Ahr locus phenotype in congenic mice influences hepatic and pulmonary DNA adduct levels of 2-amino-3-methylimidazo[4,5-f]quinoline in the absence of cytochrome P450 induction.

The potent food mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) undergoes metabolic N-hydroxylation by cytochromes P450, including cytochrome P450 1A2, followed by generation of an unstable ester catalyzed by acetyltransferases; promutagenic DNA adducts result. Genetic polymorphisms in these enzymes have been implicated in human cancer risk related to arylamine exposure. We investigated the effects of Ahr locus and acetylator polymorphisms on 32P-postlabeled IQ/DNA adducts in lungs and livers of female C57BL/6 mice congenic for slow acetylation and/or Ahr-nonresponsiveness; some groups were pretreated with beta-naphthoflavone (beta NF), a cytochrome P450 1A inducer. Total adducts in lung were doubled by beta NF pretreatment in Ahr-responsive mice only and consisted of < or = 30% adduct 2 and < or = 60% adduct 3. In contrast, in Ahr-nonresponsive mice, adducts 2 and 3 were each < or= 7% of the total. Livers of noninduced Ahr-responsive mice formed 6-18-fold more adducts than those of nonresponsive mice. This striking difference was not due to altered levels of cyp1a-2, as indicated by specific enzyme assays and immunoblotting, and was not accompanied by a comparable increase in the ability of liver preparations to activate IQ to a mutagen in the Ames test. Pretreatment of responsive mice with beta NF to induce cyp1a-1 and cyp1a-2 led to a reduction in liver adduct levels. Acetylation phenotype also had a significant effect in Ahr-responsive mice, with 3-fold more adducts in slow than in rapid acetylators. These results indicate that in uninduced mice, the normal Ah receptor facilitates formation of IQ/DNA adducts in liver and alters the profile of adducts in lung, via an unknown mechanism, whereas the Ah receptor-dependent enzyme induction reduces adducts in liver, probably due to increased detoxification, but increases them in lung.