Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine

Abstract

The most widely recognized function of reduced glutathione (GSH) is its defense against toxic compounds, whether exogenous, such as electophilic xenobiotics, or endogenous, such as reactive oxygen species, generated during normal oxidative metabolism and/or stress. However another no less significant role of GSH-namely its function as a reservoir and vehicle for packaging and transport of cyst(e)ine-has been receiving increasing attention. Because GSH is relatively more auto-oxidation resistant and stable than cyst(e)ine (CYSH), it serves as the preferred form for storage and transport of the latter especially in the extracellular and relatively much less reduced (than intracellular) milieu, where CYSH oxidizes to cystine (CYSS) rapidly. Over the past two decades, significant work has been going on to delineate the intra- and extrahepatic (interorgan) turnover, transport, and disposal of GSH and define the quantitative role of these processes in interorgan homeostasis of GSH, CYSH, and CYSS. These studies have identified the liver as the central organ of interorgan GSH homeostasis, with sinusoidal GSH efflux as the major determinant of plasma GSH, CYSH, CYSS, and thiol-disulfide status of plasma. This article focuses on the principal components and determinants of interorgan homeostasis of GSH and its breakdown products. It also presents the current state of knowledge under both normal and diseased states.