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Carcinogen-DNA Adduct Formation in the Lungs and Livers of Preweanling CD-1 Male Mice following Administration of [³H]-6-Nitrochrysene, [³H]-6-Aminochrysene, and [³H]-1,6-Dinitropyrene

National Center for Toxicological Research (HFT-110), Jefferson, Arkansas 72079

6-Nitrochrysene (NC) and 6-aminochrysene (AC) have been shown to be potent lung and liver carcinogens when administered in multiple i.p. doses to preweanling mice. 1,6-Dinitropyrene has been shown to be a strong hepatocarcinogen but a weak lung carcinogen in this same bioassay. We have examined carcinogen-DNA adduct profiles in the target tissues of preweanling male CD-1 mice following administration of single or multiple doses of these compounds. Depending on the tissue and the dosing schedule, the total level of DNA modification in animals dosed with [³H]NC was 2- to 9-fold higher than in animals dosed with [³H]AC. Regardless of the dosing schedule, DNA isolated from the lungs and livers of both [³H]NC- and [³H]AC-treated preweanling male mice contained a single major and chromatographically identical adduct. This major adduct, which accounted for as much as 90% of the total carcinogen-DNA adducts in enzymatic hydrolysates from treated animals, was chromatographically distinct from the major C8-purine-substituted adducts formed from the reaction of N-hydroxy-AC with calf thymus DNA. In contrast to the results obtained with NC and AC, the major carcinogen-DNA adduct formed in the livers of mice treated with [³H]-1,6-dinitropyrene was found to cochromatograph with 1-N-(deoxyguanosin-8-yl)amino-6-nitropyrene, a product derived from N-hydroxy-1-amino-6-nitropyrene.

Since NC and its nitro-reduced derivative, AC, yielded an identical carcinogen-DNA adduct in vivo and this adduct was not derived from N-hydroxy-AC, we conclude that the metabolic activation of NC in the neonatal mouse must involve some previously undescribed combination of ring-oxidation and nitro-reduction pathways. This activation pathway could be an important factor in determining the potency of NC and AC as carcinogens in this bioassay system.

¹ Supported in part by an interagency agreement between the Veterans Administration Hospital, Little Rock, AR and the Department of Health and Human Services, Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR. To whom requests for reprints should be addressed.

Received 6/ 8/87. Revised 8/24/87. Accepted 8/26/87.

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