Halothane-induced liver injury in outbred guinea pigs: Role of trifluoroacetylated protein adducts in animal susceptibility

Halothane causes a mild form of liver injury in guinea pigs that appears to model the hepatotoxicity seen in approximately 20% of patients treated wit h this drug. In previous studies, it was concluded that the increased susce ptibility of some outbred guinea pigs to halothane-induced liver injury is not caused by their inherent ability to metabolize halothane to form toxic levels of trifluoroacetylated protein adducts in the liver. In this study, we reevaluated the role of trifluoroacetylated protein adducts in halothane -induced liver injury in guinea pigs. Male outbred Hartley guinea pigs were treated with halothane intraperitoneally. On the basis of serum alanine am inotransferase levels and liver histology, treated animals were designated as being susceptible, mildly susceptible, or resistant to halothane, Immuno blot studies with the use of anti-trifluoroacetylated antibodies showed tha t susceptible guinea pigs for the most part had higher levels of trifluoroa cetylated protein adducts in the liver 48 h after treatment with halothane than did less susceptible animals. In support of this finding, the level of trifluoroacetylated protein adducts detected immunochemically in the sera of treated guinea pigs correlated with sera levels of alanine aminotransfer ase activity. In addition, the levels of cytochrome P450 2A-related protein but not those of other cytochrome P450 isoforms, measured by immunoblot an alysis with isoform-specific antibodies, correlated with the amount of trif luoroacetylated protein adducts detected in the livers of guinea pigs 8 h a fter halothane administration. The results of this study indicate that the susceptibility of outbred guinea pigs to halothane-induced liver injury is related to an enhanced ability to metabolize halothane in the liver to form relatively high levels of trifluoroacetylated protein adducts, They also s uggest that cytochrome P450 BA-related protein might have a major role in c atalyzing the formation of trifluoroacetylated protein adducts in the liver of susceptible guinea pigs. Similar mechanisms may be important in humans.