Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs.
Reduced glutathione has a potential role in protecting the liver against the reactive acyl acid chloride intermediate generated during the oxidative biotransformation of halothane. Glutathione is also important in maintaining the integrity of an injured cell. Thus, the effect of decreased hepatic glutathione concentrations on covalent binding of halothane metabolic intermediates to hepatic protein and lipid and the resultant hepatic injury were investigated in male, outbred Hartley guinea pigs. The animals were injected with either 1.6 g.kg-1 dl-buthionine-S,R-sulfoximine to deplete hepatic glutathione or vehicle-control solution 24 h before exposure to 0.1% (subanesthetic) halothane for 4 h (fractional inspired oxygen tension = 0.40). Buthionine sulfoximine pretreatment depleted liver glutathione concentrations by 85% at the time of halothane exposure, without affecting the degree of halothane biotransformation or causing hepatic injury. Glutathione depletion caused a significant increase in the level of organic fluorine covalently bound to hepatic protein but not lipid after halothane exposure. Glutathione-depleted animals also exhibited a significant enhancement of hepatotoxicity after halothane exposure; plasma isocitrate dehydrogenase activity was 25-fold greater than the increase observed 48 h after exposure in animals treated with vehicle plus halothane, and the incidence and severity of hepatic injury were significantly greater, as observed by light microscopic examination of tissue 96 h after exposure. These findings are in agreement with a previously proposed mechanism of halothane-associated hepatotoxicity in guinea pigs and indicate that hepatic glutathione status may play an important role in the susceptibility of patients to halothane-induced liver injury.
Lind
R C
RC
Department of Anesthesiology, University of Arizona, College of Medicine, Tucson 85724.
Gandolfi
A J
AJ
Hall
P M
PM
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D005978:Glutathione / Q000502:physiology*; D006168:Guinea Pigs; D006221:Halothane / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology
D000963:Antimetabolites; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D006221:Halothane