Genetic differences in reductive metabolism and hepatotoxicity of halothane in three rat strains.
The relationship between the reductive metabolism of halothane and hepatotoxicity was examined in three rat strains (Fischer 344, Sprague-Dawley, and black hooded Wistar) to determine if there were genetic differences in 1) the reductive metabolism of halothane under identical exposure conditions, and 2) the susceptibility to the hepatotoxic effects of halothane. Halothane hepatotoxic was produced in all rat strains by exposing phenobarbital-pretreated rats  to 1 per cent halothane under mild hypoxia (14 per cent oxygen, inspired) for 2 h. Generally the levels of both 2-chloro-1,1,1-trifluoroethane (CTF) and 2-chloro-1,1-difluoroethylene (CDF), two volatile metabolites of halothane, increased from the onset of anesthetic exposure and reached a plateau after approximately 60 min. The exception to this trend were phenobarbital-pretreated Wistar rats (exposed to 1 per cent halothane with 14 per cent oxygen) where the levels of either CDF or CTF were high initially (10-min sample) and decreased in subsequent samples to reach a plateau after 80 min. The plateau levels of both CDF (approximately 6 ppm) and CTF (approximately 20 ppm) were not significantly different among the three rat strains exposed to halothane (1 per cent) and hypoxia with prior enzyme induction. There were, however, significant differences in both biochemical and pathological changes among the three strains exposed under the above identical conditions when the rats were killed 24 h after anesthetic exposure. For example, serum alanine aminotransferase (ALT) was increased fourfold in the Fischer strain but only doubled for the other two strains. Moreover, while all three strains had various amounts of hepatocyte damage in the vicinity of the central veins when the rats were exposed to halothane, hypoxia, and enzyme induction, only the Fischer strain showed hepatocyte damage under the exposure conditions of halothane (1 per cent) and normoxia (21 per cent oxygen, inspired) with prior enzyme induction. The results support the role of reductive metabolism of halothane in the etiology of halothane hepatotoxicity. Furthermore, they suggest that genetic variations in the susceptibility of the liver to the reactive intermediates or metabolites formed during reductive metabolism of halothane may be a significant factor in halothane hepatotoxicity.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D017402:Chlorofluorocarbons; D004790:Enzyme Induction; D005030:Ethylenes / Q000032:analysis; D014644:Genetic Variation; D006221:Halothane / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000032:analysis; D000860:Hypoxia / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics*
D017402:Chlorofluorocarbons; D005030:Ethylenes; D006846:Hydrocarbons, Halogenated; C016800:1,1,1-trifluoro-2-chloroethane; D000410:Alanine Transaminase; C018483:2-chloro-1,1-difluoroethylene; D006221:Halothane; D010634:Phenobarbital