Halothane hepatotoxicity in glutathione depleted rats.
Experimental models for halothane hepatotoxicity require microsomal enzyme induction by phenobarbital or triiodo-thyronine pretreatment and hypoxic conditions. The role of GSH in the metabolism of halothane, however, is still unclear. We therefore pretreated male rats with phorone to deplete hepatic GSH, phenobarbital as a microsomal enzyme inducer and exposed them to halothane 1% for 4 h under hypoxia (10% O2). Increases in serum enzyme activities of alanine aminotransferase (GPT) and sorbitol dehydrogenase (SDH) were observed 24 and 48 h later. Histomorphological examinations showed centrilobular hepatic necrosis. In GSH-depleted rats the increments of serum enzyme activities and histomorphological alterations were significantly aggravated as compared with controls. In this model (+)-catechin protected against halothane-induced hepatotoxicity as evidenced by reduced serum enzyme elevations and morphological alterations whereas diethyldithiocarbamate failed to exert any protective effects. Free fluoride concentrations in plasma was used as an index of the non-oxidative defluorination of halothane. Increased plasma fluoride levels were observed under conditions which evoked hepatotoxicity but did not correlate with the protective effect of (+)-catechin. Our experimental data indicate that glutathione might be involved in the non-oxidative metabolic pathways of halothane. Furthermore, (+)-catechin seems capable of protecting against the direct toxic effect of halothane metabolites resulting from the reductive pathways.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005459:Fluorides / Q000097:blood; D005978:Glutathione / Q000172:deficiency*; D006221:Halothane / Q000633:toxicity*; D007659:Ketones / Q000494:pharmacology; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
D007659:Ketones; C018637:phorone; D003577:Cytochrome P-450 Enzyme System; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D005978:Glutathione; D005459:Fluorides; D006221:Halothane