Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity.
Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity.
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DOI：
10.1097/fpc.0000000000000222
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发表时间：
2016-07
影响因子：
2.6
通讯作者：
Tyndale RF
中科院分区：
文献类型：
--
作者：
Benowitz NL;St Helen G;Dempsey DA;Jacob P 3rd;Tyndale RF
尼古丁代谢率主要由CYP 2A 6活性决定，影响烟草依赖和吸烟引起的疾病风险。CYP 2A 6基因变异的患病率因种族而异，与高加索人相比，非洲裔美国人（AA）的患病率更高。我们研究了尼古丁处置动力学和代谢的CYP 2A 6基因型和酶活性，尼古丁代谢物比（NMR）测定，在AA吸烟者。受试者接受氘标记尼古丁和可替宁IV输注。测量尼古丁和代谢物的血浆和尿液浓度，并估计药代动力学参数。通过CYP 2A 6基因型和NMR分析药代动力学参数和尿液代谢产物排泄数据。许多基因变异与尼古丁和可替宁清除率显著降低相关。NMR与尼古丁（r=0.72）和可替宁（r=0.80）清除率密切相关。与NMR较低的受试者相比，NMR较高的受试者排出的尼古丁C-氧化产物显著更多，非C-氧化产物较低。CYP 2A 6基因型、NMR和尼古丁药代动力学数据可以为研究吸烟行为和尼古丁暴露生物标志物的个体差异提供信息。
The rate of nicotine metabolism, determined primarily by CYP2A6 activity, influences tobacco dependence and smoking-induced disease risk. The prevalence of CYP2A6 gene variants differs by race, with greater numbers in African American (AA) compared to Caucasians. We studied nicotine disposition kinetics and metabolism by CYP2A6 genotype and enzymatic activity, as measured by nicotine metabolite ratio (NMR), in AA smokers. Subjects were administered IV infusions of deuterium-labeled nicotine and cotinine. Plasma and urine concentrations of nicotine and metabolites were measured, and pharmacokinetic parameters estimated. Pharmacokinetic parameters and urine metabolite excretion data were analyzed by CYP2A6 genotype and by NMR. A number of gene variants were associated with markedly reduced nicotine and cotinine clearances. NMR was strongly correlated with nicotine (r=0.72) and cotinine (r=0.80) clearances. Subjects with higher NMR excreted significantly greater nicotine C-oxidation and lower non C-oxidation products compared to lower NMR subjects. CYP2A6 genotype, NMR and nicotine pharmacokinetic data may inform studies of individual differences in smoking behavior and biomarkers of nicotine exposure.