Biotransformation and hepatotoxicity of HCFC-123 in the guinea pig: potentiation of hepatic injury by prior glutathione depletion.
The chlorofluorocarbon substitute 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) is a structural analog of halothane. Both are oxidatively metabolized by CYP2EI, producing a reactive trifluoroacyl acid chloride intermediate and have been shown to cause acute liver necrosis in the guinea pig. With halothane, liver injury has been associated with the degree of reactive intermediate binding to hepatic protein. This injury can be potentiated by prior glutathione (GSH) depletion. Thus, the combination of GSH depletion and HCFC-123 exposure was evaluated for its hepatotoxic potential in this species. Male outbred Hartley guinea pigs were injected with either 0.8 g/kg l-buthionine-(S,R)-sulfoximine (BSO) to deplete hepatic glutathione or vehicle control solution 24 hr before a 4-hr inhalation exposure to 1.0% (v/v) HCFC-123 with 40% O2. HCFC-123 caused minimal liver injury with only 1 of 8 exposed animals displaying confluent zone 3 necrosis. GSH depletion potentiated injury producing submassive to massive liver necrosis in some animals. This potentiation was associated with a 36% increase in covalent binding of reactive HCFC-123 intermediates to hepatic protein. These results were not due to alterations in the biotransformation of HCFC-123 as indicated by plasma concentrations of the metabolites trifluoroacetic acid and fluoride ion which were not affected by BSO pretreatment. HCFC-123 was also found to cause a decrease in liver GSH concentrations following exposure. These findings demonstrate a role for hepatic GSH in helping to prevent covalent binding by the trifluoroacyl acid chloride intermediate. Inhalation of HCFC-123 can cause acute hepatic injury in the guinea pig that is worsened by low hepatic GSH concentrations.
Lind
R C
RC
Department of Anesthesiology, College of Medicine, University of Arizona, Tucson 85724, USA.
Gandolfi
A J
AJ
Hall
P D
PD
D000818:Animals; D001273:Atmosphere Exposure Chambers; D001711:Biotransformation; D017402:Chlorofluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D064227:Chlorofluorocarbons, Ethane; D004357:Drug Synergism; D005978:Glutathione / Q000172:deficiency*; D006168:Guinea Pigs; D007521:Isocitrate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis
D017402:Chlorofluorocarbons; D064227:Chlorofluorocarbons, Ethane; C067411:2,2-dichloro-1,1,1-trifluoroethane; D007521:Isocitrate Dehydrogenase; D005978:Glutathione