Regulation of hepatic glutathione synthesis

Glutathione (GSH) is one of the most important intracellular peptides, playing a multifunctional role ranging from antioxidant defense to modulation of immune function. GSH is synthesized by all mammalian cells, and the synthesis of GSH is a tightly regulated process. Two of the major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). In the liver, the major factors that determine the availability of cysteine are the activities of the membrane transport processes of the three sulfur amino acids--cysteine, cystine (under certain oxidative stress conditions) and methionine--and the conversion of methionine to cysteine through the trans-sulfuration pathway. Since the molecular cloning of GCS, there has been an explosion of knowledge regarding how this enzyme is regulated. Both transcriptional and posttranscriptional regulation play important roles in modulating the activity of this critical cellular enzyme.