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

The most widely recognized function of reduced glutathione (GSH) is its def ense against tonic compounds, whether exogenous, such as electophilic xenob iotics, or endogenous, such as reactive oxygen species, generated during no rmal oxidative metabolism and/or stress. However; another no less significa nt role of GSH-namely its function as a reservoir and vehicle for packaging and transport of cyst(e)ine-has been receiving increasing attention. Becau se GSH is relatively more auto-oxidation resistant and stable than cyst(e)i ne (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 o f GSH and define the quantitative role of these processes in interorgan hom eostasis of GSH, CYSH, and CYSS. These studies have identified the liver as the central organ of interorgan GSH homeostasis, with sinusoidal GSH efflu x as the major determinant of plasma GSH, CYSH, CYSS, and thiol-disulfide s tatus of plasma. This article focuses on the principal components and deter minants of interorgan homeostasis of GSH and its breakdown products. It als o presents the current state of knowledge under both normal and diseased st ates.