MOLECULAR-STRUCTURE AND HEPATOTOXICITY - COMPARED DATA ABOUT 2 CLOSELY-RELATED THIOPHENE COMPOUNDS

Two closely related compounds, a diuretic drug tienilic acid (TA) and its isomer TAI have been found to exert very different toxic effects, In human liver microsomes TA is oxidized mainly by CYP 2C9 with format ion of a reactive metabolite which covalently binds to CYP 2C9 in a ra ther specific manner, On the contrary, CYP 2C9-dependent oxidation of TAI leads to reactive metabolite(s) causing an intense covalent bindin g to several microsomal proteins, Based on these very different behavi ours and fates of TA and TAI metabolites, it is proposed that the dire ct hepatotoxic effects of TAI could be due to an intense, non-specific covalent binding of its reactive metabolite(s) to liver proteins, whe reas the toxic effects of the immunoallergic type of TA could be due t o the very specific covalent binding of its sulfoxide metabolite to CY P 2C9.