当前位置: X-MOL 学术Chem. Res. Toxicol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Methyl DNA Phosphate Adduct Formation in Rats Treated Chronically with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2017-11-30 , DOI: 10.1021/acs.chemrestox.7b00281
Bin Ma 1 , Adam T Zarth 1 , Erik S Carlson 1 , Peter W Villalta 1 , Pramod Upadhyaya 1 , Irina Stepanov 1 , Stephen S Hecht 1
Affiliation  

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:


长期用 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮及其代谢物 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁醇对映体治疗的大鼠中甲基 DNA 磷酸加合物的形成。



烟草特有的亚硝胺 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 在动物模型中是一种强效肺癌致癌物,被认为是烟草使用者肺癌的致病因素。 NNK 立体选择性且可逆地代谢为 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁醇 (NNAL),这也是一种肺癌致癌物。 NNK 和 NNAL 均通过其甲基上的 α-羟基化进行代谢活化,分别形成吡啶氧丁基和吡啶羟丁基 DNA 碱基和磷酸加合物。 NNK 和 NNAL 的 α-亚甲基碳上也会发生 α-羟基化,生成重氮甲烷,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发挥着重要作用。在这项研究中,我们对用饮用水中 5 ppm NNK、(S)-NNAL 或 (R)-NNAL 处理 10、30、50 和 70 周的大鼠肺部的甲基 DNA 磷酸加合物进行了表征和定量。采用新型液相色谱-纳流电喷雾电离-高分辨率串联质谱方法。在用 NNK、(S)-NNAL 和 (R)-NNAL 治疗的大鼠肺组织中,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,占 15-38%、8% 和 5-9%。分别为 NNK、(S)-NNAL 和 (R)-NNAL。本研究表征的甲基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。 这些结果提供了有关 NNK 和 NNAL 衍生的 DNA 损伤的重要新数据,以及与 NNK、NNAL 和其他化学甲基化剂的未来机制和生物监测研究相关的新见解。
更新日期:2017-11-30
down
wechat
bug