Nicotine and NNK Glucuronidation Pathways on Smokers

吸烟是导致90%肺癌的原因。一项大型的前瞻性研究， 该POI项目1的调查人员报告称，美国种族/少数民族之间的差异为2 - 5倍， 吸烟会增加患肺癌的风险。这个项目的总体假设是， 不同的癌症风险是由于对烟草烟雾致癌物的暴露和反应不同。的 吸烟者暴露于烟草致癌物是由尼古丁成瘾引起的。他们对尼可芬的反应， 对大多数致癌物的影响直接受这些化合物代谢的影响。两条主要路线 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- （甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）是烟草特有的亚硝胺，是指定的人 致癌物质本项目的总体目标是表征葡萄糖醛酸化中的人种/种族差异 尼古丁和NNK代谢途径，并确定与这些相关的UGT中存在的SNP 差异将研究三种葡萄糖醛酸化途径：尼可芬葡萄糖醛酸化和 两种NNK代谢物NNAL和α-羟甲基NNK的葡萄糖醛酸化。将评估这些途径 将在体外表征尿中的葡糖苷酸代谢物和UGT变体水平。我们的初步 数据提供的证据表明，非裔美国人的尼古丁葡萄糖醛酸化水平低于欧洲人 美国人，这个项目将集中在这两个群体。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，我们将扩展我们的 研究其他种族/民族群体。我们的目的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。我们将检验这个假设， 吸烟相关风险较高的人种/种族组的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。在老鼠体内，我们发现了一种 2.潜在更重要的NNK解毒途径，α-羟甲基NNK的葡萄糖醛酸化。在 本项目的最后两个目标是，我们将开发一种方法来量化吸烟者体内的葡萄糖醛酸苷， 测试我们的假设，即吸烟者中它的形成对DNA加合物的形成至关重要， 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.