Identification and mutagenicity of metabolites of aristolochic acid formed by rat liver

The rat liver 9000 g supernatant mediated metabolism of thecarcinogenic aristolochic acid, which consists of aristolochicacid I (AAI) and aristolochic acid II (AAII), was investigated.Under anaerobic conditions the major metabolites were the correspondingaristolactams for both AAI and AAII. In contrast under aerobicconditions AAII was not detectably metabolized and the onlymetabolite found for AAI was the O-demethylated derivative aristolochicacid la (AAIa). The metabolites were identified by their u.v.,mass and n.m.r. spectra and by comparison with reference standards.The mutagenic activities of the three metabolites were determinedin Salmonella typhimurium strains TA1537 and TA 100. The aristolactamswere mutagenic in both strains when a metabolizing system waspresent. These results indicate that AAI or AAII and their aristolactamsexert their effect via a common reactive intermediate, probablythe corresponding hydroxylamine. AAIa was only very weakly mutagenicand this metabolite may therefore not be regarded as a majormutagenic metabolite of AAI. These findings suggest that theacids are preferentially metabolized by two totally differentpathways in vitro, namely an oxidative pathway for AAI and areductive pathway for AAII.