Functions of intracellular glutathione in hepatic hydroperoxide and drug metabolism and the role of extracellular glutathione

Abstract

The metabolic role of glutathione was investigated with emphasis on oxidative transitions associated with hydroperoxide and drug metabolism. Hydroperoxide reduction is catalyzed by the GSH peroxidases (Se dependent or non-Se dependent) and leads to the formation of glutathione disulfide. Intracellularly, a steady state is maintained (a) by the activity of GSSG reductase operating at the expense of NADPH, and (b) by an efflux of GSSG from the cell. In the isolated perfused rat liver, hydroperoxide reduction was shown to cause substantial oxidation of NADPH to NADP +, an increase of flux through the pentose phosphate pathway, and a stimulation of glycogenolysis and glycolysis. The release of GSSG was proportional to the rate of hydroperoxide reduction, occurring at a rate of approximately 3% of the flux through GSH peroxidase. Efflux of GSSG occurs into bile as an “homoconjugate,” similar to the biliary excretion of other (hetero) S-conjugates of glutathione. Biliary GSSG efflux was increased during drug oxidations and in rats treated chronically with ethanol. Efflux of GSH from the perused liver occurs at a rate of 12–15 nmol/min per gram of liver. Like GSSG efflux, it is undirectional and contributes to a plasma pool. Plasma glutathione concentration in rat and man is 3–5 μ m. Extracellular glutathione is degraded by the kidney and other organs. Renal glutathione extraction is 90%. Since the filtration fraction amounts to only 30% of the renal plasma flow, the tubular γ-glutamyl transpeptidase in the brush border membrane must operate in conjunction with an additional uptake or degradation mechanism at the basolateral membrane. Intracellular glutathione is predominantly reduced with concentrations of approximately 10 m m GSH in cytosol and mitochondrial matrix, and approximately 0.5 m m GSSG. Extracellular glutathione is present predominantly in the oxidized disulfide form due to the existence of highly efficient GSH oxidase activities. One of the roles of plasma glutathione is given in the interorgan relationships in glutathione turnover.