Mutagenicity and in vitro covalent DNA binding of 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline.

The 2-hydroxyamino-3-methylimidazolo[4,5-f]quinoline (N-hydroxy-IQ), a metabolite of the food mutagen--carcinogen IQ, was mutagenic to Salmonella TA98 (nitroreductase deficient). When either rat hepatic cytosol, NADPH (1 mM) or ascorbate (0.5 mM) was added to the mutagenicity assay, mutagenicity increased up to 15-, 10- and 50-fold respectively. In light of the effects of ascorbate and NADPH, it appears likely that hepatic cytosol may contain factors that protect N-hydroxy-IQ from oxidative decomposition. In contrast, hepatic monooxygenase metabolism of N-hydroxy-IQ decreased mutagenicity. When pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, was added to the mutagenicity assay, a dose-dependent inhibition of N-hydroxy-IQ mutagenicity was observed. 2,6-Dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O- acetyltransferase, did not inhibit the mutagenicity of N-hydroxy-IQ at concentrations which appear to selectively inhibit only bacterial sulfotransferase. The data suggest that bacterial O-acetyltransferase rather than sulfotransferase mutagenically activates N-hydroxy-IQ. N-hydroxy-IQ covalently bound to calf thymus DNA in vitro under non-enzymatic conditions at pH 7.4. Rat hepatic cytosolic O-acetyltransferase and sulfotransferase enhanced the covalent binding of N-hydroxy-IQ to DNA 30- and 5-fold respectively. The data suggest that the mutagenicity of N-hydroxy-IQ is due to the reactivity of N-hydroxy-IQ with DNA and the ability of N-hydroxy-IQ to be further activated by bacterial O-acetyltransferase.