Cytochrome P450 Polymorphism and Nicotine Metabolism

细胞色素 P450 多态性与尼古丁代谢

• 批准号: 6598749
• 负责人: HUIJUN Z RING
• 金额: $ 9.74万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6598749
• 关键词: blood chemistry; clinical research; cytochrome P450; drug metabolism; family genetics; genetic polymorphism; human genetic material tag; human tissue; nicotine; pharmacogenetics; pharmacokinetics; twin /multiplet

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.

描述(由申请人提供)：这是一份R03申请，来自一名新的研究人员。这项研究的目标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，尼古丁代谢率的遗传变异可以在调节尼古丁依赖方面发挥作用。细胞色素P450酶家族包括细胞色素P450 A6、细胞色素P450 B6和细胞色素P450 D6，在尼古丁代谢中起着关键作用。虽然已有研究表明，CYP2A6基因的遗传变异会影响尼古丁代谢并改变个体的吸烟行为，但其对尼古丁代谢和依赖性的影响尚不清楚。因此，在本申请中概述的研究中，我们将评估CYP2B6和/或CYP2D6基因与特定的尼古丁药代动力学参数之间是否存在相关性。我们将集中在四种特定的表型上，它们在先前的体内尼古丁药代动力学研究中表现出最高的遗传力：(I)尼古丁和可替宁的半衰期，(Ii)尼古丁的清除，(Iii)可替宁的分布体积和(Iv)速率常数标记的CYP450活性。我们还将评估CYP2B6和CYP2D6基因是否调节了CYP2A6基因对尼古丁药代动力学参数的影响，并将估计这三个基因中的每一个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。林惠君博士与Neal Benowitz博士、Gary Swan博士、Rachel Tyndale博士和Ana Valdes博士组成了一个强大的多学科研究团队，这使他们有资格开展这项拟议的研究。这项拟议的研究将首次完全确定所有三个尼古丁C-氧化酶基因的基因类型，并研究它们在体内尼古丁新陈代谢中的相对作用。这个项目是探索CYP450基因多态性与尼古丁代谢关系的重要先导研究，我们打算在未来的研究中进行更大样本量的研究，以测试更多与尼古丁成瘾相关的表型。这一系统的遗传学方法将有助于确定个人对尼古丁依赖的易感性的遗传机制，为吸烟的病因提供新的见解，并将促进新的干预和预防策略的发展。