Thiols Play a Central Role in Antioxidant Recycling
Functional sulfhydryl (SH) residue-rich protein and nonprotein agents in the biological system, commonly referred to as biothiols, have multifaceted functions including protein synthesis, detoxification, cell division, and regulation of intracellular signal transduction. In addition to its other major functions, the abundant nonprotein thiol glutathione has proved to be a master physiological antioxidant. Glutathione itself, and other pro-glutathione agents such as a-lipoic acid,⁵ play a crucial role in the antioxidant chain reaction by helping to maintain favorable redox states of other major antioxidants such as vitamins C and E.²

Physical Activity Influences Tissue Glutathione Level
Studies from several laboratories have suggested that physical training may upregulate the activities of glutathione-dependent antioxidant enzymes in some tissues. Higher glutathione content in skeletal muscle of exercise-trained animals also have been reported from our laboratory and others. Somani has reported that physical training may improve the redox state of glutathione in different regions of the brain.¹ In our experiments with beagle dogs that were endurance-trained on a treadmill for 55 weeks or activity-restricted by fiber-cast immobilization of one of the pelvic limbs, we observed that the state of physical activity is an important determinant of skeletal muscle glutathione content. Endurance training increased and activity restriction decreased red gastrocnemius muscle glutathione content.

N-Acetylcysteine Spared Blood Glutathione Oxidation in Humans
Physical exercise is followed by rapid oxidation of blood glutathione, mainly in the erythrocytes. Exercise-induced tissue glutathione oxidation has been consistently observed in our laboratory as well as in several others. In a recent study of young healthy men, we observed that blood glutathione oxidation induced by maximal bicycle ergometric test (mean duration = 14 minutes) could be spared in subjects who took 200 mg of N-acetylcysteine four times daily for 2 days and an additional 800 mg 2 hours before the exercise test. N-acetylcysteine is a common mucolytic drug that has been safely used in the clinic over a long period of time. A few months after our report was published, Reid et al.⁶ reported that N-acetylcysteine inhibits muscle fatigue in humans. In a later rat study, we observed that N-acetylcysteine supplementation may also spare exercise-induced glutathione oxidation in the lung-an organ in which this drug is known to be bioavailable.

Enhancing Tissue Glutathione by use of Nutritional Supplements
When ingested, antioxidants such as vitamins C and E are bioavailable to a certain extent. However, enhancing tissue glutathione level by nutritional supplementation is a challenging task. A few reports have claimed that an oral or intraperitoneal supply of glutathione may remarkably enhance endurance during exercise. These studies were brief and did not follow any biochemical parameter to explain the results. We conducted a more thorough study to evaluate the significance of endogenous and exogenously supplied glutathione with respect to exercise-induced oxidative stress. Glutathione-deficient rats in which tissue glutathione synthesis was arrested had a remarkably lower endurance (treadmill run) before exhaustion. This suggested that endogenous glutathione is an important factor in exercise performance. This is understandable because glutathione not only functions as a antioxidant but also has several other critical functions, including delivery of cysteine for protein synthesis. When a lower exercise intensity was selected for mice, Ji and associates did not observe any effect of glutathione deficiency on endurance. In our study, exogenously supplied (intraperitoneal) glutathione was poorly available to most tissues and did not influence endurance.