Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of black African descent
Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of black African descent
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DOI：
10.1002/humu.20698
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发表时间：
2008-05-01
期刊：
影响因子：
3.9
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
--
作者：
Mwenifumbo, Jill C.;Al Koudsi, Nael;Tyndale, Rachel F.
细胞色素 P450 2A6 (CYP2A6) 是一种人类酶，以代谢烟草相关化合物而闻名，例如尼古丁、可替宁 (COT) 和亚硝胺致癌物。 CYP2A6 基因变异与吸烟状况、吸烟和烟草相关癌症有关。我们的目标是从功能上表征四个非同义 CYP2A6 序列变体的单倍型、等位基因频率以及与体内 CYP2A6 活性的关联。在体内，281 名非洲黑人后裔志愿者口服尼古丁。收集血样进行动力学表型和 CYP2A6 基因分型。在体外，评估了异源表达的变体酶的尼古丁C，氧化催化效率。在七个新等位基因 CYP2A6*24A & B、*25、*26、*27 和 *28A & B 中发现了四个未表征的序列变体；大多数与体内 CYP2A6 活性受损有关。根据变异等位基因的体内数据创建了尼古丁代谢分组。平均反式 3'-羟基可替宁/可替宁 (3HC/COT) 不同 (P
Cytochrome P450 2A6 (CYP2A6) is a human enzyme best known for metabolizing tobacco-related compounds, such as nicotine, cotinine (COT), and nitrosamine procarcinogens. CYP2A6 genetic variants have been associated with smoking status, cigarette consumption, and tobacco-related cancers. Our objective was to functionally characterize four nonsynonymous CYP2A6 sequence variants with respect to their haplotype, allele frequency, and association with in vivo CYP2A6 activity. In vivo, nicotine was administered orally to 281 volunteers of Black African descent. Blood samples were collected for kinetic phenotyping and CYP2A6 genotyping. In vitro, nicotine C,oxidation catalytic efficiencies of heterologously expressed variant enzymes were assessed. The four uncharacterized sequence variants were found in seven novel alleles CYP2A6*24A & B, *25, *26, *27, and *28A & B; most were associated with impaired in vivo CYP2A6 activity. Nicotine metabolism groupings, based on the in vivo data of variant alleles, were created. Mean trans-3'-hydroxycotinine/cotinine (3HC/COT) differed (P