title: Mechanisms of halothane toxicity: novel insights.
abstract: Exposure of individuals to halothane causes, in 20% of patients, a mild form of hepatotoxicity. In contrast, a very small subset of individuals only develops halothane hepatitis, which is thought to have an immunological basis. Sera of halothane hepatitis patients contain antibodies directed against some discrete liver trifluoroacetyl (TFA)-protein adducts, which arise upon oxidative biotransformation of halothane and include protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78 and ERp99. No immune response occurs in the majority of human individuals, although evidence suggests that TFA-protein adducts arise in all halothane-exposed individuals. The lack of immunological responsiveness of individuals might be due to tolerance, induced by a presumed repertoire of self-peptides that molecularly mimic TFA-protein adducts. Thus, constitutively expressed proteins of 52 and 64 kDa have been identified that confer molecular mimicry of TFA-protein adducts. The 64 kDa protein corresponds to the E2 subunit of the mitochondrial pyruvate dehydrogenase complex. Lipoic acid, the prosthetic group of the E2 subunit, is involved in the molecular mimicry process. A fraction of halothane hepatitis patients exhibit irregularities in the expression levels of the 52 kDa protein and the E2 subunit protein. 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.
authors.affiliation: Department of Pharmacology, the University, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Gut
authors.forename: U
authors.initials: U
authors.lastname: Christen
authors.forename: J
authors.initials: J
authors.lastname: Huwyler
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000503:physiopathology; D006221:Halothane / Q000378:metabolism / Q000633:toxicity*; D006801:Humans
chemical_list: D006221:Halothane