Molecular structure and hepatotoxicity: compared data about two closely related thiophene compounds

Abstract

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 formation of a reactive metabolite which covalently binds to CYP 2C9 in a rather specific manner. On the contrary, CYP 2C9-dependent oxidation of TAI leads to reactive metabolite(s) causing an intense covalent binding to several microsomal proteins. Based on these very different behaviours and fates of TA and TAI metabolites, it is proposed that the direct hepatotoxic effects of TAI could be due to an intense, non-specific covalent binding of its reactive metabolite(s) to liver proteins, whereas the toxic effects of the immunoallergic type of TA could be due to the very specific covalent binding of its sulfoxide metabolite to CYP 2C9.