PHARMACOKINETICS OF NICOTINE IN TWINS

描述：(申请人摘要) 尽管做出了迄今为止最大的努力，但仍有4600万人吸烟，43万人吸烟 每年都有人死于与烟草有关的疾病；估计 与吸烟相关的经济成本每年高达720亿美元。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--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对同卵 和100对双合子[DZ]从不吸烟，25对MZ和25对DZ 双胞胎中哪一个从不吸烟，另一个是现任还是前任 吸烟者)。包括从不吸烟的双胞胎将使我们能够初步测试 尼古丁代谢和动力学的生物学异同 在一组没有接触过尼古丁的人中。包括MZ和 永远吸烟的DZ双胞胎对将有助于估计 尼古丁代谢与尼古丁依赖的遗传相关性。 报告的合子和吸烟状态将通过生化检查确认 方法：研究方法。在完成一份旨在筛选以下内容的简短问卷后 排他性健康状况并评估潜在的混淆 变量，受试者将被视为双胞胎，住院8小时 尼古丁输注试验。在30分钟输液后的8小时内， 我们会定期抽取血液和尿液样本，化验 尼古丁和代谢物。在接下来的四个上午中的每一个，项目 工作人员将驱车前往受试者家中采血，24小时 尿样。化验完成后，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 遗传影响对尼古丁代谢的影响以及(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。通过后来的分子 作为这个项目的一部分，我们可能会对储存的血液进行分析 能够识别在数量和功能基础上的基因变异 负责尼古丁新陈代谢的各种酶。归根结底，这 知识可能会导致更知情和更有针对性的治疗 易受尼古丁成瘾影响的个人或已经 对这种物质上瘾的。

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.