Bioactivation of the food mutagen 2-amino-3-methyl-imidazo[4,5-f]quinoline(IQ) by prostaglandin-H synthase and by monooxygenases: DNA adduct analysis

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is a known multisite carcinoge n in rodents and a potent mutagen in acetyltransferase-proficient Salmonell a typhimurium strains on activation by either monooxygenases (MFO) or by pr ostaglandin H synthase (PHS). The primary metabolites formed by MFO- or PHS -mediated IQ-oxidation are different (Wolz et al., 1995), but secondary met abolism could ultimately result in the same DNA-binding intermediates. For further investigations, the DNA adduct pattern was now studied by means of P-32-postlabelling analysis in vitro on PHS-activation and compared to that formed on MFO-mediated activation of IQ in hepatocytes. The C8-dG-IQ-adduc t N-(deoxyguanosin-8-yl)-IQ was the major adduct in all samples, that is, i n DNA isolated from S. typhimurium YG1024 treated with PHS-oxidized IQ or i ts nitro-derivative, from ovine seminal vesicle cells, and from hepatocytes exposed to IQ or nitro-IQ. This speaks for the formation of a common DNA-r eactive species, presumably an arylnitrenium ion, generated by different pa thways in these cellular model systems. The similarity of critical biochemi cal DNA lesions suggests that PHS can contribute to the bioactivation of IQ in vivo: this is of particular interest in extrahepatic tissues since expr ession of cytochrome P450 isoenzymes known to be involved in the N-oxidatio n of IQ is largely confined to the liver. (C) 2000 Elsevier Science Ltd. Al l rights reserved.