PHARMACOKINETICS OF NICOTINE IN TWINS

尽管做出了迄今为止最大的努力，但仍有4600万人吸烟， 每年有43万人死于与烟草有关的疾病。问题是 这也是为什么有些人吸烟，而其他人不吸烟的原因。拟议的研究计划 试图首次探索基因对人类健康的影响 尼古丁的处置和动力学，稳定的特性 可能对理解尼古丁成瘾至关重要的个人 以及它的有效治疗。我们将在4年内招募250对双胞胎 (100对单合子[MZ]和100对双合子[DZ]从不吸烟，25 MZ 25对双胞胎，其中一个是从不吸烟的，另一个是 现任或前任吸烟者)。包括从不吸烟的双胞胎将 允许我们测试最初的生物学差异和相似性 一组以前没有接触过尼古丁的人的尼古丁代谢和动力学 尼古丁。MZ和DZ孪生对的包含永远不协调 吸烟将有助于估计两人之间的遗传相关性 尼古丁代谢和尼古丁依赖。报告的合子和 吸烟状态将通过生化方法确认。完工后 一份简短的问卷，旨在筛查排他性健康 条件和评估潜在的混杂变量，受试者将 在8小时的医院尼古丁输注测试中，被视为双胞胎。 在输液30分钟后的8小时内，血液和尿液样本 将定期服用，以测定尼古丁和代谢物。 在接下来的四个上午，项目工作人员将驱车前往 受试者家中采集血液和24小时尿样。后 化验完成后，数据将同时进行单变量和 确定遗传和环境的多变量遗传分析 对各药代动力学参数的影响 与其他具有生物学意义的尼古丁指数相结合 新陈代谢。本项目的影响是：1)估计 基因对尼古丁代谢的影响和2)进一步 新陈代谢表型的精炼与 尼古丁成瘾的遗传易感性。未来重要方向 在于将这项研究的知识与同伴的知识结合起来 密歇根大学尼古丁研究联盟的申请， 包括：1)基因对尼古丁代谢和代谢的影响 和敏感度，以及2)与辅助因素，如 成人注意力缺陷障碍和尼古丁代谢。一直到后来 作为这个项目的一部分，我们将收集血液的分子分析 可能能够识别构成这种数量和数量的基因变异 负责尼古丁代谢的各种酶的功能。 最终，这些知识可能会带来更多的信息和更精细的 对尼古丁易感人群的靶向治疗 上瘾或者已经上瘾了。

Despite the best efforts to date, 46 million people still smoke, and 430,000 people die from tobacco-related illness annually. The question remains why some people smoke and not others. The proposed research plan seeks to explore, for the first time, the genetic influences on the disposition and kinetics of nicotine, stable characteristics of individuals that may be central to the understanding of nicotine addiction and its effective treatment. We will recruit 250 twin pairs over 4 years (100 monozygotic [MZ] and 100 dizygotic [DZ] never-smoking pairs, 25 MZ and 25 DZ pairs in which one twin is a never smoker an the other twin is a current or former smoker). The inclusion of never-smoking twins will allow us to test initial biological differences and similarities in nicotine metabolism and kinetics in a group with no previous exposure to nicotine. The inclusion of MZ and DZ twin pairs discordant for ever smoking will facilitate the estimation of the genetic correlation between nicotine metabolism and nicotine dependence. Reported zygosity and smoking status will be confirmed by biochemical methods. After completion of a brief questionnaire designed to screen for exclusionary health conditions and to assess potentially confounding variables, subjects will be seen as twin pairs for an 8-hour in-hospital nicotine infusion test. During the 8 hours after the 30-minute infusion, blood and urine samples will be taken at regular intervals for assay of nicotine and metabolites. At each of the subsequent four mornings, project staff will drive to the homes of the subjects to collect blood and 24-hr urine samples. After the assay is completed, the data will be subjected to both univariate and multivariate genetic analyses to determine genetic and environmental influences on each pharmacokinetic parameter individually and in combination with other biologically meaningful indices of nicotine metabolism. Implications of this project are seen for: 1) estimation of the impact genetic influences on nicotine metabolism and 2) further refinement of the metabolic phenotype associated most strongly with the genetic predisposition to nicotine addiction. Important future directions lie in combining knowledge from this study with that from the companion applications in the University of Michigan Nicotine Research Consortium, including: 1) genetic influences on nicotine metabolism and metabolism and sensitivity and 2) shared genetic influences with cofactors such as Adult Attention Deficit Disorder and nicotine metabolism. Through later molecular analysis of blood to be collected as part of this project, we may be able to identify gene variants that underlie the amount and function of various enzymes responsible for nicotine metabolism. Ultimately, this knowledge may lead to more informed and more finely targeted treatment of individuals who are either susceptible to nicotine addiction or already addicted.