Enhancement of tissue glutathione for antioxidant and immune functions in malnutrition

Abstract

Glutathione (t-y-glutamyl-L-cysteinyl-glycine, GSHT), a cysteine-containing tripeptide and the most abundant non-protein thiol in mammalian cells, is receiving considerable research attention (over 1200 citations in the Medline Database for 1992). The structural uniqueness of GSH, conferred by the y-glutamyl bond, contributes to its intracellular stability (resistance to intracellular peptidases) and determines tissue specificity for uptake of extracellular GSH via y-glutamyl transpeptidase. Tissue concentrations of GSH, like many other metabolically important compounds, are highly regulated. For example, it is difficult to deplete hepatic GSH to less than 30% of control values even with xenobiotic challenge or prolonged starvation [l-6]. Also, it is difficult to exceed the physiological ma~mum concentration for hepatic GSH with supplementation of GSH precursors unless hepatic GSH stores have been depleted previously with xenobiotics or by fasting [4,6]. GSH, a substrate for GSH-S-transferase (EC 2.5.1.18) and GSH peroxidase (EC 1.11.1.9), was initially studied for its role in detoxification of xenobiotics and antioxidation of reactive oxygen species and free radicals, This also led to an appreciation of GSH for transport and storage of cysteine, and for the effects of nutritional status (e.g. sulfur amino acid deficiency) and physiological state on tissue GSH concentrations. With increasing knowledge, the recognized functions of GSH have been expanded to include many aspects of cell biology, such as regulation of cellular redox balance, leukotriene and prostaglandin metabolism, deoxyribonucleotide synthesis, immune function and cell proliferation [for recent GSH reviews, see Refs. 7-111. At the same time, there has been increased interest in the potential therapeutic use of GSH or GSH precursors for treatment of toxicity or diseases, especially those conditions that are believed to be free radical-mediated and that have depleted stores of tissue GSH. The concept of using GSH or GSH precursors