Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.
Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.
复制标题
使用体内尼古丁动力学表征新型 CYP2A6*21 等位基因。
DOI：
10.1007/s00228-006-0113-3
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发表时间：
2006
影响因子：
2.9
通讯作者：
Tyndale,RachelF
中科院分区：
文献类型：
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作者：
AlKoudsi,Nael;Mwenifumbo,JillC;Sellers,EdwardM;Benowitz,NealL;Swan,GaryE;Tyndale,RachelF
目的探讨CYP2A6*21(K476R)对体内尼古丁代谢和处置的影响。方法建立两步等位基因特异性聚合酶链式反应方法，检测该基因的6573A和GT；G单核苷酸多态性(SNP)。来自先前描述的静脉标记尼古丁和可替宁输注研究的尼古丁代谢表型[1]被用来评估CYP2A6*21的影响。对222例高加索人群(111对同卵和异卵双生子)的基因组DNA进行了CYP2A6等位基因(-1x2、-1B、-*2、-*4、-*7、-*9、-*10、-*12和-*21)的基因分型。比较未检出CYP2A6*1/*1变异个体(n=163)和杂合子个体(n=9)的药代动力学参数。结果在高加索人群中，CYP2A6*21等位基因频率为2.3%(n=5/222等位基因，每对双胞胎中有1对评估)。体内药代动力学参数，如尼古丁清除率(1.32±0.37vs.1.18±0.20vs.1.18±0.20vs.1.18±0.20)，尼古丁到可替宁的清除率(1.02±0.36vs.0.99±0.23vs.L/min)，尼古丁半衰期(111±37vs.116±29min)，以及3‘-羟基可替宁与可替宁的比率(1.92±1.0vs.1.55±0.58，n=163)，表明尼古丁代谢在无变异(CYP2A6*1/*1，n=163)和有变异(CYP2A6*1/21，n=9)之间没有显著差异结论CYP2A6*21对体内尼古丁代谢无明显影响。我们的数据表明，对于未来尼古丁代谢及其对吸烟行为的影响的研究，CYP2A6*21可能并不重要。
ObjectiveThe impact ofCYP2A6*21(K476R) on in vivo nicotine metabolism and disposition was investigated.MethodsA two-step allele-specific PCR assay was developed to detect the 6573A>G single nucleotide polymorphism (SNP) inCYP2A6*21. Nicotine metabolism phenotypes from a previously described intravenous labeled nicotine and cotinine infusion study [1] was used to assess the impact ofCYP2A6*21. Genomic DNA samples from 222 (111 monozygotic and dizygotic twin pairs) Caucasian subjects were genotyped forCYP2A6alleles (CYP2A6*1X2,-*1B,-*2,-*4,-*7,-*9,-*10,-*12, and-*21). The pharmacokinetic parameters were compared between individuals with no detectedCYP2A6variants (CYP2A6*1/*1,n=163) and individuals heterozygous for theCYP2A6*21allele (CYP2A6*1/*21,n=9).ResultsThe frequency of theCYP2A6*21allele was found to be 2.3% in Caucasians (n=5/222 alleles, evaluated in one twin from each twin pair). In vivo pharmacokinetic parameters, such as nicotine clearance (1.32±0.37 vs. 1.18±0.20 L/min), fractional clearance of nicotine to cotinine (1.02±0.36 vs. 0.99±0.23 L/min), nicotine half-life (111±37 vs. 116±29 min), and thetrans-3′-hydroxycotinine to cotinine ratio (1.92±1.0 vs. 1.55±0.58) indicated no substantial differences in nicotine metabolism between those without the variant (CYP2A6*1/*1,n=163) and those with the variant (CYP2A6*1/*21,n=9), respectively.ConclusionsCYP2A6*21does not have a detectable impact on nicotine metabolism in vivo. Our data suggest thatCYP2A6*21may not be important for future studies of nicotine metabolism and the resulting impacts on smoking behaviors.