[Xenobiotics and glutathione]

Abstract

Mercapturic acids (MA) are the final step in the biotransformation of compounds deriving from conjugation of electrophiles to glutathione (GSH). GSH is an important endogenous tripeptide (g glutamyl-cysteinil-glycine) present in mammalians essentially in erythrocytes, liver and kidney. It is involved in several intracellular detoxification routes. Among these routes, the conjugation with electrophiles, usually epoxides of aromatic and aliphatic organic compounds, avoids the formation of covalent bounds between alkylating compounds and cellular macromolecules (DNA, RNA, proteins) and prevents their mutagenic and cancerogenic effects. The conjugation of electrophiles to GSH can proceed spontaneously or catalysed by GSH-S-transferase (GST). Cytosolic isoenzymes GST-T1 and GST-M1 show a genetic polymorphism in rats and humans, which determines the individual hypersusceptibility to the toxic effects of xenobiotics and the variability in the formation of MA. GSH-S-conjugates are biotransformed to their corresponding MA through several steps, involving the removal of the glutamic acid and then of the glycine. Finally, the residual cystein-S-conjugate is acetylated by a genetically polymorphic acetyltransferase to form a N-acetyl-cystein-S-conjugate or mercapturic acid. The MA metabolic pathway is a process that involves several organs, particularly the liver, the kidney and the small intestine. The intensity of the metabolic processes of these routes in the various organs is strongly dependent of the activities of the involved enzymes and it is different in the various species. As shown by several studies in the last fifteen years, the formation of MA takes place in humans too. Therefore the importance of their use in biological monitoring as internal dose indicators of occupational and environmental exposure to electrophiles appears undoubted.