MECHANISMS OF HALOTHANE TOXICITY - NOVEL INSIGHTS

Exposure of individuals to halothane causes, in 20% of patients, a mil d form of hepatotoxicity. In contrast, a very small subset of individu als only develops halothane hepatitis, which is thought to have an imm unological basis. Sera of halothane hepatitis patients contain antibod ies directed against some discrete liver trifluoroacetyl (TFA)-protein adducts, which arise upon oxidative biotransformation of halothane an d include protein disulfide isomerase, microsomal carboxylesterase, ca lreticulin, ERp72, GRP 78 and ERp99. No immune response occurs in the majority of human individuals, although evidence suggests that TFA-pro tein adducts arise in all halothane-exposed individuals. The lack of i mmunological responsiveness of individuals might be due to tolerance, induced by a presumed repertoire of self-peptides that molecularly mim ic TFA-protein adducts. Thus, constitutively expressed proteins of 52 and 64 kDa have been identified that confer molecular mimicry of TFA-p rotein adducts. The 64 kDa protein corresponds to the E2 subunit of th e mitochondrial pyruvate dehydrogenase complex. Lipoic acid, the prost hetic group of the E2 subunit, is involved in the molecular mimicry pr ocess. A fraction of halothane hepatitis patients exhibit irregulariti es in the expression levels of the 52 kDa protein and the E2 subunit p rotein. Molecular mimicry of TFA-protein adducts by the 52 kDa protein and the E2 subunit protein might play a role in the susceptibility of individuals to development of halothane hepatitis.