Biologic and pharmacologic regulation of mammalian glutathione synthesis

Glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcyste ine synthetase (gamma-GCS) and GSH synthetase. The intracellular GSH concen tration, typically 1-8 mM, reflects a dynamic balance between the rate of G SH synthesis and the combined rate of GSH. consumption within the cell and loss through efflux. The gamma-GCS reaction is rate limiting for GSH synthe sis, and regulation of gamma-GCS expression and activity is critical for GS H homeostasis. Transcription of the gamma-GCS subunit genes is controlled b y a variety of factors through mechanisms that are not yet fully elucidated . Glutathione synthesis is also modulated by the availability of gamma-GCS substrates, primarily L-cysteine, by feedback inhibition of gamma-GCS by GS H, and by covalent inhibition of gamma-GCS by phosphorylation or nitrosatio n. Because GSH plays a critical role in cellular defenses against electroph iles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention. Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under con ditions that would otherwise result in GSH depletion and cytotoxicity. Conv ersely, inhibitors of gamma-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites to certain therapeu tic interventions. (C) 1999 Elsevier Science Inc.