长期接受4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮和（S）-4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇处理的F344大鼠肺和肝脏中的线粒体DNA加合物
Mitochondrial DNA adducts in the lung and liver of F344 rats chronically treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and (S)-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol.
作者信息
Stepanov Irina, Hecht Stephen S
机构信息
Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.
出版信息
Chem Res Toxicol. 2009 Feb;22(2):406-14. doi: 10.1021/tx800398x.
Two recent studies conducted in our laboratory have demonstrated formation and accumulation of pyridyloxobutyl (POB) and pyridylhydroxybutyl (PHB) adducts in lung and liver total DNA of F344 rats chronically treated with the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and (R)- and (S)-enantiomers of its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we measured POB and PHB adducts in lung and liver mitochondrial DNA (mtDNA), as previous studies suggest a potentially important role of mtDNA in carcinogenesis. Rats were sacrificed after 1, 2, 5, 10, 16, and 20 weeks of treatment with 10 ppm of NNK or (S)-NNAL in drinking water, and mtDNA and nuclear DNA (nDNA) adduct levels in the lung and liver were determined by LC-ESI-MS/MS-SRM. The mean levels of individual POB adducts in mtDNA at all time points were slightly higher than those in nDNA for both NNK and (S)-NNAL-treated rats in the lung (P < 0.001 for both treatments) but not in the liver (P > 0.05). Lung mtDNA of both NNK- and (S)-NNAL-treated rats contained higher concentrations of the sum of three POB adducts (P < 0.001 for both treatments) than nDNA, while the levels of mtDNA and nDNA total POB adducts in the liver were not significantly different in either NNK- or (S)-NNAL-treated rats. Analysis of PHB adducts in mtDNA and nDNA produced results similar to those obtained for POB adducts. The steady accumulation of the lung and liver mtDNA adducts over the course of the study indicates inefficient repair of these adducts in mtDNA. This is the first study to examine the formation of NNK- and (S)-NNAL-derived adducts in rat mtDNA. The results support the hypothesis that preferential binding of tobacco carcinogens to mtDNA of the lung might be functionally important in the development of smoking-induced lung cancer.
我们实验室最近进行的两项研究表明，在长期用烟草特异性致癌物4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮（NNK）及其代谢物4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁醇（NNAL）的（R）-和（S）-对映体处理的F344大鼠的肺和肝脏总DNA中，吡啶氧基丁基（POB）和吡啶基羟基丁基（PHB）加合物形成并积累。在本研究中，我们测量了肺和肝脏线粒体DNA（mtDNA）中的POB和PHB加合物，因为先前的研究表明mtDNA在致癌过程中可能起重要作用。在用饮用水中10 ppm的NNK或（S）-NNAL处理1、2、5、10、16和20周后处死大鼠，并通过LC-ESI-MS/MS-SRM测定肺和肝脏中mtDNA和核DNA（nDNA）加合物水平。在所有时间点，对于肺中NNK和（S）-NNAL处理的大鼠，mtDNA中单个POB加合物的平均水平略高于nDNA中的水平（两种处理均P < 0.001），但在肝脏中并非如此（P > 0.05）。NNK和（S）-NNAL处理的大鼠的肺mtDNA中三种POB加合物总和的浓度均高于nDNA（两种处理均P < 0.001），而在NNK或（S）-NNAL处理的大鼠中，肝脏中mtDNA和nDNA总POB加合物水平无显著差异。对mtDNA和nDNA中PHB加合物的分析产生了与POB加合物相似的结果。在研究过程中，肺和肝脏mtDNA加合物的稳定积累表明mtDNA中这些加合物的修复效率低下。这是第一项研究大鼠mtDNA中NNK和（S）-NNAL衍生加合物形成的研究。结果支持这样的假设，即烟草致癌物与肺mtDNA的优先结合在吸烟诱导的肺癌发生中可能在功能上很重要。
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