Importance and Regulation of Hepatic Glutathione

Abstract

Glutathione plays a key role in the liver in detoxification reactions and in regulating the thiol-disulfide status of the cell. Glutathione synthesis is regulated mainly by the availability of precursor cysteine and the concentration of glutathione itself which feeds back to regulate its own synthesis. Degradation of hepatic glutathione is principally regulated by the efflux of reduced and oxidized glutathione into both sinusoidal plasma and bile. In addition, glutathione may be consumed in conjugation reactions. Under conditions of oxidative stress, the liver exports oxidized glutathione into bile in a concentrative fashion, whereas under basal conditions, mainly reduced glutathione is exported into bile and blood. The mechanism of export of reduced glutathione into bile and sinusoidal blood is poorly understood.Glutathione is a tripeptide, -y-glutamylcysteinylglycine, which appears to have key functions in protective processes ( [3]. Thus, glutathione participates in important detoxification reactions. In addition, the ratio of reduced to oxidized glutathione is critical in regulating protein and enzyme functions and protein synthesis, and the maintenance of the redox state [1]. Excess oxidized (as would occur with reduction of peroxides or with a change in the redox potential) leads to the interaction of oxidized glutathione with protein-SH groups, forming mixed disulfides [4] (Fig. 1). Conversely, maintaining the normal concentration of reduced glutathione supports the maintenance of the reduced state of protein thiols. Formation of glutathione-protein mixed disulfides has been shown to alter a variety of cell functions, including enzyme function, protein synthesis, cell integrity, microtubular function, transport processes, and release mechanisms [1,5]. Since oxidized glutathione, when present in 497

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