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

Abstract

The rat liver 9000 g supernatant mediated metabolism of the carcinogenic aristolochic acid, which consists of aristolochic acid I (AAI) and aristolochic acid II (AAII), was investigated. Under anaerobic conditions the major metabolites were the corresponding aristolactams for both AAI and AAII. In contrast under aerobic conditions AAII was not detectably metabolized and the only metabolite found for AAI was the O-demethylated derivative aristolochic acid Ia (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 determined in Salmonella typhimurium strains TA1537 and TA 100. The aristolactams were mutagenic in both strains when a metabolizing system was present. These results indicate that AAI or AAII and their aristolactams exert their effect via a common reactive intermediate, probably the corresponding hydroxylamine. AAIa was only very weakly mutagenic and this metabolite may therefore not be regarded as a major mutagenic metabolite of AAI. These findings suggest that the acids are preferentially metabolized by two totally different pathways in vitro, namely an oxidative pathway for AAI and a reductive pathway for AAII.

Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi)

“…4 This herb contains aristolochic acids, a mixture of nitrophenanthrene derivatives known for their potent carcinogenic action in rats 5 and their mutagenic properties in bacterial 6 and mammalian 7 models. Moreover, Schmeiser et al were able to detect DNA adducts formed by metabolites of aristolochic acid (aristolactams) in samples of kidneys removed from five patients with Chinese-herb nephropathy.…”

Liquid chromatography—tandem mass spectrometry analysis of the DNA adducts of aristolochic acids

“…However, aristolactams were found not to be mutagenic and required exogenous metabolic°activation° [28].°Instead,°a°cyclic°aristolactam-nitrenium ion with a delocalized positive charge is generally believed to be the ultimate carcinogen (Scheme°1)°[9,°11,°12,°17,°18].°Electrophilic°attack°of aristolactam-nitrenium ion by its C7 position to the exocyclic amino group in the purine bases led to the major°adducts°[4°-12,°16° -18].…”

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

“…These include the microsomal enzymes NADPH: cytochrome P450 reductase (Stiborová et al, 2001c(Stiborová et al, , 2005a, prostaglandin H synthase (Stiborová et al, 2001a(Stiborová et al, , 2005a, and CYP1A1/2 under anaerobic conditions (Schmeiser et al, 1986;Stiborová et al, 2001bStiborová et al, , 2005b. Cytoplasmic enzymes implicated in AA activation include NAD(P)H:quinone oxidoreductase (Stiborová et al, 2002(Stiborová et al, , 2003(Stiborová et al, , 2005a and sulfotransferase A1 (Meinl et al, 2006).…”