The hepatic glutathione system--influences of xenobiotics.
The hepatic glutathione (GSH) system and the influences of xenobiotics have been reviewed. Key steps in the regulation of hepatic GSH are GSH biosynthesis, the GSH-peroxidase/reductase cycle, the cystathionine pathway, and the carrier-mediated export processes. Influences of xenobiotics on these different pathways are discussed. Xenobiotics may lead to liver injury after biotransformation to highly reactive electrophilic metabolites (mainly cytochrome P-450 mediated), which easily conjugate with GSH, thus producing GSH depletion. This GSH depletion and probably an additional loss of protein sulfhydryl groups cause a disturbance of the intracellular calcium homeostasis which leads to an irreversible cell injury. The different acinar distribution of cytochromes P-450 and of GSH and GSH-related detoxication pathways points to a greater susceptibility of perivenous hepatocytes to xenobiotic-induced damage. Also, the intracellular compartmentation of GSH is important for the understanding of hepatocellular injury induced by several xenobiotics.
Kretzschmar
M
M
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, GDR.
Klinger
W
W
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002451:Cell Compartmentation / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D015262:Xenobiotics / Q000494:pharmacology*
D015262:Xenobiotics; D005978:Glutathione