Cytochrome P450 Polymorphism and Nicotine Metabolism

描述（由申请人提供）：这是一份来自新研究者的R 03申请。这项研究的目的是确定与人类尼古丁依赖相关的基因和基本机制。越来越多的证据表明，尼古丁代谢速率的遗传变异在调节尼古丁依赖中发挥作用。CYP 450酶家族，包括CYP 2A 6、CYP 2B 6和CYP 2D 6，在尼古丁代谢中起关键作用。虽然CYP 2A 6基因的遗传变异已被证明会影响尼古丁代谢并改变个体的吸烟行为，但CYP 2B 6和CYP 2D 6基因变异对尼古丁代谢和依赖性的影响仍有待阐明。因此，在本申请中概述的研究中，我们将评估CYP 2B 6和/或CYP 2D 6基因型与特定尼古丁药代动力学参数之间是否存在相关性。我们将集中研究在既往体内尼古丁药代动力学研究中显示遗传性最高的四种特定表型：（i）尼古丁和可替宁半衰期，（ii）尼古丁清除率，（iii）可替宁分布容积和（iv）标记CYP 450活性的速率常数。我们还将评价CYP 2B 6和CYP 2D 6基因型是否调节CYP 2A 6基因型对尼古丁药代动力学参数的影响，并将估计这三种基因中的每一种以及它们之间的任何基因-基因相互作用所解释的尼古丁代谢变异的比例。Huijun Ring博士沿着Neal Benowitz博士、加里Swan博士、Rachel Tyndale博士和Ana Valdes博士组成了一支强大的多学科研究团队，使他们有资格开展拟议的研究。这项研究将首次完全表征所有三种尼古丁C氧化酶基因的基因型，并研究它们在体内尼古丁代谢中的相对作用。本项目是一项重要的探索CYP 450多态性与尼古丁代谢关系的先导性研究，我们打算在未来进行更大样本量的研究，以检测更多的尼古丁成瘾相关表型。这种系统的遗传学方法将有助于确定个体对尼古丁依赖易感性的遗传机制，并为吸烟的病因学提供新的见解，并将促进新的干预和预防策略的发展。

DESCRIPTION (provided by applicant): This is an R03 application from a new investigator. The goal of this research is to identify the genes and basic mechanisms that are associated with nicotine dependence in humans. Converging evidence suggests that genetic variations in the rate of metabolism of nicotine can play a role in mediating nicotine dependence. The family of CYP450 enzymes, including CYP2A6, CYP2B6 and CYP2D6, play a pivotal role in nicotine metabolism. While genetic variation in the CYP2A6 gene has been shown to affect nicotine metabolism and alter an individuals' smoking behavior, the effects of genetic variation in CYP2B6 and CYP2D6 on nicotine metabolism and dependence remain to be elucidated. Thus, in the research outlined in this application, we will assess whether there is a correlation between CYP2B6 and/or CYP2D6 genotypes and specific nicotine pharmacokinetic parameters. We will concentrate on four specific phenotypes, which have shown the highest heritabilities in previous in vivo nicotine pharmacokinetics studies: (i) nicotine and cotinine half-life, (ii) nicotine clearance, (iii) cotinine volume of distribution and (iv) rate constant marking CYP450 activity. We will also evaluate whether the CYP2B6 and CYP2D6 genotypes modulate the effect of the CYP2A6 genotype on nicotine pharmaeokinctic parameters and will estimate the proportion of the variation in nicotine metabolism that is explained by each of these three genes and by any gene-gene interactions between them. Dr. Huijun Ring, along with Drs. Neal Benowitz, Gary Swan, Rachel Tyndale and Ana Valdes, form a strong multi-disciplinary research team that uniquely qualifies them to carry out the proposed research. The proposed research will be the first to completely characterize the genotypes of all three nicotine C-oxidase genes and to study their relative roles in in vivo nicotine metabolism. This project is an important pilot study to explore the relationship between CYP450 polymorphisms and nicotine metabolism, and we intend to follow it up with future studies that have larger sample size in order to test for more nicotine addiction related phenotypes. This systematic genetic approach will help to identify genetic mechanisms that underlie individual susceptibility to nicotine dependence and provide new insights into the etiology of smoking and will facilitate the development of new intervention and preventive strategies.