HUMAN CYTOCHROME-P450 2E1 IS A MAJOR AUTOANTIGEN ASSOCIATED WITH HALOTHANE HEPATITIS

Autoantibodies against specific human cytochrome P450s have been found in the sera of patients suffering from a variety of diseases, includi ng those caused by drugs. in the cases of tienilic acid- and dihydrala zine-induced hepatitis, patients have serum autoantibodies directed ag ainst cytochromes P450 2C9 and P450 1A2, respectively. In the present study, we have found that 25 of 56 (45%) patients diagnosed with halot hane hepatitis have autoantibodies that react with human cytochrome P4 50 2E1 that was purified from a baculovirus expression system. The aut oantibodies inhibited the activity of cytochrome P450 2E1 and appeared to be directed against mainly conformational epitopes. In addition, b ecause cytochrome P450 2E1 became trifluoroacetylated when it oxidativ ely metabolized halothane, it is possible that the covalently altered form of cytochrome P450 2E1 may be able to bypass the immunologic tole rance that normally exists against cytochrome P450 2E1. A similar mech anism may explain the formation of autoantibodies that have been found against other cellular targets of the reactive trifluoroacetyl chlori de metabolite of halothane.