EXPRESSION OF AUTOANTIBODIES TO SPECIFIC CYTOCHROMES P450 IN A CASE OF DISULFIRAM HEPATITIS

Background/Aims: Immunological mechanisms are involved in many adverse drug reactions. In certain forms of drug-induced hepatitis, patients have been reported to express specific autoantibodies to hepatic drug- metabolising enzymes. The alcohol deterrent disulfiram is associated w ith a low frequency of severe liver toxicity, including hepatitis, but the mechanism of the toxicity is unknown. We investigated whether aut oantibodies to cytochrome P450 enzymes were expressed in the serum of a 28-year-old male patient, who developed hepatitis after 7 weeks of d isulfiram treatment and in whom possible causes of hepatitis other tha n disulfiram had been ruled out. Methods: Patient serum IgG reactivity was analysed by immunoblotting or ELISA against test antigens consist ing of recombinant/purified human or rat liver P450 enzymes, or isolat ed rat liver microsomes. Results: A significant serum reactivity was f ound in immunoblotting against human cytochromes P450 1A2 and rat P450 3A1, using serum dilutions of up to 1:900 and 1:2400, respectively. I n contrast, the reactivity against cytochromes P450 2E1, 2C9, 2D6, 3A4 , and rat liver P450 reductase was either very low or undetectable. EL ISA reactivity was low in general, indicating that the P450 epitopes w ere not surface exposed. Immunoblotting of rat liver microsomes reveal ed that autoantibodies recognised one major polypeptide corresponding to P450 3A. Autoantibody titres remained stable for at least 6 months after acute hepatitis. A similar reactivity was not found in any of te n control sera. Conclusions: The expression of autoantibodies directed against specific cytochromes P450 in a case of disulfiram hepatitis s uggests that immunological mechanisms are involved in this adverse dru g reaction, and that these P450 proteins should be evaluated as possib le diagnostic test antigens in disulfiram hepatotoxicity.