Quantitation of Pyridyloxobutyl-DNA Adducts in Tissues of Rats Treated Chronically with (R)- or (S)-N鈥?Nitrosonornicotine (NNN) in a Carcinogenicity Study

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• 作者：Lijiao Zhao ; Silvia Balbo ; Mingyao Wang ; Pramod Upadhyaya ; Samir S. Khariwala ; Peter W. Villalta ; Stephen S. Hecht
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：October 21, 2013
• 年：2013
• 卷：26
• 期：10
• 页码：1526-1535
• 全文大小：548K
• 年卷期：v.26,no.10(October 21, 2013)
• ISSN：1520-5010

文摘

We quantified DNA adducts resulting from 2鈥?hydroxylation of enantiomers of the tobacco-specific nitrosamine N鈥?nitrosonornicotine (NNN) in tissues of male F-344 rats after 10, 30, 50, and 70 weeks of treatment with 14 ppm in the drinking water. These rats were in subgroups of a carcinogenicity study in which (S)-NNN was highly tumorigenic in the oral cavity and esophagus, while (R)-NNN was relatively weakly active. DNA adducts were quantified by liquid chromatography鈥揺lectrospray ionization鈥搕andem mass spectrometry in six tissues: oral mucosa, esophageal mucosa, nasal respiratory mucosa, nasal olfactory mucosa, liver, and lung. O²-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O²-POB-dThd, 7) and 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2鈥?deoxyguanosine (7-POB-dGuo, 8), the latter as 7-[4-(3-pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua, 11), were detected at each time point in each tissue. In the target tissues for carcinogenicity, oral mucosa and esophageal mucosa, levels of 7-POB-Gua (11) and O²-POB-dThd (7) were similar, or 11 predominated, while in all other tissues at all time points for both enantiomers, 7 was clearly present in greater amounts than 11. Total measured DNA adduct levels in esophageal mucosa and oral mucosa were higher in rats treated with (S)-NNN than (R)-NNN. The highest adduct levels were found in the nasal respiratory mucosa. DNA adducts generally persisted in all tissues without any sign of substantial decreases throughout the 70 week time course. The results of this study suggest that inefficient repair of 7-POB-dGuo (8) in the rat oral cavity and esophagus may be important in carcinogenesis by NNN and support the development of these DNA adducts as potential biomarkers of NNN metabolic activation in people who use tobacco products.