细胞色素P450 2A6基因分型与尼古丁的代谢及处置动力学

CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.

作者信息

Benowitz Neal L, Swan Gary E, Jacob Peyton, Lessov-Schlaggar Christina N, Tyndale Rachel F

机构信息

Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, and Department of Medicine, University of California, San Francisco, San Francisco 94143-1220, USA.

出版信息

Clin Pharmacol Ther. 2006 Nov;80(5):457-67. doi: 10.1016/j.clpt.2006.08.011.

DOI:10.1016/j.clpt.2006.08.011

PMID:17112802

Abstract

BACKGROUND AND OBJECTIVE

The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously.

METHODS

Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A61, CYP2A62, CYP2A64, CYP2A67, CYP2A68, CYP2A69, CYP2A610, and CYP2A612.

RESULTS

On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1.

CONCLUSIONS

We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.

摘要

背景与目的

肝脏酶细胞色素P450（CYP）2A6主要负责尼古丁的代谢。CYP2A6基因的变异与尼古丁代谢改变及吸烟行为的影响有关。我们的目的是确定CYP2A6基因变异型与静脉注射尼古丁的处置和代谢之间的关系。

方法

对278名健康双胞胎志愿者（大多数为白人）静脉输注氘标记的尼古丁和可替宁。对他们进行CYP2A61、CYP2A62、CYP2A64、CYP2A67、CYP2A68、CYP2A69、CYP2A610和CYP2A612基因分型。

结果

根据尼古丁向可替宁的分数清除率以及3'-羟基可替宁与可替宁的血浆比值（两者均显示为CYP2A6酶活性指标），将受试者分为3组。第1组包括野生型变异CYP2A6*1/1（n = 215），假定具有100%的活性。第2组包括1/9（n = 21）和1/12（n = 12），平均活性约为正常活性的80%。第3组包括1/*2（n = 10）、*1/*4（n = 2）、*9/*12（n = 3）、*9/4（n = 2）和9/*9（n = 3），平均活性约为正常活性的50%。第1、2和3组中尼古丁的平均总血浆清除率（±标准差）分别为18.8±6.0、15.5±4.9和11.7±5.1 mL·min⁻¹·kg⁻¹，第1组的清除率显著快于第2组（P<0.05）和第3组（P<0.01）。总体而言，与第1组相比，第2组和第3组的可替宁总清除率也较低，尼古丁和可替宁的半衰期较长，尿液中以未改变的尼古丁和尼古丁葡糖醛酸形式排泄的尼古丁剂量比例更大，而以3'-羟基可替宁形式排泄的较少。