PHARMACOKINETICS OF NICOTINE IN TWINS

描述：（申请人摘要） 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1000人死于与烟草有关的疾病;估计 每年与吸烟有关的经济损失为720亿美元。 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，个体的稳定特征 这可能是理解尼古丁成瘾及其有效性的核心， 治疗 我们将在4年内招募250对双胞胎（100对单卵双胞胎）， [MZ]和100个双合子[DZ]从不吸烟对，25个MZ和25个DZ对， 双胞胎中的哪一个从不吸烟，另一个是现任或前任 吸烟者）。 包括从不吸烟的双胞胎将使我们能够测试最初的 尼古丁代谢和动力学的生物学差异和相似性 在一组之前没有接触过尼古丁的人中。 加入MZ和 DZ双胞胎不一致的吸烟史将有助于估计 尼古丁代谢和尼古丁依赖之间的遗传相关性。 报告的接合性和吸烟状况将通过生化检查确认。 方法. 在完成一份简短的问卷调查后， 排除性健康状况，并评估潜在的混杂因素 变量，受试者将被视为双胞胎，住院8小时 尼古丁注入试验 在30分钟输注后的8小时内， 将定期采集血液和尿液样本， 尼古丁和代谢物。 在随后的四个早晨，项目 工作人员将开车到受试者家中采集血液， 尿样 试验完成后，将对数据进行 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， 与尼古丁的其他生物学意义指标结合 新陈代谢. 该项目的意义在于：（1）估计 遗传因素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 通过后来的分子 作为本项目的一部分，我们可能会收集储存的血液进行分析， 能够识别基因变异的数量和功能， 负责尼古丁代谢的各种酶。 最终这 知识可能导致更知情和更有针对性的治疗， 对尼古丁上瘾或已经上瘾的人 对这种物质上瘾。

DESCRIPTION: (Applicant's Abstract) Despite the best efforts to date, 46 million people still smoke, and 430,000 people die from tobacco-related illness annually; the estimated smoking-related cost to the economy is $72 billion 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 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 and 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 of genetic influences on nicotine metabolism and (2) further refinement of the metabolic phenotype associated most strongly with the genetic predisposition to nicotine addiction. Through later molecular analysis of the stored 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 metabolism of nicotine. Ultimately, this knowledge may lead to more informed and more finely targeted treatment of individuals who are either susceptible to nicotine addiction or are already addicted to this substance.