PHARMACOKINETICS OF NICOTINE IN TWINS

尽管迄今为止做出了最大的努力，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 这就是为什么有些人吸烟，而不是其他人。 拟议的研究计划 第一次试图探索基因对 尼古丁的处置和动力学， 这些人可能是理解尼古丁成瘾的核心 及其有效的治疗。 我们将在4年内招募250对双胞胎 (100单卵[MZ]和100个双卵[DZ]从不吸烟对，25个MZ 和25对DZ双胞胎，其中一个从不吸烟，另一个是 现在或以前的吸烟者）。 包括从不吸烟的双胞胎将 使我们能够测试最初的生物学差异和相似之处， 尼古丁代谢和动力学在一组没有以前暴露于 尼古丁。 包含MZ和DZ双胞胎对永远不一致 吸烟将有助于估计 尼古丁代谢和尼古丁依赖。 报告的接合性和 吸烟状况将通过生物化学方法进行确认。 完成后 一份简短的调查问卷， 为了评估潜在的混杂变量，受试者将 在医院接受8小时的尼古丁注射测试。 在30分钟输注后的8小时内，血液和尿液样本 将定期进行尼古丁和代谢物含量测定。 在随后的四个上午，项目工作人员将开车前往 在受试者家中采集血液和24小时尿液样本。 后 试验完成后，数据将接受单变量和 多变量遗传分析，以确定遗传和环境 对每个药代动力学参数的影响 与其他尼古丁生物学有意义的指标相结合 新陈代谢. 该项目的影响被认为是：1）估计 遗传对尼古丁代谢的影响，以及2）进一步 代谢表型的细化与 尼古丁成瘾的遗传倾向 未来的重要方向 在于将这项研究的知识与同伴的知识相结合 密歇根大学尼古丁研究联盟的申请， 包括：1）遗传对尼古丁代谢和代谢的影响 和敏感性，2）与辅助因子共享遗传影响， 成人注意力缺陷障碍和尼古丁代谢。 通过后期 作为该项目的一部分，我们将对收集的血液进行分子分析， 也许能够识别基因变异的基础数量， 负责尼古丁代谢的各种酶的功能。 最终，这些知识可能会导致更知情，更精细 对尼古丁敏感的个体进行靶向治疗 上瘾或已经上瘾。

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.