Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington.
Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
Cancer Epidemiol Biomarkers Prev. 2023 Jan 9;32(1):54-65. doi: 10.1158/1055-9965.EPI-22-0868.
Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3'-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels.
Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data.
Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N'-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N'-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N'-oxide, and CYP2B6 genotype and levels of nicotine-N'-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid.
These data suggest that several pathways are important in nicotine metabolism.
Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation.
尼古丁代谢是尼古丁依赖的一个主要因素，大约 70%至 80%的尼古丁在白种人中代谢为可替宁。可替宁的形成主要由 CYP2A6 催化，该酶还将可替宁转化为反式-3'-羟基可替宁（3HC）。本研究的目的是研究 CYP2A6 缺乏对体内尼古丁代谢谱的影响，以及尼古丁代谢酶基因中的遗传变异对尿尼古丁代谢物水平的重要性。
使用 UPLC-MS/MS 分析来自参加新加坡华人健康研究的 722 名吸烟者的尿液样本，以检测尼古丁和其 8 种尿代谢物，并在其中 475 名具有信息丰富的基因分型数据的受试者中研究了 12 个基因中与尼古丁代谢相关的 58 个变体。
根据 3HC/可替宁比值分层的尿液样本显示，与下 3HC/可替宁分位数相比，3HC/可替宁比值较高时，尼古丁-N'-氧化物增加了 7 倍，尼古丁-葡萄糖醛酸（Gluc）增加了 6 倍，3HC-Gluc 减少了 5 倍。功能代谢酶基因型与各种尿尼古丁代谢物水平之间存在显著（P < 0.0001）关联，包括 CYP2A6 基因型与尼古丁、尼古丁-葡萄糖醛酸、尼古丁-N'-氧化物和 3HC 的水平，UGT2B10 基因型与可替宁、尼古丁-葡萄糖醛酸和可替宁-葡萄糖醛酸的水平，UGT2B17 基因型与 3HC-Gluc 的水平，FMO3 基因型与尼古丁-N'-氧化物的水平，以及 CYP2B6 基因型与尼古丁-N'-氧化物和 4-羟基-4-(3-吡啶基)-丁酸的水平。
这些数据表明，几种途径在尼古丁代谢中很重要。
几种尼古丁代谢酶途径的基因型差异可能导致尼古丁依赖和吸烟行为以及戒烟的差异。
