Identification of O2-Substituted Pyrimidine Adducts Formed in Reactions of 4-(Acetoxymethylnitrosamino)- 1-(3-pyridyl)-1-butanone and 4-(Acetoxymethylnitros- amino)-1-(3-pyridyl)-1-butanol with DNA

• DOI: 10.1021/tx034263t
• Publication Date: 2004-05-17T13:53:11Z
• Authors: Stephen S. Hecht; Peter W. Villalta; Shana J. Sturla; Guang Cheng; Nanxiong Yu; Pramod Upadhyaya; Mingyao Wang
• Keywords: Hydroxylation

Metabolic hydroxylation of the methyl group tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) results in formation intermediates that can alkylate DNA. Similarly, metabolic 2'-position N'-nitrosonornicotine gives DNA alkylating intermediates. The resulting pyridyloxobutyl pyridylhydroxybutyl adducts with dGuo have been characterized, but there are no reports pyrimidine adducts. Therefore, this study, we investigated reactions 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKCH(2)OAc) 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanol (NNALCH(2)OAc) DNA, dCyd, dThd. NNKCH(2)OAc NNALCH(2)OAc stable precursors to products formed upon NNK NNAL. Analysis by LC-ESI-SIM enzyme hydrolysates had allowed react demonstrated presence major dCyd were thermally unstable, releasing 4-HPB (18) or 4-hydroxy-1-(3-pyridyl)-1-butanol (25) treatment at 100 degrees C, pH 7.0. dThd under these conditions. adduct was characterized MS UV conversion neutral thermal hydrolysis corresponding Cyt adduct, which identified MS, UV, NMR. similarly characterized. Treatment NaBH(4) gave material, identical produced reaction These data demonstrate O(2)[4-(3-pyridyl)-4-oxobut-1-yl]dCyd (26) O(2)[4-(3-pyridyl)-4-oxobut-1-yl]dThd (30) while those from O(2)[4-(3-pyridyl)-4-hydroxybut-1-yl]dCyd (28) andO(2)[4-(3-pyridyl)-4-hydroxybut-1-yl]dThd (31). Levels substantially greater than NNKCH(2)OAc, based on peak area. Furthermore, 26 as a NNKCH(2)OAc. suggest nitrosamines may be important contributors their mutagenic carcinogenic activity.