Formation and efflux of glutathione disulfide studied in isolated rat hepatocytes

The efflux of intracellular GSH and GSSG to the extracellular space has been studied in various experimental systems including the isolated, perfused liver [ 1,2] and suspensions of isolated hepatocytes [3,4] under various metabolic conditions. It appears that both GSH and GSSG are continuously released from liver cells into plasma and bile, respectively, and that their translocation may be mediated by distinct transport systems, since neither GSH nor GSSG readily diffuses through the plasma membrane. Release of GSH from the liver may be the major source of plasma GSH and GSSG [5,6], and GSSG efflux into bile may reflect the operation of a transport system normally involved in the secretion of glutathione conjugates [5]. The release of GSSG from the isolated, perfused liver, or from isolated hepatocytes, is markedly increased by exogenously added organic hydroperoxides [ 1,7], as well as under conditions of enhanced rates of endogenous HzOs generation [8]. This phenomenon is therefore thought to reflect the intracelluar activity of glutathione peroxidase, a cytosolic selenoprotein that catalyzes the reduction of HZOZ and organic hydroperoxides with the concomitant oxidation of GSH to GSSG. However, only a fraction of the GSSG that is formed in the glutathione peroxidase reaction is actually released from the hepatocytes [4], and most of the GSSG is reduced back to GSH by the ~avoprotein, ~utathione reductase, which utilizes NADPH as a reductant.