用 N'-亚硝基降烟碱对大鼠进行慢性处理后，用质谱法定量分析吡啶烷酮基丁烷 DNA 磷酸盐加合物。
Mass Spectrometric Quantitation of Pyridyloxobutyl DNA Phosphate Adducts in Rats Chronically Treated with N'-Nitrosonornicotine.
机构信息
Masonic Cancer Center , University of Minnesota , Minneapolis , Minnesota 55455 , United States.
Beijing Key Laboratory of Environmental and Virus Oncology, College of Life Science and Bioengineering , Beijing University of Technology , Beijing 100124 , China.
出版信息
Chem Res Toxicol. 2019 Apr 15;32(4):773-783. doi: 10.1021/acs.chemrestox.9b00007. Epub 2019 Feb 26.
The tobacco-specific carcinogens N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) require metabolic activation to exert their carcinogenicity. NNN and NNK are metabolized to the same reactive diazonium ions, which alkylate DNA forming pyridyloxobutyl (POB) DNA base and phosphate adducts. We have characterized the formation of both POB DNA base and phosphate adducts in NNK-treated rats and the formation of POB DNA base adducts in NNN-treated rats. However, POB DNA phosphate adducts in NNN-treated rats are still uncharacterized. In this study, we quantified the levels of POB DNA phosphate adducts in tissues of rats chronically treated with ( S)-NNN or ( R)-NNN for 10, 30, 50, and 70 weeks during a carcinogenicity study. The highest amounts of POB DNA phosphate adducts were observed in the esophagus of the ( S)-NNN-treated rats, with a maximum level of 5400 ± 317 fmol/mg DNA at 50 weeks. The abundance of POB DNA phosphate adducts in the esophagus was consistent with the results of the carcinogenicity study showing that the esophagus was the primary site of tumor formation from treatment with ( S)-NNN. Compared to the ( R)-NNN group, the levels of POB DNA phosphate adducts were higher in the oral mucosa, esophagus, and liver, while lower in the nasal mucosa of the ( S)-NNN-treated rats. Among 10 combinations of all isomers of POB DNA phosphate adducts, Ap(POB)C and combinations with thymidine predominated across all the rat tissues examined. In the primary target tissue, esophageal mucosa, Ap(POB)C accounted for ∼20% of total phosphate adducts in the ( S)-NNN treatment group throughout the 70 weeks, with levels ranging from 780 ± 194 to 1010 ± 700 fmol/mg DNA. The results of this study showed that POB DNA phosphate adducts were present in high levels and persisted in target tissues of rats chronically treated with ( S)- or ( R)-NNN. These results improve our understanding of DNA damage during NNN-induced carcinogenesis. The predominant POB DNA phosphate isomers observed, such as Ap(POB)C, may serve as biomarkers for monitoring chronic exposure of tobacco-specific nitrosamines in humans.
烟草特异性致癌物质 N'-亚硝基降烟碱（NNN）和 4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮（NNK）需要代谢激活才能发挥其致癌性。NNN 和 NNK 被代谢为相同的反应性重氮离子，这些离子烷基化 DNA，形成吡啶基氧丁基（POB）DNA 碱基和磷酸加合物。我们已经描述了 NNK 处理的大鼠中 POB DNA 碱基和磷酸加合物的形成，以及 NNN 处理的大鼠中 POB DNA 碱基加合物的形成。然而，NNN 处理的大鼠中的 POB DNA 磷酸加合物仍未得到表征。在这项研究中，我们在致癌性研究中，用（S）-NNN 或（R）-NNN 慢性处理大鼠 10、30、50 和 70 周后，定量分析了组织中 POB DNA 磷酸加合物的水平。在（S）-NNN 处理的大鼠中，食管中 POB DNA 磷酸加合物的含量最高，在 50 周时达到 5400±317 fmol/mg DNA。食管中 POB DNA 磷酸加合物的丰度与致癌性研究结果一致，表明从（S）-NNN 处理中，食管是肿瘤形成的主要部位。与（R）-NNN 组相比，（S）-NNN 处理的大鼠口腔黏膜、食管和肝脏中的 POB DNA 磷酸加合物水平较高，而鼻腔黏膜中的 POB DNA 磷酸加合物水平较低。在所有 POB DNA 磷酸加合物的 10 种异构体组合中，Ap（POB）C 和以胸苷为主的组合在所有检测的大鼠组织中均占优势。在主要靶组织食管黏膜中，在整个 70 周的（S）-NNN 处理组中，Ap（POB）C 占总磷酸加合物的约 20%，水平范围为 780±194 至 1010±700 fmol/mg DNA。这项研究的结果表明，（S）-或（R）-NNN 慢性处理的大鼠靶组织中存在高水平的 POB DNA 磷酸加合物，并持续存在。这些结果提高了我们对 NNN 诱导的致癌过程中 DNA 损伤的认识。观察到的主要 POB DNA 磷酸异构体，如 Ap（POB）C，可能作为监测人类烟草特异性亚硝胺慢性暴露的生物标志物。
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