Analysis of Pyridyloxobutyl DNA Adducts in F344 Rats Chronically Treated with (R)- and (S)-N'-Nitrosonornicotine

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• 作者：Yanbin Lao ; Nanxiong Yu ; Fekadu Kassie ; Peter W. Villalta ; Stephen S. Hecht
• 刊名：Chemical Research in Toxicology
• 出版年：2007
• 出版时间：February 2007
• 年：2007
• 卷：20
• 期：2
• 页码：246 - 256
• 全文大小：289K
• 年卷期：v.20,no.2(February 2007)
• ISSN：1520-5010

文摘

NNN (1) is an esophageal carcinogen in rats. 2'-Hydroxylation of NNN is believed to be the majorbioactivation pathway for NNN tumorigenicity. (S)-NNN is preferentially metabolized by 2'-hydroxylationin cultured rat esophagus, whereas there is no preference for 2'-hydroxylation versus 5'-hydroxylation inthe metabolism of (R)-NNN. 2'-Hydroxylation of NNN generates the reactive intermediate 4-oxo-4-(3-pyridyl)butanediazohydroxide (8), resulting in the formation of pyridyloxobutyl (POB)-DNA adducts.On the basis of these observations, we hypothesized that (S)-NNN treatment would produce higher levelsof POB-DNA adducts than that by (R)-NNN in the rat esophagus. We tested this hypothesis by treatingmale F344 rats with 10 ppm of (R)-NNN or (S)-NNN in drinking water. After 1, 2, 5, 10, 16, or 20weeks of treatment, POB-DNA adducts in esophageal, liver, and lung DNA were quantified by HPLC-ESI-MS/MS. In the rat esophagus, (S)-NNN treatment generated levels of POB-DNA adducts 3-5 timeshigher than (R)-NNN treatment, which supports our hypothesis. 7-[4-(3-Pyridyl)-4-oxobut-1-yl]guanine(7-POB-Gua, 14) was the major adduct detected, followed by O²-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine(O²-POB-dThd, 11) and O²-[4-(3-pyridyl)-4-oxobut-1-yl]cytosine (POB-Cyt, 15). O⁶-[4-(3-Pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O⁶-POB-dGuo, 10) was not detected. The total POB-DNA adduct levelsin the esophagus were 3-11 times higher than those in the liver for (R)-NNN and 2-6 times higher thanthose for (S)-NNN. In contrast to the esophagus and liver, (R)-NNN treatment produced more POB-DNA adducts than (S)-NNN treatment in the rat lung, which suggested an important role for cytochromeP450 2A3 in NNN metabolism in the rat lung. In both the liver and lung, O²-POB-dThd was thepredominant adduct and accumulated during the experiment. The results of this study demonstrate thatindividual POB-DNA adducts form and persist in the esophagi, livers, and lungs of rats chronicallytreated with NNN enantiomers and demonstrate that (S)-NNN produces higher levels of POB-DNA adductsin the esophagus than (R)-NNN, suggesting that (S)-NNN is more tumorigenic than (R)-NNN to the ratesophagus.