically excited species. Cilento and Waldemar (21) have indicated that such excited species might induce beneficial or potentially harmful processes.

Free-radical damage to proteins has been the subject of several reviews (22, 23). It is now known that damage may proceed indirectly, by altering amino acids, or directly, by denaturation, structure alteration, and glycation. Cells also have repair processes for damaged protein, however, the influence of exercise on such oxidative damage and repair processes has been virtually ignored.

Lipid hydroperoxides and conjugated dienes were only rarely assayed in EXOS studies. Many studies claiming to have assayed lipid hydroperoxides actually used the TBA assay. There is no distinct advantage to determining the presence of either compound. Lipid hydroperoxides are unstable in the presence of metal ions and decompose to a variety of reaction products, whereas conjugated dienes take up O2 and form peroxyl radicals or lipid hydroperoxides. Furthermore, conjugated dienes are not adequate markers of polyenoic lipid peroxidation.

Obviously, in vivo studies involving antioxidant supplementation should be accompanied by marker assays to demonstrate that the dosage regimen has altered the antioxidant status of the subjects. The Methods in Enzymology series (24–27) and the text by Rice-Evans et al (28) provide a source of reliable assays. Because antioxidants often are involved in an interrelated chemistry, it is useful to attempt to understand how the protocol of interest has influenced the total antioxidant milieu. Cao et al (29) developed a technique that is suitable for that purpose.


   OTHER ISSUES
TOP
 ABSTRACT
 INTRODUCTION
 IS THERE A BEST...
 OTHER ISSUES
SUMMARY
 REFERENCES
 
The focus on potential EXOS has distracted researchers' attention from the fact that many forms of physical activity initiate ischemia-reperfusion episodes. Skeletal muscle was shown to be among the tissues that are least tolerant to ischemic stress (30). Ischemic states result in tissues becoming more reduced because reducing equivalents cannot be transferred to oxygen. This condition may be considered reductive stress and often may precede oxidative stress. Kehrer and Lund (31) reviewed the relationship between cellular reducing equivalents and oxidative stress. A sequence of events that may lead to muscle dysfunction is shown in Figure 1Go.



View larger version (16K):
[in this window]
[in a new window]
  		FIGURE 1. . Sequence of events that may lead to muscle dysfunction. When muscle blood flow is compromised, ATP production declines and the availability of reducing equivalents is reduced. Exercise training may provide a greater ability to maintain the reducing equivalent pool, thus affording protection during the typical brief ischemia-reperfusion episodes that accompany repetitive muscle contractions. Adapted from reference 31.

 
Cyclic voltammetry has been applied to the study of radical scavenging defense, and it was noted that oxidative stress decreased the tissue's reductive capacity (32). Interestingly, voltammetry was used to demonstrate a decrease in saliva's reducing capacity, which appeared to be related to oxidative stress (33). This finding offers some promise as a potential noninvasive marker of oxidative stress.

Robinson et al (34) demonstrated that an increased electron flux capacity is necessary to achieve the increased peak oxygen consumption derived by training. When Bolter and Chefurka (35) added myxothiazol, a tight inhibitor of mitochondrial complex III, to mouse liver, they found that it mimicked reductive stress and significantly increased hydrogen peroxide production. It should be noted that inherited respiratory chain disorders were documented in humans (36).

The ability to tolerate oxidative stress during exercise may vary between the sexes and is likely to be influenced by genetics. For instance, females appear to lose some protection against heart disease and some cancers after menopause. That observation has raised the question of whether there may be a causal link between estrogen and some free-radical mechanisms related to those disorders. A Medline search was conducted employing the terms sex differences, radicals, females, oxidative stress, and exercise or physical activity. The extent of the limitations of the EXOS literature on this subject is illustrated in Table 2Go. Tiidus (37) recently reviewed a series of studies indicating that exercised female rats experience little or no oxidative stress. Whether the same is true in humans and whether menopause might remove such protection is not known.


View this table:
[in this window]
[in a new window]
  		TABLE 2.. Comparison of citations identified in scientific literature from 1985 to 1999 with use of the Medline Bibliographic Database to search for free-radical terms with and without exercise1
 
Furthermore, just as some members of the general population with genetic predisposition to obesity or connective tissue disorders are apt to sustain orthopedic trauma from certain types of intense exercise, persons from some genetic sets may be unable to cope with oxidative stress (38). The history of the development of mitochondrial medicine and its connection to mitochondrial DNA was reviewed by Luft (39), who recorded the first mitochondrial disorder (Luft's disease) in 1959. As Luft pointed out, mitochondrial DNA mutates {approx}5–10 times faster than nuclear DNA and is less efficient in repairing itself. Its location adjacent to the prime source of oxygen consumption and radical production places it at risk for damage. Strenuous exercise was shown to damage DNA by an oxidative stress route that was prevented by vitamin E administration (40). Similarly, Simopoulos (41) emphasized the necessity of considering genetic predisposition when attempting to understand multifactorial health problems. For instance, when dealing with overnutrition, it is necessary to focus on individual rather than universal dietary recommendations (42).

The role of exercise in relation to potential oxidative stress in children has been ignored completely. This is surprising because there appears to be an increased prevalence of asthma, a disorder that is common in children and that is often provoked by exercise. Hatch (43) reviewed the literature, which indicates that inhaled oxidants may increase children's requirements for dietary antioxidants. At the other end of the age spectrum, there is evidence that the elderly may be more susceptible to oxidative stress (44), and De La Asuncion et al (45) showed a correlation between age-associated glutathione oxidation and damage to mitochondrial DNA.

We are beginning to understand that free radicals play many vital roles in biochemistry. The unfolding story from free-radical research is not all bad news. Molecular biological approaches are beginning to elucidate the importance of radicals to cellular control systems (46, 47). There is evidence that programmed cell death, or apoptosis, may be initiated by oxidative stress (48). For instance, it was shown that the rate of apoptosis is accelerated by iron mobilization (49), and that exercise may induce processes that increase such mobilization (50). In a review, McCord (51) concluded that "excessive iron stores serve no known useful function in an otherwise healthy body." The influence of iron overload to health status is also the subject of several reviews (52, 53). Sempos et al (53) pointed out that a 2-phased approach that takes into account both the catalytic potential and the antioxidant capacity of subjects is likely to be required to resolve questions that attempt to link transition metals to disease states.


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 IS THERE A BEST...
 OTHER ISSUES
 SUMMARY
REFERENCES
 
Can exercise induce an oxidant stress that might exert potentially adverse effects on human health? If so, what type of exercise might prove this and can the risk be eliminated by antioxidant supplementation? The study of free radicals and antioxidants within the context of exercise is scarcely more than a decade old and lacks the necessary depth and breadth to definitively answer such questions. To a large extent, EXOS research is dominated by the type of descriptive studies that characterize virtually every new area of investigation. Although research from hundreds of laboratories around the world has produced a rapidly expanding list of radical effects on biological systems, the few laboratories interested in exercise have continued to focus primarily on lipid peroxidation. Most studies fail to include multiple markers of oxidative stress and do not consider that particular markers may be quickly removed to the urine.

EXOS research has typically been dominated by animal studies because of the invasive procedures that are required. The development of better, noninvasive, or minimally invasive techniques is needed to allow research to expand in human populations. Existing studies in humans have centered on young male adults; future studies should be extended to children, women, and the aging population. Within all populations, there may be a genetic susceptibility to oxidative stress that is potentiated by certain types of exercise. Additionally, in light of the growing evidence that radicals serve a variety of beneficial functions, investigators must begin to consider whether high concentrations of antioxidant supplementation might perturb such beneficial chemistry.

Some true believers consider exercise a panacea for virtually all ills, similar to "grandma's chicken soup": it is always good and hurts no one. Although some epidemiologic studies support the health benefits of exercise, it is premature to conclude that EXOS research is inaccurate and that exercise is innocuous. There probably has never been a time in human history when such a broad cross-section of humans have consumed such large doses of oxygen for concentrated periods of time. Primitive hunters stalked game; they probably did not spend a half-hour or an hour each day running at a pace equal to 70–80% of their maximal oxygen uptake. Aerobic exercise for prolonged portions of the human life span is a phenomenon that began in the early 1960s. Until then, few athletes continued intense aerobic exercise beyond their competitive years. Because the incubation period for disorders such as certain cancers is 30–40 y, the effects of continued oxygen exposure may yet appear.

Until investigators apply a broader spectrum of research tools to the study of this topic, our ability to assess the relationship between physical activity and oxidative stress will remain limited. Evidence is inadequate to make conclusive statements relating EXOS to health. Additionally, too few data are available to suggest that antioxidant supplementation is either necessary or advisable.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 IS THERE A BEST...
 OTHER ISSUES
 SUMMARY
 REFERENCES
 

  1. McCord JM, Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem 1968;243:5753–60.[Abstract/Free Full Text]
  2. McCord JM. Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science 1974;185:529–30.[Abstract/Free Full Text]
  3. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev 1979;59:527–605.[Free Full Text]
  4. Vladimirov YA, Oleenev VI, Suslova TB, Cheresmisnina ZP. Lipid peroxidation in mitochondrial membrane. Adv Lipids Res 1980;17: 173–249.
  5. Forster RE, Estabrook RW. Is oxygen an essential nutrient? Annu Rev Nutr 1993;13:383–403.[Medline]
  6. Haramaki N, Packer L. Oxidative stress indices in exercise. In: Sen CK, Packer L, Hänninen O, eds. Exercise and oxygen toxicity. New York: Elsevier, 1994:77–87.
  7. Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev 1994;74:139–62.[Free Full Text]
  8. Halliwell B. Antioxidants: sense or speculation? Nutr Today 1994;29:15–9.
  9. Maxwell SRJ. Prospects for the use of antioxidant therapies. Drugs 1995;49:345–61.[Medline]
  10. Sen CK, Packer L, Hänninen O, eds. Exercise and oxygen toxicity. New York: Elsevier, 1994.
  11. Asmus K-D, Bonifacic M. Free radical chemistry. In: Sen CK, Packer L, Hänninen O, eds. Exercise and oxygen toxicity. New York: Elsevier, 1994:1–48.
  12. Ji LL. Exercise and oxidative stress: role of cellular antioxidant systems. Exerc Sport Sci Rev 1995;23:135–66.[Medline]
  13. Sen KS, Hänninen O. Physiological antioxidants. In: Sen CK, Packer L, Hänninen O, eds. Exercise and oxygen toxicity. New York: Elsevier, 1994:89–126.
  14. Bird RP, Hung SO, Hadley M, Drapper HH. Determination of malondialdehyde in biological materials by high-pressure liquid chromatography. Anal Biochem 1983;128:240–4.[Medline]
  15. Ichinose T, Miller MG, Shibamoto T. Gas chromatographic analysis of free and bound malondialdehyde in rat liver homogenates. Lipids 1989;24:895–8.[Medline]
  16. Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 1990;9:515–40.[Medline]
  17. Jenkins RR, Krause K, Schofield LS. Influence of exercise on clearance of oxidant stress products and loosely bound iron. Med Sci Sports Exerc 1993;25:213–7.[Medline]
  18. Snider MT, Balke P-O, Oerter KE, et al. Methods for measuring lipid peroxidation products in the breath of man. Life Chem Reports 1985;3:168–73.
  19. Boveris A, Cadenas E, Reiter R, Filipkowski M, Nakase Y, Chance B. Organ chemiluminescence: noninvasive assay for oxidative radical reactions. Proc Natl Acad Sci U S A 1980;77:347–51.[Abstract/Free Full Text]
  20. Warren JA, Jenkins RR, Packer L, Witt EH, Armstrong RB. Elevated muscle vitamin E does not attenuate eccentric exercise-induced muscle injury. J Appl Physiol 1992;72:2168–75.[Abstract/Free Full Text]
  21. Cilento G, Waldemar A. From free radicals to electronically excited species. Free Radic Biol Med 1995;19:103–14.[Medline]
  22. Pacifici RE, Davies KJA. Protein, lipid and DNA repair systems in oxidative stress: the free-radical theory of aging revisited. Gerontology 1991;37:166–80.[Medline]
  23. Dean RT, Gebicki J, Gieseg S, Grant AJ, Simpson JA. Hypothesis: a damaging role in aging for reactive protein oxidation products? Mutat Res 1992;275:387–93.[Medline]
  24. Colowick SP, Kaplan NO, eds. Methods in enzymology. Vol 105. New York: Academic Press, 1984.
  25. Abelson JN, Simon MI, eds. Methods in enzymology. Vol 186. New York: Academic Press, 1990.
  26. Abelson JN, Simon MI, eds. Methods in enzymology. Vol 233. New York: Academic Press, 1994.
  27. Abelson JN, Simon MI, eds. Methods in enzymology. Vol 234. New York: Academic Press, 1994.
  28. Rice-Evans CA, Diplock AT, Symons MCR. Techniques in free radical research. Amsterdam: Elsevier, 1991.
  29. Cao GC, Alessio HM, Cutler RG. Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med 1993;14:303–11.[Medline]
  30. Nishikawa H, Manek S, Barnett SS, Charlett A, Green CJ. Pathology of warm ischemia and reperfusion injury in adipomusculocutaneous flaps. Int J Exp Pathol 1993;74:35–44.[Medline]
  31. Kehrer JP, Lund LG. Cellular reducing equivalents and oxidative stress. Free Radic Biol Med 1994;17:65–75.[Medline]
  32. Kohen R, Tirosh O, Gorodetsky R. The biological reductive capacity of tissues is decreased following exposure to oxidative stress: a cyclic voltammetry study of irradiated rats. Free Radic Res Commun 1992;17:239–48.[Medline]
  33. Kohen R, Tirosh O, Kopolovich K. The reductive capacity index of saliva obtained from donors of various ages. Exp Gerontol 1992;27: 161–8.[Medline]
  34. Robinson DM, Ogilvie RW, Tullson PC, Terjung R. Increased peak oxygen consumption of trained muscle requires increased electron flux capacity. J Appl Physiol 1994;77:1941–52.[Abstract/Free Full Text]
  35. Bolter C, Chefurka W. Extramitochondrial release of hydrogen peroxide from insect and mouse liver mitochondria using the respiratory inhibitors phosphine, myxothiazol, and antimycin and spectral analysis of inhibited cytochromes. Arch Biochem Biophys 1990; 278:65–72.[Medline]
  36. Duncan DB, Herholz K, Kugel H. Positron emission tomography and magnetic resonance spectroscopy of cerebral glycolysis in children with congenital lactic acidosis. Ann Neurol 1995;37:351–8.[Medline]
  37. Tiidus PM. Can estrogens diminish exercise induced muscle damage? Can J Appl Physiol 1995;20:26–38.[Medline]
  38. Joenje H. Genetic toxicology of oxygen. Mutat Res 1989;219: 193–208.[Medline]
  39. Luft R. The development of mitochondrial medicine. Biochem Biophys Acta 1995;1271:1–6.
  40. Hartmann A, Niess AM, Grünert-Fuchs M, Poch B, Speit G. Vitamin E prevents exercise-induced DNA damage. Mutat Res 1995; 346:195–202.[Medline]
  41. Simopoulos A. Part 1: Genetic variation, nutrition, and chronic diseases. Nutr Today 1995;30:157–67.
  42. Simopoulos A. Part 2: Genetic variation, nutrition, and chronic diseases. Nutr Today 1995;30:194–67.
  43. Hatch GE. Asthma, inhaled oxidants, and dietary antioxidants. Am J Clin Nutr 1995;61(suppl):625S–30S.[Abstract/Free Full Text]
  44. Meydani M. Vitamin E requirement in relation to dietary fish oil and oxidative stress in elderly. EXS 1992;62:411–8.[Medline]
  45. de la Asuncion JG, Millan A, Pla R, et al. Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA. FASEB J 1996;10:333–8.[Abstract]
  46. Jenkins RR. Tissue iron and reactive oxygen—it's not all bad. In: Maughan RJ, ed. Biochemistry of exercise IX conference proceedings. Champaign, IL: Human Kinetics, 1996:471–81.
  47. Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. FASEB J 1996;10:709–20.[Abstract]
  48. Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today 1994;15:7–10.[Medline]
  49. Wolfe JT, Ross D, Cohen GM. A role for metals and free radicals in the induction of apoptosis in thymocytes. FEBS Lett 1994;352:58–62.[Medline]
  50. Jenkins RR, Halliwell B. Metal binding agents: possible role in exercise. In: Sen CK, Packer L, Hanninen O, eds. Exercise and oxygen toxicity. New York: Elsevier, 1994:59–76.
  51. McCord JM. Effects of positive iron status at a cellular level. Nutr Rev 1996;54:85–8.[Medline]
  52. Lynch SR. Iron overload: prevalence and impact on health. Nutr Rev 1996;53:255–60.
  53. Sempos CT, Looker AC, Gillum RF. Iron and heart disease: the epidemiologic data. Nutr Rev 1996;54:73–84.[Medline]



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
J.-Y. Park, R. E. Ferrell, J.-J. Park, J. M. Hagberg, D. A. Phares, J. M. Jones, and M. D. Brown
NADPH oxidase p22phox gene variants are associated with systemic oxidative stress biomarker responses to exercise training
J Appl Physiol, November 1, 2005; 99(5): 1905 - 1911.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
E. F. Rosa, A. C. Silva, S. S. M. Ihara, O. A. Mora, J. Aboulafia, and V. L. A. Nouailhetas
Habitual exercise program protects murine intestinal, skeletal, and cardiac muscles against aging
J Appl Physiol, October 1, 2005; 99(4): 1569 - 1575.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. M. Bailey, I. S. Young, J. McEneny, L. Lawrenson, J. Kim, J. Barden, and R. S. Richardson
Regulation of free radical outflow from an isolated muscle bed in exercising humans
Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1689 - H1699.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. E. Davis, H. Cai, L. McCann, T. Fukai, and D. G. Harrison
Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training
Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1449 - H1453.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jenkins, R. R
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jenkins, R. R
Agricola
Right arrow Articles by Jenkins, R. R

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS