Characterization of hypoxic model for halothane hepatotoxicity

The two most critical variables necessary to initiate halothane induced liver injury are induction of the hepatic biotransformation enzyme system and a reduced inspired oxygen concentration, which results in an increased rate of halothane biotransformation by the reductive, hepatotoxic pathway. Additional evidence implicating halothane bioactivation as a causative factor is indicated by the inhibition of the lesion by pretreatment of rats with inhibitors of drug metabolism. At present the hypoxic model does not completely correlate with the reported clinical cases of fulminating liver injury following halothane anesthesia. The lesion that develops in rat liver rapidly repairs and does not progress to liver failure. Also, female rats appear resistant. The latter problem has been partially resolved by pretreatment of female rats with testosterone a hormone necessary for maximal microsomal cytochrome P-450 mediated reactions in both male and female rats. Some progress has also been made at prolonging the duration of liver injury by inhibition of liver repair processes with inhibitors of protein synthesis. However, it should be stressed that only a small percentage of animals would be expected to develop progressive liver failure and that only a small number have been studied longer than 2 days post exposure. Perhaps the most exciting finding is the inhibition of lesion development by post-anesthetic treatment with sulfhydryl containing compounds. Cystamine, cysteine and N-acetylcysteine produced nearly complete inhibition when administered 4 hours after end of anesthesia and afford partial protection 8 hours post anesthesia.