Pharraac. Ther. Vol. 47, pp. 61-71, 1990 0163-7258/90 $0.00+ 0.50 Printed in Great Britain.All rights reserved © 1990PergamonPress pie Specialist Subject Editor: J. L. HOLTZMAN GLUTATHIONE-DEPENDENT PROTECTION AGAINST OXIDATIVE INJURY XIAOQIN SHAN, TAK YEE AW and DEANP. JONES Department of Biochemistry and Winship Cancer Center, Emory University School of Medicine, Atlanta, Georgia 30322, U.S.A. Abstract--Functions of GSH in detoxication during radical-induced injury in specific pathological and toxicological conditions are discussed. GSH protects against oxidative damage in systems that scavenge radicals, eliminate lipid peroxidation products, preserve thiol-disulfide status of proteins, and repair oxidant damage. Several factors which affect cellular GSH homeostasis can affect these functions, including nutritional status, hypoxia and pharmacological intervention. Evidence from a variety of pathological and toxicological conditions, e.g. ischemia-reperfusion injury, chemically induced oxidative injury, radiation damage, aging, and degenerative diseases, indicate that GSH is a primary component of physiological systems to protect against oxidant and free-radical-mediated cell injury. CONTENTS 1. Introduction 2. Glutathione Homeostasis 3. Functions of GSH in Detoxication During Radical-induced Injury 4. Role of GSH in Protection Against Free Radical Processes under Pathological and Toxicological Conditions 4.1. Ischemia-Reperfusion Injury 4.2. Chemically Induced Oxidative Injury and Radiation Damage 4.3. Lipid Peroxidation 4.4. Aging and Degenerative Diseases 5. Summary and Conclusions Acknowledgement References 61 61 63 64 64 65 66 67 68 68 68 1. INTRODUCTION Oxidation-reduction reactions are central to many aspects of cell function, and abnormal electron trans- fer is commonly involved in cellular damage. Several biological mechanisms are used to defend against this type of injury, including highly specific electron trans- fer pathways, radical scavengers, detoxication en- zymes and repair systems. Glutathione (GSH) plays a central role in several of these, and its depletion potentiates oxidative injury. The purpose of this review is to summarize recent studies of GSH homeostasis, review the functions of GSH in detoxication during radical-induced injury and discuss the role of GSH in protection in specific pathological and toxicological conditions. 2. GLUTATHIONE HOMEOSTASIS GSH is a tripeptide (7-glu-cys-gly) with two bio- logically important structural features: a thiol (SH) group and a ?-glutamyi linkage. The intraceUular concentration of GSH is relatively high, about 0.5-10raM, and it is usually the most abundant intraceUular thiol. Because of its important biological functions, especially in detoxication, its synthesis, transport and degradation have been studied exten- sively in many cell types. The overall balance is determined by the rates of introduction (synthesis, uptake) and the rates of elimination (conjugation, efflux). GSH is synthesized in all mammalian cells from its amino acid precursors through a pathway involving two ATP-dependent reactions. In the first reaction, which is catalyzed by ~-glutamyicysteine synthetase, glutamate and cysteine are linked by the iso-peptide bond to form y-giutamyicysteine. The second and final step in GSH synthesis is catalyzed by GSH synthetase. GSH synthesis is normally regulated through feedback inhibition by GSH and through the availability of cysteine. However, other factors may also be involved because normal concentrations vary over an order of magnitude. In recent studies, we found that the availability of ATP can also limit synthesis, particularly if cysteine concentration is low (Shan et al., 1989). In liver cells, cysteine is synthesized from methionine via the cys- tathionine pathway (Beatty and Reed, 1980), which requires one molecule of ATP in the first reaction, the 61