DNA-ADDUCTS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE (IQ) IN COLON,BLADDER, AND KIDNEY OF CONGENIC MICE DIFFERING IN AH RESPONSIVENESS AND N-ACETYLTRANSFERASE GENOTYPE

Heterocyclic amines, suspected as cancer initiators, require metabolic activation to exert genotoxicity. The food carcinogen 2-amino-3-methy limidazo[4,5-f]quinoline (IQ) undergoes activation via N-hydroxylation by cytochrome P450 1A2, followed by O-esterification by N-acetyltrans ferase. We examined the effects of the Ah locus and acetylator polymor phisms (implicated in human colon and bladder cancer risk) on levels o f P-32-postlabeled IQ-DNA adducts in C57BL/6 mice congenic for slow ac etylation acid/or Ah nonresponsiveness. Some were pretreated with beta -naphthoflavone (beta NF), an inducer of cytochromes P450 1A. Guanine adducts were detected in all organs, the predominant one corresponding to N-2-(deoxyguanosin-8-yl)-IQ. In the kidney, beta NF pretreatment r educed total adducts by 50% in Ah-responsive animals (P = 0.021); the Ah or acetylator phenotype did not otherwise affect total adducts. In the colon of Ah-nonresponsive animals, rapid acetylators had 3-fold mo re adducts than slow acetylators (P = 0.0001, vehicle-pretreated; P = 0.0031, beta NF-pretreated). In Ah-responsive mice of either acetylato r phenotype, beta NF pretreatment reduced total adducts in the colon b y 70% (P = 0.0003). A significant interaction of phenotypes occurred i n the bladder; beta NF-pretreatment caused a 2.5-fold increase in addu cts but only in the Ah-responsive, rapid acetylator mice. In sum, thes e polymorphisms influenced the level of IQ-DNA adducts in the kidney, urinary bladder, and colon in complex ways.