Case reports of idiosyncratic enflurane hepatitis and an apparent cross-sensitization between halothane and enflurane exposure have suggested to us that the oxidative metabolism of enflurane to a reactive acylating intermediate might produce covalently bound protein adducts which act as antigens, similar to those implicated in the genesis of halothane hepatitis. Use of immunoblotting and enzyme linked immunosorbent assay techniques revealed that several microsomal protein adducts that react with an anti-trifluoroacetyl (TFA) hapten antibody were formed in rat liver after halothane, enflurane, or isoflurane administration. The relative extents of adduct formation were halothane much greater than enflurane much greater than isoflurane and correlated with the relative rates of metabolism of these drugs. Moreover, antibodies found in the serum of patients with fulminant hepatic necrosis induced by halothane, recognized these adducts. These studies indicate that a common molecular mechanism involving potentially immunogenic, covalently bound metabolites may be responsible for the idiosyncratic hepatitis seen after enflurane in patients sensitized to halothane. Moreover, they also suggest that the relatively safe inhalation anesthetic, enflurane, probably should not be administered to patients that have been sensitized previously to halothane or enflurane.
