Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane‐associated hepatitis.

Abstract

1. Previous studies have demonstrated the presence of antibodies to trifluoroacetylated hepatic proteins (TFA‐proteins) in sera from patients with the severe form of halothane‐associated hepatitis (halothane hepatitis). The TFA‐proteins are produced via cytochrome P450‐mediated metabolism of halothane to the reactive species TFA‐ chloride. 2. To investigate the presence of autoantibodies (which recognize various non‐TFA‐modified human hepatic polypeptides) in patients with halothane hepatitis immunoblotting experiments were performed using microsomal fractions prepared freshly from livers of five different (halothane‐free) tissue donors. Blots were developed using 15 well‐characterised sera from patients with halothane hepatitis. 3. Autoantibodies to human hepatic polypeptides were detected in most, but not all, of the patients' sera. The pattern of antibody reactivity varied markedly between sera. Although no common pattern of antibody recognition was observed, polypeptides of molecular mass between 60 and 80 kDa were the predominant targets. A similar protein recognition pattern was seen when each positive serum was tested against the five individual human liver samples. 4. Such autoantibodies were not detected in sera from 16 normal human blood donors, but were detected in three of six sera from patients exposed to halothane without developing hepatitis. 5. The autoantibodies are thought to arise in patients exposed to halothane as a consequence of a halothane‐induced immune response to chemically‐modified proteins. Such antibodies could contribute to the complex pathological processes involved in halothane hepatitis.

Inflammation and Drug Idiosyncrasy—Is There a Connection?

“…This hypothesis has become a "default assumption", typically based on the lack of obvious relationship of the reaction to drug dose and on observations that some patients don't experience reactions until they have been treated with the drug for a period long enough to develop antibodies. For a few drugs, autoantibodies to drug-protein adducts have been detected in serum of patients, but the role of these in causing idiosyncratic reactions remains questionable (Kitteringham et al, 1995). Halothane hepatotoxicity is one of the most widely studied reactions.…”

Role of Drug Disposition in Drug Hypersensitivity: A Chemical, Molecular, and Clinical Perspective

“…Antibodies of the IgG class have been detected in sera of patients with hepatitis and are directed against the trifluoroacetyl antigen and against natural antigens on microsomal proteins (34), thus demonstrating the ability of drug (metabolite) conjugation to break tolerance to self-proteins. Human P4502E1 is one of a number of major autoantigens (35).…”

The identification of toxicophores for the prediction of mutagenicity, hepatotoxicity and cardiotoxicity

“…Thus, foreign compounds can undergo biotransformation to metabolites that have intrinsic chemical reactivity toward cellular macromolecules. The propensity of a molecule to form such chemically reactive metabolites is a function of its chemistry, and structural alerts are well defined [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. The versatility of cytochrome P450 together with the reactivity of its oxygen intermediates enables it to functionalize even relatively inert substrates, leading to the formation of chemically reactive species.…”

“…Halothane is the best-studied drug with respect to immunoallergic hepatitis (see Fig. 17) [46,47]. The drug undergoes bioactivation in hepatocytes leading to drug-protein conjugate formation, through the modification of lysine residues in target proteins such as CYP 2E1 (P450), in the liver, increasing transaminase levels.…”