MECHANISMS OF DRUG-INDUCED TOXICITIES

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In our studies this year of the mechanism of hepatitis caused by inhalation anesthetics, it was found that 25 of 56 (45%) patients diagnosed with halothane hepatitis have autoantibodies that react with human cytochrome P450 2E1 that was purified from a baculovirus expression system. The autoantibodies inhibited the activity of cytochrome P450 2E1 and appeared to be directed against mainly conformational epitopes. In addition because cytochrome P450 2E1 became trifluoroacetylated when it oxidatively metabolized halothane, it is possible that the covalently altered form of cytochrome P450 2E1 may be able to by-pass the immunologic tolerance that normally exists against cytochrome P450 2E1. A similar mechanism may explain the formation of autoantibodies that have been found against other cellular targets of the reactive trifluoroacetyl chloride metabolite of halothane. We have continued to study the protein adducts of the nonsteroidal antiinflammatory drug diclofenac, in an effort to determine how this widely used drug causes hepatitis. The 50 kDa microsomal covalent adduct of diclofenac found in rat liver was identified last year as male specific cytochrome P4502C11. This year we have found that this enzyme catalyzes its own covalent alteration and inactivation, when it metabolizes diclofenac into a reactive metabolite. It has also been discovered that diclofenac is metabolically activated into a reactive metabolite by another specific form of cytochrome P450 in human liver. Moreover, only a small percent of individuals appear to have sufficient levels of this enzyme in their liver to catalyze the formation of protein adducts of diclofenac, which may be responsible for causing diclofenac hepatotoxicity. These findings suggest that one factor that may predispose a patient to develop diclofenac hepatitis is the expression of high levels of liver cytochrome P450 that metabolically activates this drug.