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The Journal of Nutrition Vol. 128 No. 12 December 1998,
pp. 2420-2426
Department of Kinesiology, Interdepartmental Graduate Program of Nutritional Sciences, University of Wisconsin-Madison, WI 53706
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ABSTRACT |
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Abstract
Introduction
Methods
Results
Discussion
References
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The present study examined the effect of glutathione (GSH) and glutathione ethyl ester (GSH-E) supplementation on GSH homeostasis and exercise-induced oxidative stress. Male Swiss-Webster mice were randomly divided into 4 groups: starved for 24 h and injected with GSH or GSH-E (6 mmol/kg body wt, i.p.) 1 h before exercise, starved for 24 h and injected with saline (S); and having free access to food and injected with saline (C). Half of each group of mice was killed either after an acute bout of exhaustive swimming (E) or after rest (R). Plasma GSH concentration was 100-160% (P < 0.05) higher in GSH mice vs. C or S mice at rest, whereas GSH-E injection had no effect. Plasma GSH was not affected by exercise in C or S mice, but was 44 and 34% lower (P < 0.05) in E vs. R mice with GSH or GSH-E injection, respectively. S, GSH- and GSH-E-treated mice had significantly lower liver GSH concentration and the GSH:glutathione disulfide (GSSG) ratio than C mice. Hepatic and renal GSH and the GSH:GSSG ratio were significantly lower in E vs. R mice in all groups. GSH-E-treated mice had a significantly smaller exercise-induced decrease in GSH vs. C, S, and GSH-treated mice and no difference in the GSH:GSSG ratio in the kidney. Activities of 
-glutamylcysteine synthetase and -glutamyltranspeptidase in the liver and kidney were not affected by either GSH treatment or exercise. GSH concentration and the GSH:GSSG ratio in quadriceps muscle were not different among C, S and GSH-treated mice, but significantly lower in GSH-E-treated mice (P < 0.05). Hepatic malondialdehyde (MDA) content was greater in exercised mice in all but GSH-E-treated groups. GSH and GSH-E increased MDA levels in the kidney of E vs. R mice, but attenuated exercise-induced lipid peroxidation in muscle. Swim endurance time was ~2 h longer in GSH (351 ± 22 min) and GSH-E (348 ± 27) than S mice (237 ± 17). We conclude that 1) acute GSH and GSH-E supplementation at the given doses does not increase tissue GSH content or redox status; 2) both GSH and GSH-E improve endurance performance and prevent muscle lipid peroxidation during prolonged exercise; and 3) while both compounds may impose a metabolic and oxidative stress to the kidney, this side effect is smaller with GSH-E supplementation.
The antioxidant function of glutathione (GSH)5 is well established in physiological and pathological states (Deleve and Kaplowitz 1990 Liver is the primary organ for de novo GSH synthesis. Liver GSH content was shown to decline after an acute bout of prolonged exercise (Leeuwenburgh and Ji 1995
Several experimental approaches were adopted to raise tissue GSH levels. Supplementation of free GSH has shown limited promise mainly because of the feedback inhibition of GCS by high GSH levels (Meister 1991 Animals.
Male Swiss-Webster mice (age 2 mo, body wt 25-30 g) were purchased from Harlan Sprague-Dawley Inc. (Indianapolis, IN) and housed two per cage in a temperature controlled room (22°C) with a 12-12 h dark-light cycle (8:00-20:00 h light; 2000-800 h dark) at the Animal Science Facilities of the University of Wisconsin-Madison. Before the experiments began, mice were monitored daily and had free access to water and food as previously reported (Leeuwenburg and Ji 1996). The experimental protocol was approved by the University of Wisconsin Research Animal Resources Center.
GSH and GSH ethyl ester supplementation.
After 1 wk of acclimation, the mice were randomly divided into 4 groups: 1) deprived of food for 24 h and injected i.p. with 6 mmol free GSH/kg body wt (Sigma, St. Louis, MO) dissolved in 0.75 mL of 9g/L saline (GSH), 2) deprived of food for 24 h and injected i.p. with 6 mmol/ GSH ethyl ester/kg body wt ( Exercise.
The exercise groups of mice were subjected to an acute bout of swimming to exhaustion. Mice swam individually in a 2-L glass beaker filled with water ~30 cm deep. The beakers were submerged in a thermostatic water bath set at 30°C. The fur of the mice was washed with liquid soap prior to swimming and air bubbles trapped in the fur were removed periodically to reduce buoyancy and ensure the imposed work load (Leeuwenburgh and Ji 1995 Tissue preparation.
After the mice were killed ~0.5 mL of arterio-venous blood was immediately collected in an Ependorf tube containing 50 µL of 9 g saline/L including 6 g heparin/L (wt/v). An aliquot of blood (0.4 mL) was added to 0.4 mL of saline containing 1,10-phenanthroline (10 mmol/L) that had been chilled on ice. Plasma was obtained by centrifugation of the blood sample in a desk-top microfuge at 500 x g for 2 min. The plasma sample (0.4 mL) was deproteinized by adding 0.4 mL 140 g perchloric acid/L with 2 mmol 1,10-phenanthroline/L. The mixture was vortexed and stored at Biochemical analysis.
GSH and GSSG concentrations in the liver, kidney, quadriceps and plasma were analyzed using HPLC method (Reed et al. 1980 Statistics.
All data were analyzed with a two-way ANOVA, except swim endurance time, which was analyzed by a one-way ANOVA. When a significant F value was found for the main treatment effect (i.e., GSH or GSH-E treatment; exercise; and/or interaction) was found, Fisher`s least-significant-difference test was employed to determine whether differences between group means were significant. P < 0.05 was considered statistically significant.
Body weight and endurance time.
The initial body weight before food deprivation was not significantly different among rested C, S, GSH- and GSH-E-treated groups (Table 1). After 24 h starvation the body weights of S, GSH- and GSH-E-treated mice were 6-9% lower (P < 0.05) than that of C mice, but there was no difference among the three groups. The exhaustive exercise had no significant effect on body weight in any group of mice.
Plasma glutathione concentration.
Twenty-four-hour starvation had no significant effect on plasma GSH or GSSG concentration at rest (Table 2). Likewise, the GSH:GSSG ratio and plasma total glutathione levels (TGSH) were no different between S and C groups. Rested GSH-supplemented mice had more than 100% greater plasma GSH and TGSH concentrations than C and S mice (P < 0.05), whereas GSSG levels were two- to three-fold higher in GSH-treated mice than in other groups (P < 0.05). In contrast, rested GSH-E-treated mice did not differ from C and S groups in plasma GSH or GSSG. Despite the differences in GSH and GSSH levels, the plasma GSH:GSSG ratio was not significantly different among resting treatment groups.
Liver glutathione status.
Liver GSH concentrations in resting mice were 16, 28 and 32% lower (P < 0.05) in S, GSH- and GSH-E-treatedgroups, respectively, than that in C (Table 2). GSH and TGSH concentrations were not significantly different among S, GSH- and GSH-E-treated resting mice. GSSG concentration in resting mice was 32 and 29% lower (P < 0.05) in GSH-E than in S and GSH-treated groups, respectively. The GSH:GSSG ratio was significantly lower in S and GSH-treated mice than that in C mice (P < 0.05). However, the GSH:GSSG ratio in GSH-E treated-treated mice was not different from those in C, but was higher than that in S and GSH-treated mice (P < 0.05).
Kidney glutathione status.
Starvation had little effect on resting kidney GSH level comparing S vs. C mice (Table 2). GSH-treated mice had 26 and 24% (P < 0.05) lower GSH and TGSH levels, respectively, as well as a lower GSH:GSSG ratio (P < 0.05) than S mice. In contrast, GSH-E treatment did not alter resting kidney GSH status. GSSG concentrations were not different among the various groups of mice.
Skeletal muscle glutathione status.
Muscle GSH and TGSH concentrations did not differ among C, S and GSH-treated mice (Table 2). However, these values were significantly lower in GSH-E-treated group than in other groups (P < 0.05). Furthermore, GSSG concentration was twice that in GSH-E-treated mice than in S mice, resulting in a 60% drop of the GSH:GSSG ratio (P < 0.05).
Tissue enzymatic response.
Resting GGT, GCS, GPX and GR activities in the liver were not significantly altered with GSH or GSH-E treatment (Table 3). Hepatic GGT activity was 27% lower in E vs. R of C mice (P < 0.05), but other groups showed no exercise effect. Liver GPX activity was significantly higher in E vs. R mice for C (15%, P < 0.05) and GSH-E treatment (26%, P < 0.05). No significant alteration in GCS or GR activity was detected as a result of exercise.
Lipid peroxidation.
There was no significant difference in resting MDA concentration among treatment groups in any of the tissues measured (Fig. 1). Exercise increased liver MDA levels by 138, 60 and 65% (P < 0.05) in C, S and GSH-treated mice, respectively, but not in those treated with GSH-E. Kidney MDA levels were 52 and 79% higher (P < 0.05) in E vs. R mice treated with GSH and GSH-E, respectively, but did not differ in C or S mice. Muscle MDA level was 190 % higher (P < 0.05) in E vs. R for S treated mice, but had no difference in C, GSH- or GSH-E-treated mice.
Exercise and GSH homeostasis.
Disturbance of GSH homeostasis is involved in exercise-induced oxidative stress (Ji and Leeuwenburgh 1995 GSH supplementation.
Despite two- to three-fold greater plasma GSH, liver and muscle GSH status was not improved and kidney GSH was lower in the GSH-injected mice than in saline-injected mice. These findings indicate that plasma GSH was not imported into these tissues. In a similar experiment, Puri and Meister (1983) GSH-E supplementation.
According to our knowledge, the current study was the first to examine the effect of GSH ethyl ester supplementation in exercised animals. The dose of GSH-E we injected (6 mmol/kg) was similar to other published data (2.5-10 mmol/kg, cf. Meister 1991
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
, Meister and Anderson 1983). Clear evidence has shown that strenuous physical exercise can cause a disturbance of GSH homeostasis, such as decreasing its tissue concentration, degrading cellular redox status and interfering with GSH synthesis and transport (Ji and Leeuwenburgh 1995, Kretzschmar and Muller 1993). This may be caused at least in part by increased production of reactive oxygen species (ROS), due to enhanced mitochondrial respiration and activation of other ROS-producing pathways, in skeletal muscle, heart and liver during prolonged aerobic exercise (Davies et al. 1982, Ji and Leichtweis 1997, Kumar et al. 1992). Previous studies suggest that endogenous GSH content is not sufficient to withstand increased oxidation, resulting in diminished antioxidant protection and exercise-induced oxidative stress (Gohil et al. 1988, Ji and Fu 1992, Lew et al. 1985, Sastre et al. 1992, Sen et al. 1992). Thus, it is beneficial for the cell to increase GSH levels to protect against ROS. Unfortunately, most tissues cannot synthesize GSH de novo and have to import GSH from circulatory sources via the -glutamyl cycle (Deneke and Fanburg 1989).
and 1996, Lew et al. 1985). This decrease may be caused by several factors. First, hepatic GSH export to the plasma is stimulated by glucagon, catecholamines and vasopression, the levels of which are elevated during exercise (Lu et al. 1990). Second, GSH is used by GSH peroxidase (GPX) as a substrate and oxidized to glutathione disulfide (GSSG) by hydroperoxides, the levels of which are also increased during exercise (Davies et al. 1982, Ji and Fu 1992). Furthermore, hepatic de novo GSH synthesis is limited by -glutamylcysteine synthetase (GCS) activity and influenced by cysteine and ATP availability (Deneke and Fanburg 1989, Meister and Anderson 1983, Tateishi et al. 1977). Decreased liver blood flow and increased competition from other metabolic demands during exercise may attenuate GSH synthesis. As liver GSH output and reserve diminish, extrahepatic tissues such as kidney, heart, and skeletal muscle may suffer from reduced circulatory resource of GSH, resulting in a decreased GSH:GSSG ratio and a net GSH deficit in these tissues. Furthermore, -glutamyltranspeptidase (GGT), the enzyme that controls the cleavage of plasma GSH as the first step of the -glutamyl cycle, may be down regulated in skeletal muscle with acute exercise (Leeuwenburgh and Ji 1995 and 1996, Sen 1992). Thus, it is conceivable that exogenous GSH supplementation may be advantageous in preserving plasma GSH homeostasis, thereby reducing exercise-induced oxidative stress.
View this table:
Table 1.
Body weight and swimming time in control, saline, glutathione (GSH)- and glutathione ethyl ester (GSH-E)-treated
mice at rest (R) and after exercise (E)1,2
View this table:
Table 2.
Glutathione concentrations in the plasma, liver, kidney and quadriceps of control, saline, glutathione (GSH)- and glutathione ethyl ester (GSH-E)-treated mice at rest (R) and after exercise (E)1,2
View this table:
Table 3.
Enzymes activities in the liver, kidney and quadriceps of control, saline, glutathione (GSH)- and glutathione ethyl ester
(GSH-E)-treated mice at rest (R) and after exercise (E)1,2
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Fig 1.
Malondialdehyde (MDA) levels in the liver (top), kidney (middle) and quadriceps muscle (bottom) of ) mice: control (had free access to food and water and injected with saline), saline (starved for 24 h and injected with saline), GSH-treated (starved for 24 h and injected with 6 mmol GSH/kg body wt) and GSH-E-treated (starved for 24 h and injected with 6 mmolGSH ethyl ester/kg body wt . Each bar represents mean ± SEM, n. * P < 0.05, Exercised vs. Rested mice after two-way ANOVA detected a significant (P < 0.05) exercise effect.
). However, several previous studies have reported that GSH supplementation can improve exercise performance (Cazzulani et al. 1991, Novelli et al. 1990). Administration of N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate was shown to increase cysteine transport into the cell and protect against oxidative stress, but tissue GSH levels are not always increased because GSH synthesis is limited mainly by GCS activity (Bray and Taylor 1994, Meister 1991, Sen et al. 1994). As an alternative strategy, GSH esters have been used to deliver GSH moiety directly into the cell, bypassing the enzymatic control of GGT and GCS (Anderson et al. 1985, Martensson and Meister 1989). GSH esters have shown considerable merit under a number of pathological and clinical conditions requiring high levels of tissue GSH (Meister 1991). However, there are no previous data on the efficacy of GSH ester supplementation during exercise. Thus, the present study was undertaken to investigate the effects of exogenous supplementation of GSH and GSH ethyl ester in mice at rest and after an exhaustive bout of exercise. We determined GSH content, GSH redox status and GSH-related enzyme activities in the plasma, liver, kidney and skeletal muscle, which are actively involved in the regulation of GSH homeostasis. Our hypotheses were 1) GSH and GSH ester supplementation would increase tissue GSH content;2) GSH ester would be superior to free GSH as a GSH supplementing agent and 3) increased intracellular GSH levels, due to supplementation, would attenuate exercise-induced oxidative stress.
MATERIALS AND METHODS
Abstract
Introduction
Methods
Results
Discussion
References
-Glu-Cys-Gly-O-CH2CH3, Sigma, St. Louis, MO) dissolved in an equal volume of saline (GSH-E), 3) deprived of food 24 h and injected i.p. with an equal volume of saline (S) and 4) having free access to food and water during the 24-h period and injected i.p. with an equal volume of saline as control (C). All injections were performed 1 h before the experiment. Because GSH at the given concentrations are acidic, aqueous solutions of both GSH and GSH-E were adjusted to pH 6.8 by cautious addition of 2 mol NaOH/L immediately before injection. A short period of starvation has been shown to facilitate GSH uptake after i.p. injection (Anderson et al. 1985). After injection, mice in each treatment group were randomly divided into two subgroups, exercised (E) and rested (R).
). Exhaustion was determined by the inability of the mice to remain at the surface of water. The exercised mouse was killed immediately after exhaustion, while a matched control mouse was rested for the same amount of time and killed approximately 10 min after its exercised counterpart. All mice were killed by decapitation during early phase of the dark cycle to avoid diurnal effect.
80°C. One lobe of the liver, one kidney and the whole quadriceps muscles of one hindlimb were quickly dissected and rinsed with cold saline to remove blood. A consistently similar part of the liver lobe was dissected to avoid regional differences of GSH in the liver. After blotting, tissues were immediately submerged in 70 gperchloric acid/L and 2 mmol phenanthroline/L (pH < 2.0) and homogenized with a motor-driven Potter-Elvejhem homogenizer at 0-4°C until a uniform suspension was obtained. All deproteinized tissue homogenates were stored at 80°C for assay of GSH and GSSG contents. The other kidney, quadriceps muscles of the other hindlimb and a small part of the same liver lobe were submerged in a medium containing 0.1 mol tris-(hydroxymethyl) aminomethane hydrochloride/L (Tris-HCl, pH 7.4) and homogenized at 0-4°C. The homogenates were stored at 80°C.
) with slight modification as described previously (Ji and Fu 1992). Activities of glutathione peroxidase (GPX, EC 1.11.1.9), glutathione reductase (GR, EC 1.6.4.2) and superoxide dismutase (SOD, EC 1.15.1.1) were determined as previously described (Ji and Fu 1992). GGT (EC 2.3.2.2) activity was measured at 37°C according to Meister et al (1981). GCS (EC 6.3.3.2) activity was determined according to Seelig and Meister (1985). The assay couples ADP formation from the GCS reaction with two enzymatic procedures in the presence of pyruvate kinase, lactate dehydrogenase, phosphoenopyruvate and NADH. Rate of formation of ADP is followed by the decrease of NADH at 340 nm. Lipid peroxidation was determined by measuring malondialdehyde (MDA) content in tissue homogenate according to Uchiyama and Mihara (1978) with some modification (Leeuwenburgh and Ji 1996). Protein content was measured by the Bradford method using bovine serum albumin as a standard.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). After an acute bout of exhaustive swimming, GSH concentration and the GSH:GSSG ratio in the liver and kidney were markedly decreased regardless of prior treatment (Leeuwenburgh and Ji 1995 and 1996; Lew et al. 1985, Sen et al. 1994). The mechanisms for the loss of GSH in these tissues, however, may be different. Liver exports GSH to the circulation under the stimulation of glucagon and catecholamines, plasma levels of which are elevated during prolonged exercise (Ji et al. 1993; Lu et al. 1990). Thus, plasma GSH concentration was kept remarkably constant in both C and S mice despite 4-5 h of swimming (Table 2). Liver GSH might also be oxidized to GSSG due to ROS generation, as exercised mice had significantly greater hepatic MDA concentration and GPX activity. In the kidney, the dramatic decreases of GSH after exercise may be explained primarily by a reduction of renal blood flow (Anderson et al. 1985). Epithelial cells of proximal renal tubules have the highest GGT activity and -glutamyl cycle turnover rate among all tissues (Meister and Anderson 1983). A diminished renal blood flow could reduce circulatory GSH supply to the kidney and produce an oxidative stress, as shown by the decreased GSH:GSSG ratio. It is interesting that although 24 h starvation suppressed the hepatic GSH and GSH:GSSG ratio in resting mice, it did not cause further disturbance in GSH status in either liver or kidney in S mice after exercise. A possible explanation is that starved mice swam for almost 2 h less than the fed mice. Hepatic and renal GSH levels in mice have been shown to correlate negatively with exercise duration during prolonged swimming (Leeuwenburgh and Ji 1995).
). Muscle GSH and the GSH:GSSG ratio were not affected by exhaustive swimming in the fed mice, and there was only a modest decrease in GSH level after exercise in the starved mice. Although exercise can promote muscle ROS production, muscle blood flow is increased during prolonged exercise, facilitating GSH import via the -glutamyl cycle (Ji and Fu 1992, Ji et al. 1993). Our previous work demonstrated that skeletal muscle is capable of maintaining GSH homeostasis during exercise in fed rats (Leeuwenburght and Ji 1996). In the starved mice that had a compromised hepatic GSH export and lower plasma GSH levels, quadriceps muscle appeared to have enhanced -glutamyl cycle turnover, as reflected by a doubled GGT activity. Nevertheless, quadriceps muscle in S mice was apparently under oxidative stress after exercise, as shown by a dramatically higher GPX activity and MDA levels.
showed that 10 mmol GSH/kg injected i.p. had no effect on liver GSH status in 24 h starved mice. The reason that tissues cannot benefit from high plasma GSH may be explained by a feedback inhibition of GCS, the rate-limiting enzyme of the -glutamyl cycle, exerted by GSH (Deneke and Fansburg 1989; Meister and Anderson 1983).
-glutamyl cycle during exercise when GCS activity is adequate (Inoue et al. 1987; Leeuwenburg et al. 1997). Additionally, GSH was also shown to be imported intact into certain cell types, such as epithelial cells of the lung, intestine, kidney, and eye by a Na+-dependent transport system (Deneke and Fanburg 1989, Hagen and Jones 1989). We speculate that a GGT-independent mechanism might have played a role in utilizing the abundant plasma GSH, thus providing better protection against ROS.
, Novelli et al. 1992). An energetic effect of GSH was unlikely because skeletal muscle cannot oxidize cysteine or glycine, and its ability to use exogenous glutamate is quite limited (Newsholme and Leech 1983). The alternative route for using GSH via hepatic gluconeogenesis probably does not occur at appreciable rate due to a low GGT activity in the liver. There is now increasing evidence that fatigue may be associate with muscle oxidative stress. Shindoh et al. (1990) showed that NAC treatment attenuated fatigue during isometric contraction in rabbit diaphragm muscles. Reid et al. (1994) also reported an anti-fatigue effect of NAC in human leg muscles. Therefore, it is possible that GSH supplementation enhanced endurance performance because it reduced muscle fatigue.
). In comparison with free GSH, GSH-E has demonstrated some unique effects that may substantiate its antioxidant potential during exercise. GSH-E-treated mice showed no elevation in plasma GSH levels as seen in GSH-treated mice despite the same dosage, indicating that 1-h after the injection GSH-E was already cleared from the plasma and probably taken by tissues due to its lipophillic property (Meister 1991). It was somewhat disappointing that tissue GSH levels in the GSH-E-treated mice were not increased as we hypothesized; however, time span from GSH-E injection to tissue collection was almost 7 h (1 h prior to exercise plus ~6 h swimming). Puri and Meister (1983) showed that liver and kidney GSH reached peak levels 2 h after 10 mmol GSH-E injection, but returned to pretreatment levels at ~8 h. Thus, it is possible that liver and kidney GSH levels were indeed elevated shortly after GSH-E injection, but gradually decreased over time.
). In the current study, GSH-E-treated-mice had lower liver GSH content than S mice, but maintained a higher liver GSH:GSSG ratio due to a concomitant decrease of GSSG. In contrast to GSH, GSH-E injection did not cause any adverse effect on renal GSH status as discussed previously. GSH-E treatment dramatically increased endurance time and suppressed exercise-induced muscle lipid peroxidation in a similar fashion to free GSH. Thus, many of the benefits of GSH supplementation in muscle were accomplished with GSH-E treatment, whereas the adverse effects of GSH on liver and kidney were minimized. Ironically, GSH-E treatment decreased muscle GSH content and the GSH:GSSG ratio. It is unclear whether muscle GSH level was initially increased followed by a declination.
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FOOTNOTES |
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-glutamylcysteine synthetase; GGT, -glutamyltranspeptidase; GPX, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione and glutathione injected mice; GSH-E, glutathione ethyl ester and GSH-E injected mice; GSSG, glutathione disulfide; HPLC, high pressure liquid chromatography; MDA, malondialdehyde; NAC, N-acetylcysteine; R, rested; ROS, reactive oxygen species; S, starved and saline injected mice; SOD, superoxide dismutase; TGSH, total glutathione defined as GSH+GSSG; Tris-HCl, tris-(hydroxymethyl) aminomethane hydrochloride.
Manuscript received 9 April 1998. Initial reviews completed 21 May 1998. Revision accepted 26 August 1998.
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LITERATURE CITED |
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Abstract
Introduction
Methods
Results
Discussion
References
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-Glutamyl Transpeptidase.
Methods. Enzymol.
1981;
77:237-242[Medline]-glutamylcysteinylglycyl ester, into liver and kidney. Proc. Natl. Acad. Sci. USA, 80: 5258-5260.This article has been cited by other articles:
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 F. Mariotti, K. L. Simbelie, L. Makarios-Lahham, J.-F. Huneau, B. Laplaize, D. Tome, and P. C. Even Acute Ingestion of Dietary Proteins Improves Post-Exercise Liver Glutathione in Rats in a Dose-Dependent Relationship with their Cysteine Content J. Nutr., January 1, 2004; 134(1): 128 - 131. [Abstract] [Full Text] [PDF]
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 A. M. Abushamaa, T. A. Sporn, and R. J. Folz Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L336 - L345. [Abstract] [Full Text] [PDF]
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 L. L. Ji Antioxidants and Oxidative Stress in Exercise Experimental Biology and Medicine, December 1, 1999; 222(3): 283 - 292. [Abstract] [Full Text]
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