用烟草特异性亚硝胺代谢物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇对大鼠进行慢性对映体处理后，大鼠体内吡啶基羟丁基和吡啶基氧代丁基DNA磷酸加合物的形成。
Pyridylhydroxybutyl and pyridyloxobutyl DNA phosphate adduct formation in rats treated chronically with enantiomers of the tobacco-specific nitrosamine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol.
作者信息
Ma Bin, Zarth Adam T, Carlson Erik S, Villalta Peter W, Stepanov Irina, Hecht Stephen S
机构信息
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
出版信息
Mutagenesis. 2017 Dec 31;32(6):561-570. doi: 10.1093/mutage/gex031.
The tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is metabolically converted to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in a reaction which is both stereoselective and reversible. NNAL is also a lung carcinogen, with both (R)-NNAL and (S)-NNAL inducing a high incidence of lung tumours in rats. Both NNAL and NNK undergo metabolic activation to intermediates which react with DNA to form pyridylhydroxybutyl and pyridyloxobutyl DNA adducts, respectively. DNA adduct formation by NNAL and NNK is an important step in their mechanisms of carcinogenesis. In this study, we quantified both pyridylhydroxybutyl and pyridyloxobutyl DNA phosphate adducts in the lung of rats treated with 5 ppm of (R)-NNAL or (S)-NNAL in drinking water for 10, 30, 50 and 70 weeks. In (R)-NNAL-treated rats, the pyridylhydroxybutyl and pyridyloxobutyl phosphate adducts were 4530-6920 fmol/mg DNA and 46-175 fmol/mg DNA, accounting for 45-51% and 0.3-1% of the total measured DNA phosphate and base adducts, respectively. In (S)-NNAL-treated rats, the two types of phosphate adducts were 3480-4180 fmol/mg DNA and 1180-4650 fmol/mg DNA, accounting for 30-36% and 11-38% of the total adducts, respectively. Distinct patterns of adduct formation were observed, with higher levels of NNAL-derived pyridylhydroxybutyl phosphate adducts and lower levels of NNK-derived pyridyloxobutyl phosphate adducts in the (R)-NNAL treatment group than the (S)-NNAL group. The persistence and increase over time of certain pyridylhydroxybutyl phosphate adducts over the course of the study suggest that these adducts could be useful biomarkers of chronic exposure to NNAL and NNK. The results of this study provide important new information regarding DNA damage by NNAL and NNK, and contribute to understanding mechanisms of tobacco-related carcinogenesis.
烟草特异性肺致癌物4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮(NNK)在一个既具有立体选择性又可逆的反应中代谢转化为4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁醇(NNAL)。NNAL也是一种肺致癌物，(R)-NNAL和(S)-NNAL均可在大鼠中诱发高发性肺肿瘤。NNAL和NNK都会代谢活化为中间体，这些中间体分别与DNA反应形成吡啶基羟基丁基和吡啶基氧代丁基DNA加合物。NNAL和NNK形成DNA加合物是其致癌机制中的重要一步。在本研究中，我们对饮用水中添加5 ppm (R)-NNAL或(S)-NNAL处理10、30、50和70周的大鼠肺中的吡啶基羟基丁基和吡啶基氧代丁基DNA磷酸加合物进行了定量。在(R)-NNAL处理的大鼠中，吡啶基羟基丁基和吡啶基氧代丁基磷酸加合物分别为4530 - 6920 fmol/mg DNA和46 - 175 fmol/mg DNA，分别占所测DNA磷酸加合物和碱基加合物总量的45 - 51%和0.3 - 1%。在(S)-NNAL处理的大鼠中，这两种磷酸加合物分别为3480 - 4180 fmol/mg DNA和1180 - 4650 fmol/mg DNA，分别占总加合物的30 - 36%和11 - 38%。观察到不同的加合物形成模式，(R)-NNAL处理组中源自NNAL的吡啶基羟基丁基磷酸加合物水平高于(S)-NNAL组，而源自NNK的吡啶基氧代丁基磷酸加合物水平低于(S)-NNAL组。在研究过程中，某些吡啶基羟基丁基磷酸加合物的持续存在和随时间增加表明，这些加合物可能是慢性暴露于NNAL和NNK的有用生物标志物。本研究结果提供了关于NNAL和NNK引起的DNA损伤的重要新信息，并有助于理解烟草相关致癌作用的机制。
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