AHR LOCUS PHENOTYPE IN CONGENIC MICE INFLUENCES HEPATIC AND PULMONARYDNA 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]quino line (IQ) undergoes metabolic N-hydroxylation by cytochromes P450, inc luding cytochrome P450 1A2, followed by generation of an unstable este r catalyzed by acetyltransferases; promutagenic DNA adducts result. Ge netic polymorphisms in these enzymes have been implicated in human can cer risk related to arylamine exposure. We investigated the effects of Ahr locus and acetylator polymorphisms on P-32-postlabeled IQ/DNA add ucts in lungs and livers of female C57BL/6 mice congenic for slow acet ylation and/or Ahr-nonresponsiveness; some groups were pretreated with beta-naphthoflavone (beta NF), a cytochrome P450 1A inducer. Total ad ducts in lung were doubled by beta NF pretreatment in Ahr-responsive m ice only and consisted of less than or equal to 30% adduct 2 and less than or equal to 60% adduct 3. In contrast, in Ahr-nonresponsive mice, adducts 2 and 3 were each less than or equal to 7% of the total. Live rs of noninduced Ahr-responsive mice formed 6-18-fold more adducts tha n 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 t he ability of liver preparations to activate IQ to a mutagen in the Am es test. Pretreatment of responsive mice with beta NF to induce cyp1a- 1 and cyp1a-2 led to a reduction in liver adduct levels. Acetylation p henotype also had a significant effect in Ahr-responsive mice, with 3- fold more adducts in slow than in rapid acetylators. These results ind icate that in uninduced mice, the normal Ah receptor facilitates forma tion of IQ/DNA adducts in liver and alters the profile of adducts in l ung, via an unknown mechanism, whereas the Ah receptor-dependent enzym e induction reduces adducts in liver, probably due to increased detoxi fication, but increases them in lung.