CYP2A6 genotype and the metabolism and disposition kinetics of nicotine
CYP2A6 genotype and the metabolism and disposition kinetics of nicotine
复制标题
DOI：
10.1016/j.clpt.2006.08.011
复制
发表时间：
2006-11-01
影响因子：
6.7
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
--
作者：
Benowitz, Neal L.;Swan, Gary E.;Tyndale, Rachel F.
背景和目的：肝酶细胞色素 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的改变以及吸烟行为的影响有关。我们的目的是确定变异 CYP2A6 基因型与静脉注射尼古丁的处置和代谢之间的关系。方法。 278 名健康双胞胎志愿者（其中大多数是白人）接受了静脉输注氘标记的尼古丁和可替宁。对它们进行了 CYP2A6*1、CYP2A6*2、CYP2A6*4、CYP2A6*7、CYP2A6*8、CYP2A6*9、CYP2A6*10 和 CYP2A6*12 的基因分型。结果。根据尼古丁与可替宁的清除率以及血浆中 3'-羟基可替宁与可替宁的比率（两者均被证明是 CYP2A6 酶活性的指标），将受试者分为 3 组。 I 组包括野生型变体 CYP2A6*1/*1 (n = 215)，并假定具有 100% 活性。第 2 组包括 *1/*9 (n = 21) 和 *1/*12 (n = 12)，平均约为正常活动的 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)，平均约为正常活动的 50%。尼古丁的平均总血浆清除率 (+/- SD) 为 18.8 +/- 6.0、15.5 +/- 4.9 和 11.7 +/- 5.1 mL。分钟(-1) 。第 1、2 和 3 组分别为 kg(-1)，且 I 组的清除速度明显快于第 2 组 (P < .05) 和第 3 组 (P < .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较低，尼古丁和可替宁的半衰期较长，并且以未变化的尼古丁和尼古丁葡萄糖醛酸形式在尿液中排泄了较大比例的尼古丁剂量，而以 3'-羟基可替宁的形式排泄较少。结论。我们提供了与常见 CYP2A6 基因型相关的全身给药后尼古丁的新药代动力学和代谢数据。我们的数据将增强对吸烟行为及其健康后果关联研究中使用的 CYP2A6 基因型数据的解释。
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 CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12.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 I 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 I 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.