Glutathione in disease.

Glutathione and disease GSH is the most abundant intracellular non-protein thiol and has been implicated in many cellular functions including detoxification, synthesis, cell-cycle regulation, regulation of gene expression, protection of proteins and other cellular components, and as an antioxidant [l-41. It can scavenge free radicals and electrophiles nonenzymically, as well as detoxify xenobiotics via the glutathione S-transferase reaction. It reduces lipid peroxides and hydrogen peroxide via glutathione peroxidase. Oxidation converts it to the disulphide form (GSSG). As a tripeptide, y-glutamylcysteinylglycine, it is synthesized from its constituent amino acids in two steps requiring ATP. The first step is catalysed by y-glutamylcysteine synthetase (y-GCS) and is rate-determining. This enzyme is inhibited by the final product GSH exerting feedback control. Thus when tissue GSH levels fall, the inhibition of p G C S is released promoting further synthesis of GSH. Often GSH synthesis is limited by the supply of free cysteine, present at very low concentrations in plasma. It would be wasteful if GSH were a singleshot antioxidant so after conversion to the oxidized form (GSSG), it is recycled via the glutathione reductase (GR) reaction (Figure 1). This reaction requires NADPH mostly produced in the initial steps of the pentose phosphate pathway. If this system is overloaded and GSSG accumulates it will form disulphides with proteins (PSSG), and it can be expelled from the cell. Raised GSSG levels will also inactivate thiol enzymes. Oxidative stress increases GSSG and may initially deplete GSH, but a number of adaptive responses, including increased uptake of cysteine, glutamate and glycine together with induction of GR and glutathione peroxidase, may eventually lead to elevated concentrations of GSH [l].