The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a powerful lung carcinogen in animal models and is considered a causative factor for lung cancer in tobacco users. NNK is stereoselectively and reversibly metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also a lung carcinogen. Both NNK and NNAL undergo metabolic activation by α-hydroxylation on their methyl groups to form pyridyloxobutyl and pyridylhydroxybutyl DNA base and phosphate adducts, respectively. α-Hydroxylation also occurs on the α-methylene carbons of NNK and NNAL to produce methane diazohydroxide, which reacts with DNA to form methyl DNA base adducts. DNA adducts of NNK and NNAL are important in their mechanisms of carcinogenesis. In this study, we characterized and quantified methyl DNA phosphate adducts in the lung of rats treated with 5 ppm of NNK, (S)-NNAL, or (R)-NNAL in drinking water for 10, 30, 50, and 70 weeks, by using a novel liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry method. A total of 23, 21, and 22 out of 32 possible methyl DNA phosphate adducts were detected in the lung tissues of rats treated with NNK, (S)-NNAL, and (R)-NNAL, respectively. Levels of the methyl DNA phosphate adducts were 2290-4510, 872-1120, and 763-1430 fmol/mg DNA, accounting for 15-38%, 8%, and 5-9% of the total measured DNA adducts in rats treated with NNK, (S)-NNAL, and (R)-NNAL, respectively. The methyl DNA phosphate adducts characterized in this study further enriched the diversity of DNA adducts formed by NNK and NNAL. These results provide important new data regarding NNK- and NNAL-derived DNA damage and new insights pertinent to future mechanistic and biomonitoring studies of NNK, NNAL, and other chemical methylating agents.

中文翻译：

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长期用4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮及其代谢物对映体4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇对甲基丙烯酸磷酸酯加合物的形成。

烟草特有的亚硝胺4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）在动物模型中是一种强大的肺癌致癌物，被认为是烟草使用者肺癌的致病因素。NNK立体选择性和可逆地代谢为4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇（NNAL），这也是一种肺致癌物。NNK和NNAL均通过其甲基上的α-羟基化反应进行代谢活化，分别形成吡啶基氧丁基和吡啶基羟丁基DNA碱基和磷酸盐加合物。NNK和NNAL的α-亚甲基碳上也会发生α-羟基化反应，生成甲烷重氮氢氧化物，该甲烷重氮氢氧化物与DNA反应形成甲基DNA碱基加合物。NNK和NNAL的DNA加合物在其致癌机制中很重要。在这项研究中，我们通过使用一种新型药物，在饮用水中用5 ppm NNK，（S）-NNAL或（R）-NNAL处理10、30、50和70周的大鼠，对肺中的甲基DNA磷酸加合物进行了表征和定量液相色谱-纳米电喷雾电离-高分辨率串联质谱法。在分别用NNK，（S）-NNAL和（R）-NNAL处理的大鼠的肺组织中，分别检测到32种可能的甲基DNA磷酸加合物中的23种，21种和22种。甲基DNA磷酸加合物的水平为2290-4510、872-1120和763-1430 fmol / mg DNA，分别占接受过磷酸酶处理的大鼠中测得的DNA加合物总量的15-38％，8％和5-9％。 NNK，（S）-NNAL和（R）-NNAL。在这项研究中表征的甲基DNA磷酸加合物进一步丰富了NNK和NNAL形成的DNA加合物的多样性。