A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent
A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent
复制标题
DOI：
10.1097/fpc.0b013e3282f3606e
复制
发表时间：
2008-01-01
影响因子：
2.6
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
--
作者：
Ho, Man Ki;Mwenifumbo, Jill C.;Tyndale, Rachel F.
目标 CYP2A6 是参与人体尼古丁代谢的主要酶。我们在非洲黑人血统的个体中鉴定出一种新的等位基因 CYP2A6*23 (2161C>T, R203C)，并研究了其对酶活性的影响以及与吸烟状况的关联。方法表达了含有氨基酸变化的野生型和变异酶 R203C (CYP2A6*23)、R203S (CYP2A6*16) 和 V365M (CYP2A6*17)在大肠杆菌中。在给予 4 mg 口服尼古丁的非洲黑人后裔个体中检查了 CYP2A6*23 的体内作用。结果 CYP2A6*23 在非洲黑人后裔个体中以 2.0% 的等位基因频率出现（N=560 个等位基因，95% 置信区间，0.8-3.1%），在白种人（N=334 个等位基因）、中国人中未检测到。 （N=288 个等位基因）或日语（N=104 个等位基因）。在体外，与 CYP2A6.17 相似，CYP2A6.23 大大降低了尼古丁 C-氧化活性，并降低了香豆素 7-羟基化。相反，与野生型酶相比，CYP2A6.16 的活性没有差异。与 CYP2A6*1/*1 个体（平均调整比率 1.21，n=150）相比，反式 3' 羟基可替宁与可替宁比率（体内 CYP2A6 活性的表型测量）在 CYP2A6*1/*23 和 CYP2A6*23/*23 个体中较低（平均调整比率为 0.60，n=5）（P
Objectives CYP2A6 is the main enzyme involved in nicotine metabolism in humans. We have identified a novel allele, CYP2A6*23 (2161C>T, R203C), in individuals of Black-African descent and investigated its impact on enzyme activity and association with smoking status.Methods Wild-type and variant enzymes containing amino acid changes R203C (CYP2A6*23), R203S (CYP2A6*16) and V365M (CYP2A6*17) were expressed in Escherichia coli. The effect of CYP2A6*23 in vivo was examined in individuals of Black-African descent given 4 mg oral nicotine.Results CYP2A6*23 occurred at an allele frequency of 2.0% in individuals of Black-African descent (N=560 alleles, 95% confidence interval, 0.8-3.1%) and was not detected in Caucasians (N=334 alleles), Chinese (N=288 alleles) or Japanese (N= 104 alleles). In vitro, CYP2A6.23 had greatly reduced activity toward nicotine C-oxidation similar to CYP2A6.17, as well as reduced coumarin 7-hydroxylation. Conversely, CYP2A6.16 did not differ in activity compared with the wild-type enzyme. The trans-3 ' hydroxycotinine to cotinine ratio, a phenotypic measure of CYP2A6 activity in vivo, was lower in CYP2A6*1/*23 and CYP2A6*23/*23 individuals (mean adjusted ratio of 0.60, n=5) compared with CYP2A6*1/*1 individuals (mean adjusted ratio of 1.21, n=150) (P