Molecular basis of halothane hepatitis.

Abstract

The formation of covalent adducts to cellular macromolecules, including proteins, phospholipids, and DNA or RNA, is associated with the exposure of humans and animals (most probably to any given living organism) to a large number of xenobiotics, including drugs as well as occupational and environmental pollutants (Hinson and Roberts, 1992; Park and Kitteringham, 1990; Nelson and Pearson, 1990). Only few parent compounds form, based on their intrinsic chemical reactivity, such adducts spontaneously; the majority of compounds do form adducts to cellular macromolecules only after metabolic activation to reactive intermediates (Park and Kitteringham, 1990; vanWelie et al., 1992). From an immunological point of view, adducted cellular target molecules constitute “modified self” or even “non-self” structures, which might provoke immune responses against themselves (Allison 1989; deWeck 1983). In general, low molecular mass organic compounds (<l000 Da), such as most drugs, are thought to be non-immunogenic per se. However, many of these compounds (coined haptens) may become immunogenic, when covalently linked to a macromolecular carrier such as a protein. Once formed, drug-carrier conjugates might act as immunogens and elicit immune responses at the humoral level, at the cellular level, or at both levels (Allison 1989; deWeck 1983). These immune responses might be directed against at least three different types of antigenic determinants. First, haptenic epitopes may include the derivative of the xenobiotic (i.e. hapten) bound to the carrier molecule. Second, new antigenic determinants (NAD) may comprise newly created linear or conformational structures on the carrier molecule elicited upon binding of the hapten to the carrier molecule. Last, cryptic autoantigenic determinants of the carrier molecule, which normally are seen as self or are ignored, could bypass the mechanisms of immunological self-tolerance as a consequence of hapten binding (Allison, 1989; Blooksma and Schuurman, 1989; Roitt et al., 1985). An immunological basis for the development, in susceptible individuals, of a number of severe, sometimes life-threatening adverse effects after therapeuticKeywordsLipoic AcidProtein Disulfide IsomeraseMolecular MimicryOctanoic AcidPyruvate Dehydrogenase ComplexThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.