Anesthesiology · 1994
A model for fatal halothane hepatitis in the guinea pig.
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Lind R C, Gandolfi A J, Hall P M
Аннотация
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.
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.