A model for fatal halothane hepatitis in the guinea pig.
BACKGROUND
In the guinea pig, depleting hepatic glutathione before inhaling subanesthetic 0.1% halothane increases covalent binding of halothane biotransformation intermediates to hepatic protein and potentiates resultant liver injury. Because inhalation of a higher concentration of halothane is known to produce greater levels of covalent binding than with subanesthetic halothane, this study was undertaken with 0.25-1.0% halothane concentrations to further examine glutathione depletion as an etiology for halothane hepatitis.


METHODS
Male Hartley guinea pigs were injected intraperitoneally with either vehicle control solution (Veh) or 1.6 g/kg buthionine sulfoximine (BSO), to decrease hepatic glutathione by > 80%, 24 h before a 4-h exposure to 0.25%, 0.5%, or (v/v) halothane with 40% O2. Some BSO-pretreated animals also received 2.0 g/kg glutathione monoethyl ester (GEE), intraperitoneally, 2 h before inhaling halothane to replenish hepatic glutathione.


RESULTS
Glutathione-depleted animals developed significantly worse hepatic injury with each halothane concentration. One-third to one-half of BSO+halothane-treated animals developed fatal submassive to massive hepatic necrosis. Covalent binding of halothane intermediates to hepatic protein increased by 45% in BSO + 1.0% halothane-treated guinea pigs. Administration of GEE to BSO-pretreated animals before 1.0% halothane decreased binding to protein and blunted development of liver necrosis. Following Veh + 1.0% halothane, hepatic glutathione was found to be decreased by 60%.


CONCLUSIONS
Glutathione would appear to help protect hepatocytes to some degree from covalent binding by reactive halothane biotransformation intermediates. These studies present the first animal model to produce fatal halothane-induced hepatic necrosis.
Lind
R C
RC
Department of Anesthesiology, College of Medicine, University of Arizona, Tucson.
Gandolfi
A J
AJ
Hall
P M
PM
D000818:Animals; D019328:Buthionine Sulfoximine; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006221:Halothane / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009336:Necrosis
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D006221:Halothane