Metabolism of NNK among African Americans

肺癌在非洲裔美国人中比在欧洲裔美国人中更普遍， 吸烟是这两个群体的主要危险因素。烟草特有的亚硝胺是最常见的 烟草制品中的致癌物质。这些化合物中最普遍的一种，4- （甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK），存在于未燃烧的烟草和香烟烟雾中，在实验室动物中是一种非常有效的肺致癌物，能不依赖于给药途径诱发啮齿类动物的肺肿瘤。NNK的代谢产物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇（NNAL）也是一种肺部致癌物，其血清水平与吸烟者的肺癌有关。代谢和DNA加合物的形成是NNK诱发肿瘤的关键。我们的目标是了解观察到的肺癌发病率的种族/人种差异是否是由于NNK代谢的变化。我们的总体假设是，癌症易感性与致癌物剂量以及致癌物代谢活性和解毒活性之间的平衡有关。我们的具体目标是： 1)对NNK代谢活化和解毒的尿生物标志物进行全面分析， 非裔美国人和欧洲裔美国人吸烟者。这项研究建立在我们最近开发的 基于使用氘标记的NNK的方法。 2)非裔美国人和欧洲裔美国人吸烟者口腔粘膜脱落细胞DNA的测量 由于NNK代谢活化而形成的加合物。这对于理解 NNK代谢产物的尿排泄与NNK DNA结合程度之间的关系。未来这个 平衡可以作为人类癌症易感性的直接指标。 3)研究口腔粘膜细胞中测量的NNK衍生DNA加合物水平与受试者培养的淋巴细胞中这些加合物的修复率之间的关系。这项研究将补充在具体目标1和2中取得的成果。 总之，这些实验的结果将提供关于NNK代谢活化和解毒的差异以及NNK衍生的DNA加合物的形成和非裔美国人和欧洲裔美国人中相关DNA修复能力的令人兴奋的新数据。这也将有助于检验NNK致癌机制的差异与人类肺癌易感性相关的总体假设。

Lung cancer is more prevalent in African Americans as compared to European Americans, and cigarette smoking is the major risk factor in both these groups. Tobacco-specific nitrosamines are among the most significant carcinogens in tobacco products. One ofthe most prevalent of these compounds, 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is present in both unburned tobacco and cigarette smoke, and is a remarkably effective lung carcinogen in laboratory animals, inducing lung tumors in rodents independent ofthe route of administrafion. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of NNK, is also a pulmonary carcinogen, and its serum levels are related to lung cancer in smokers. Metabolism and DNA adduct formafion are crifical in cancer inducfion by NNK. Our goal is to understand whether the observed ethnic/racial differences in lung cancer incidence are due to variafions in NNK metabolism. Our overall hypothesis is that cancer susceptibility relates to carcinogen dose and to the balance between carcinogen metabolic acfivafion and detoxificafion. Our specific aims are: 1) Conduct a comprehensive analysis of urinary biomarkers of NNK metabolic acfivafion and detoxificafion in African American and European American smokers. This research builds on our recently developed methodology based on the use of deuterium-labeled NNK. 2) Measure in exfoliated oral mucosa cells of African American and European American smokers DNA adducts formed as a result of NNK metabolic activafion. This is crifical to an understanding of the balance between the urinary excrefion of NNK metabolites and the extent of NNK DNA binding. In the future, this balance could serve as a direct indicator of cancer suscepfibility in humans. 3) Investigate the relationship between levels of NNK-derived DNA adducts measured in oral mucosa cells and the rates of repair of these adducts in cultured lymphocytes from our subjects. This research will complement the results obtained in Specific Aims 1 and 2. In summary, the results of these experiments will provide excifing new data on differences in NNK metabolic activation and detoxification, as well as formation of NNK-derived DNA adducts and related DNA repair capacity in African Americans and European Americans. This will also help to test the overall hypothesis that differences in the mechanisms of NNK carcinogenesis are related to lung cancer susceptibility in humans.