MOLECULAR MIMICRY IN HALOTHANE HEPATITIS - BIOCHEMICAL AND STRUCTURALCHARACTERIZATION OF LIPOYLATED AUTOANTIGENS

Exposure of human individuals to halothane causes, in about 20% of all cases, a mild transient form of hepatotoxicity. A small subset of exp osed individuals, however, develops a potentially severe and life-thre atening form of hepatic damage, coined halothane hepatitis. Halothane hepatitis is thought to have an immunological basis. Sera of afflicted individuals contain a wide variety of autoantibodies against hepatic proteins, in both trifluoroacetylated form (CF3CO-proteins) and, at le ast in part, in native form. CF3CO-proteins are elicited in the course of oxidative biotransformation of halothane, and include the trifluor oacetylated forms of protein disulfide isomerase, microsomal carboxyle sterase, calreticulin, ERp72, GRP 78, and ERp99. Current evidence sugg ests that CF3CO-proteins arise in all halothane-exposed individuals; h owever, the vast majority of individuals appear to immunochemically to lerate CF3CO-proteins. The lack of immunological responsiveness of the se individuals towards CF3CO-proteins might be due to tolerance, induc ed through the occurrence of structures in the repertoire of self-dete rminants, which immunochemically and structurally mimic CF3CO-proteins very closely. In fact,lipoic acid, the prosthetic group of the consti tutively expressed E2 subunits of the family of mammalian 2-oxoacid de hydrogenase complexes and of protein X, was shown by immunochemical an d molecular modelling analysis to be a perfect structural mimic of N-6 -trifluoroacetyl-L-lysine (CF3 CO-Lys), the major haptenic group of CF 3CO-proteins. As a consequence of molecular mimicry, autoantibodies in patients' sera not only recognize CF3CO-proteins, but also the E2 sub unit proteins of the 2-oxoacid dehydrogenase complexes and protein X, as autoantigens associated with halothane hepatitis. Furthermore, a fr action of patients with halothane hepatitis exhibit irregularities in the hepatic expression levels of these native, not trifluoroacetylated autoantigens. Collectively, these data suggest that molecular mimicry of CF3CO-Lys by lipoic acid, or the impairment thereof, might play a role in the susceptibility of individuals for the development of halot hane hepatitis.