Characterization and properties of the DNA adducts formed from N-methyl-4-aminoazobenzene in rats during a carcinogenic treatment regimen |
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Authors: | Tullis, D.L. Dooley, K.L. Miller, D.W. Baetcke, K.P. Kadlubar, F.F. |
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Affiliation: | National Center for Toxicological Research, Jefferson, AR 72079 and University of Arkansas for Medical Sciences Little Rock, AR 72205, USA 1Present address: Department of Chemistry, University of Arkansas at Little Rock Little Rock, AR 72205, USA 2Present address: Health and Environmental Review Division, US Environmental Protection Agency Washington, DC 20460, USA |
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Abstract: | Chronic oral administration of the carcinogenic aminoazo dyeN-methyl-4-aminoazobenzene (MAB) to rats is known to resultin the induction of liver tumors. In order to assess the roleof carcinogen-DNA adduct formation in MAB hepatocarcinogenesis,male rats were fed 0.06% [3'-3H]MAB in the diet for 1, 3 or5 weeks. Groups were sacrificed at 0, 24 and 72 h after dosing,and DNA was isolated from the liver and from two non-targettissues, the kidney and spleen. Upon enzymatic hydrolysis ofthe DNA, [3H]aminoazo dye-nucleoside adduct levels in thesetissues were determined by h.p.l.c. Rats concurrently administeredunlabeled MAB for 5 weeks and continued on a control diet for9 months developed hepatocellular carcinomas (16/30 animals).No tumors were observed in 21 rats given only control diets.After chronic administration of [3H]MAB, three major MAB-DNAadducts were found in vivo: N-(deoxyguanosin-8-yl)-MAB (C8-dG-MAB),3-(deoxyguanosin-N2-yl)-MAB (N2-dG-MAB) and 3-(deoxyadenosin-N6-yl)-MAB(N6-dA-MAB). In addition, several minor products were identifiedas: (i) an (8,9)-purine ring-opened derivative of C8-dG-MABthat may represent an intermediate in DNA repair; (ii) N-guanosin-8-yl-MABwhich is present due to trace RNA contamination; (iii) cis isomersof C8-dG-MAB and N-guanosin-8-yl-MAB, formed by photo-illuminationduring analyses; and (iv) N-(guanin-8-yl)-MAB, a deribosylatedproduct resulting from thermal depurination of C8-dG-MAB. Inaddition, N-(deoxyguanosin-8-yl)-4-aminoazobenzene (C8-dG-AB),a major adduct previously detected in mouse liver after a singledose of 4-aminoazobenzene, was found in rat liver but appearedto be present in significant amounts only after chronic treatmentwith MAB. This product co-chromatographed with N6-dA-MAB butcould be removed by selective decomposition in 0.1 N NaOH. Forall tissues examined N2-dG-MAB and C8-dG-MAB were the majoradducts observed with each accounting for 40-50% of the totalcarcinogen bound to DNA in rats that were sacrificed immediatelyafter MAB feeding for 1, 3 or 5 weeks. The levels of total MAB-DNAadducts in the liver were 210 times greater than in thekidney or spleen and appeared to increase 2- to 3-fold overthe dosing period. However, by 2472 h after cessationof MAB treatment, hepatic C8-dG-MAB showed a rapid decline tolevels similar to that found in non-target tissues. The minoradducts, N6-dA-MAB and C8-dG-AB, exhibited similar behaviorand never accounted for > 510% of the total DNA binding.In contrast, hepatic N2-dG-MAB was a persistent lesion throughoutthe treatment regimen; at 72 h after dosing, it accounted for6090% of the hepatic DNA adducts and was the only adductwhose levels correlated with target tissue specificity aftera complete hepatocarcinogenic dose of MAB. |
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