A study of the mechanism of halothane-induced liver necrosis. Role of covalent binding of halothane metabolites to liver proteins in the rat.

Various anesthetic and nonanesthetic doses of [1-14C]halothane were administered separately to normal and phenobarbital-pretreated (PBP) rats by ip route. The rats were sacrificed at 0.5-24 h after dosing, and livers were removed and examined histopathologically for tissue necrosis. Only PBP rats that received anesthetic doses of halothane (11.5 or 23 mmol/kg) and sacrificed 24 h after dosing exhibited liver toxicity. Determination of the radioactivity distribution among various liver macromolecules revealed that the protein fraction contained the highest activity at all time points in all animals. The lipid fraction showed some radioactivity during the initial 1-6 h period which disappeared after 6-8 h, while the DNA fraction was devoid of radioactivity in all animals injected with [14C]halothane. All the PBP rats that exhibited liver necrosis consistently attained higher covalent binding of halothane metabolites to liver proteins (2.13-2.20 nmol/mg of protein) when compared with the protein binding (1.12-1.41 nmol/mg of protein) observed among the rats that did not exhibit liver toxicity during the same time period. These results suggest a correlation between covalent binding of halothane metabolites to liver proteins and halothane-induced liver necrosis.