Nicotine and NNK Glucuronidation Pathways on Smokers

烟草的使用导致了90%的肺癌。进行的一项大型前瞻性研究 这项POI项目1的调查人员报告说，在美国的种族/少数民族中， 吸烟导致肺癌的风险。该计划项目拨款的总体假设是，这 不同的癌症风险是由于接触和对烟草烟雾致癌物质的反应不同所致。这个 吸烟者接触烟草致癌物质是由尼古丁成瘾引起的。他们对尼古丁和 对大多数致癌物的作用直接受这些化合物代谢的影响。两条关键路线 尼古丁和致癌物的代谢是P450催化的氧化和UGT催化的结合。4- (甲基亚硝氨基)-1-(3-吡啶)-1-丁酮(NNK)是一种烟草特有的亚硝胺，是一种指定的人类 致癌物质。该项目的总体目标是确定葡萄糖醛酸化反应中的种族/民族差异。 尼古丁和NNK代谢途径及其相关SNPs的研究 不同之处。将研究三种葡萄糖醛酸化途径：尼古丁葡萄糖醛酸化反应，以及 两种NNK代谢物NNAL和α-羟甲基NNK的葡萄糖醛酸化反应。将对这些路径进行评估 通过尿糖醛酸代谢产物和UGT变异体的尿液水平将在体外进行表征。我们的预赛 数据提供的证据表明，非裔美国人的尼古丁葡萄糖醛酸化程度低于欧洲人 美国人，这个项目将专注于这两个群体。然而，通过与大型 致癌物暴露和代谢的全基因组关联研究在项目1中，我们将延长我们的 向其他民族/种族群体学习。我们的目标是确认观察到的种族/种族差异 尼古丁葡萄糖醛酸化，并将我们的研究扩展到NNAL葡萄糖醛酸化。我们将检验这一假设 在吸烟相关风险较高的种族/民族中，NNAL/V-葡萄糖醛酸化程度较低 肺癌。NNAL葡萄糖醛酸化是NNK的关键解毒途径。在老鼠身上，我们发现了一种 2“‘可能更重要的NNK解毒途径，α-羟甲基NNK的葡萄糖醛酸化。 这个项目的最后两个目标我们将开发方法来量化吸烟者中的这种葡萄糖醛酸苷，并 测试我们的假设，即它在吸烟者中的形成对DNA加合物的形成和调节至关重要 潜在的癌症风险。

Tobacco use is responsible for 90% of all lung cancers. A large prospective study carried out by the investigators of Project 1 of this POI reported a 2-5 fold difference among US racial/ethnic minorities in the risk of lung cancer due to cigarette smoking. The overall hypothesis of this program project grant is that this differential cancer risk is due to dissimilarities in exposure and response to tobacco smoke carcinogens. The exposure of a smoker to tobacco carcinogens is driven by nicotine addiction. Their response to nicofine and to most carcinogens is directiy influenced by the metabolism of these compounds. Two key routes of nicotine and carcinogen metabolism are P450-catalyzed oxidation and UGT-catalyzed conjugation. 4- (Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific nitrosamine, is a designated human carcinogen. It is the overall goal of this project to characterize racial/ethnic differences in the glucuronidation pathway of nicotine and NNK metabolism and to determine the SNPs present in UGTs associated with these differences. Three glucuronidation pathways will be studied: nicofine glucuronidation, and the glucuronidation oftwo NNK metabolites, NNAL and a-hydroxymethylNNK. The pathways will be assessed by urinary levels of glururonide metabolites and UGT variants will be characterized in vitro. Our preliminary data provided evidence of lower nicotine glucuronidation in African Americans relative to European Americans, and this project will focus on these two groups. However, through interactions with the large genome wide association study of carcinogen exposure and metabolism in project 1 we will extend our studies to other ethnic/racial groups. Our aims are to confirm the observed ethnic/racial difference in nicotine glucuronidation, and to extend our studies to NNAL glucuronidation. We will test the hypothesis that the extent of NNAL /V-glucuronidation is lower in racial/ethnic groups with a higher risk of smoking related lung cancer. NNAL glucuronidation is a key detoxification pathway of NNK. In the rat we have identified a 2"'^ potentially more important NNK detoxification pathway, glucuronidation of a-hydroxymethylNNK. In the last two aims of this project we will develop the methodology to quantify this glucuronide in smokers and to test our hypothesis that its formation in smokers is critical to the regulation of DNA adduct formation and potentially cancer risk.