Immunologic Idiosyncrasy

The clinico-pathologic features of some idiosyncratic drug reactions suggest that immunological mechanisms could play an important role in the pathogenesis of drug hepatotoxicity. These include (a) fever, rash, lymphadenopathy, eosinophilia and involvement of other organs; (b) hepatic inflammatory infiltrates; (c) low frequency (<1/ 1000 users); (d) delay in appearance of the disease (2 weeks to several months); and (e) accelerated onset after rechallenge (Beaune and Lecoeur, 1997; Robin et al., 1997). In hepatitis secondary to sulphonamides, phenytoin and nitrofurantoin, the liver is implicated as part of a systemic hypersen-sitivity reaction, and evidence for immunological responsiveness to these drugs can be obtained by in vitro rechallenge with the drug or its metabolite (Spielberg et al., 1981; Shear and Spielberg, 1988; Rieder et al., 1989). Interestingly, the immune response may not be directed at the drug per se, but at compounds arising as a result of its metabolism. Drug hepatotoxicity may therefore be the result of both metabolic and immunological idiosyncrasy. In this respect the superimposition of cytochrome P-450 and the immune system in the liver has potential disadvantages. The covalent binding of the reactive metabolites to "self" proteins results in the formation of neoantigens that "mislead" the immune system into mounting an immune response against hepatocytes.

The initial and crucial event underlying so-called immuno-allergic hepatitis is the oxidative metabolism of a drug by a cytochrome P-450 enzyme resulting in the formation of reactive metabolites. Electrophilic metabolites react with and covalently bind to nucleophilic groups of proteins to form protein adducts. The best-studied example is that of halothane which is oxidised into a reactive acyl chloride (CF3COCl) by cytochrome P450 2E1. The metabolite reacts with the e-NH2 group of the lysine residues of proteins to form trifluoroacety-

lated proteins (CF3CO-lysine proteins) (Gut et al., 1993). The reactive metabolite may also bind covalently to the CYP 2E1 protein itself (Eliasson and Kenna, 1996). Alkylation of cytochrome P450 proteins may lead both to anti-P450 autoanti-bodies and to antibodies against the modified part of the protein. Therefore a single drug such as halothane may concomitantly give rise to both ''immuno-allergic'' as well as "autoimmune" hepatitis.

Factors Influencing Immunologically Mediated Drug Hepatotoxicity

Genetic factors influencing the development of immune-mediated drug hepatotoxicity can be grouped into factors affecting the amount of the reactive metabolite and therefore protein adduct formed and factors affecting the immune response to the adducts. Dihydralazine hepatitis is a good example of how a ''metabolic'' genetic factor can contribute to susceptibility to immune-mediated hepatotoxicity. Dihydralazine is predominantly acetylated by the polymorphic N-acetyl transferase 2. In slow acetylators, the majority of the drug is available for metabolic activation by CYP 1A2 into a free radical. The alkylation of hepatic proteins is more extensive and the incidence of immunemediated hepatitis is higher (Bourdi et al., 1994).

The second group of genetic factors influencing susceptibility to immune-mediated hepatic drug reactions is the genes whose products are involved in immune regulation. Genetic polymorphism in major histocompatibility complex (MHC) molecules is the most obvious example. The presence or absence of a given human leukocyte antigen (HLA) molecule may determine the efficient presentation of an alkylated immunogenic peptide. Associations have been reported between HLA A11 and hepatotoxicity due to halothane, tricyclic antide-pressants and diclofenac, HLA DR6 and liver injury secondary to chlorpromazine and nitrofur-antoin, HLA B8 and clometacine hepatitis (Berson et al., 1994). More recently, the often serious co-amoxiclav-induced jaundice has been strongly associated with HLA DRB1 *1501-DQA1 *0102-DQB1 *0602 haplotype in the northern European population (Hautekeete et al., 1999).

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