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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

Laboratory of Comparative Carcinogenesis, National Cancer Institute [P. V. N., L. M. A., J. M. R.], and Data Management Services, Inc. [C. W. R.], Frederick Cancer Research and Development Center, Frederick, Maryland 21702; Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699 [H. A. J. S.]; Laboratory of Experimental Carcinogensis, National Cancer Isntitute, Bethesda, Maryland 20892 [E. G. S., S. S. T.]; and Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109 [W. W. W., G. N. L.]

Heterocyclic amines, suspected as cancer initiators, require metabolic activation to exert genotoxicity. The food carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) undergoes activation via N-hydroxylation by cytochrome P450 1A2, followed by O-esterification by N-acetyltransferase. We examined the effects of the Ah locus and acetylator polymorphisms (implicated in human colon and bladder cancer risk) on levels of ³²P-postlabeled IQ-DNA adducts in C57BL/6 mice congenic for slow acetylation and/or Ah nonresponsiveness. Some were pretreated with ß-naphthoflavone (ßNF), an inducer of cytochromes P450 1A. Guanine adducts were detected in all organs, the predominant one corresponding to N²-(deoxyguanosin-8-yl)-IQ. In the kidney, ßNF pretreatment reduced 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 more adducts than slow acetylators (P = 0.0001, vehicle-pretreated; P = 0.0031, ßNF-pretreated). In Ah-responsive mice of either acetylator phenotype, ßNF pretreatment reduced total adducts in the colon by 70% (P = 0.0003). A significant interaction of phenotypes occurred in the bladder; ßNF-pretreatment caused a 2.5-fold increase in adducts but only in the Ah-responsive, rapid acetylator mice. In sum, these polymorphisms influenced the level of IQ-DNA adducts in the kidney, urinary bladder, and colon in complex ways.

¹ To whom requests for reprints should be addressed, at Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Building 538, Room 205E, Frederick, MD 21702-1201.

Received 1/23/95. Accepted 5/16/95.

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