Nakajima Miki, Fukami Tatsuki, Yamanaka Hiroyuki, Higashi Eriko, Sakai Haruko, Yoshida Ryoko, Kwon Jun-Tack, McLeod Howard L, Yokoi Tsuyoshi
Department of Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Clin Pharmacol Ther. 2006 Sep;80(3):282-97. doi: 10.1016/j.clpt.2006.05.012.
Human cytochrome P450 (CYP) 2A6 metabolizes nicotine to cotinine and is a possible modulator of nicotine addiction. Quantitative and qualitative differences in nicotine addiction have been observed between ethnic groups. However, there are few data on the ethnic influences of the CYP2A6-nicotine metabolism relationship, particularly with regard to black subjects. We determined the nicotine metabolism and CYP2A6 genotype in 176 white subjects and 160 black subjects, comparing them with our previous data from 209 Korean subjects and 92 Japanese subjects. Large interindividual differences were observed in the cotinine/nicotine ratios in plasma calculated as an index of nicotine metabolism in white subjects (range, 0.6-36.5) and in black subjects (range, 0.9-30.4). No ethnic difference in the metabolic ratio was observed among white subjects (mean, 7.2 +/- 5.0), black subjects (mean, 7.1 +/- 4.7), and Korean subjects (mean, 8.7 +/- 11.9), whereas Japanese subjects showed a significantly (P < .005) lower metabolic ratio (mean, 3.8 +/- 3.1) compared with the other populations. Women showed significantly (P < .05) higher metabolic ratios than men in the black population (8.0 +/- 5.3 versus 6.0 +/- 3.7). Obvious ethnic differences in the CYP2A6 alleles were observed among these 4 populations. The combined frequencies of the alleles lacking or showing reduced enzymatic activity (CYP2A62, CYP2A64, CYP2A65, CYP2A67, CYP2A69, CYP2A610, CYP2A611, CYP2A617, CYP2A619, and CYP2A620) were 9.1%, 21.9%, 42.9%, and 50.5% in white, black, Korean, and Japanese subjects, respectively. These CYP2A6 alleles were associated with reduced nicotine metabolism. Among the homozygotes of CYP2A6*1, interindividual and ethnic differences in the metabolic ratio were still observed. Thus some factors other than genetic ones might also contribute to the interindividual and ethnic differences. This comprehensive study of 4 populations extends our understanding of nicotine metabolism and the impact of genetic polymorphisms of the CYP2A6 gene.
人类细胞色素P450（CYP）2A6可将尼古丁代谢为可替宁，它可能是尼古丁成瘾的一个调节因子。不同种族在尼古丁成瘾方面存在定量和定性的差异。然而，关于CYP2A6-尼古丁代谢关系的种族影响的数据很少，尤其是关于黑人受试者的数据。我们测定了176名白人受试者和160名黑人受试者的尼古丁代谢情况及CYP2A6基因型，并将其与我们之前来自209名韩国受试者和92名日本受试者的数据进行比较。以血浆中可替宁/尼古丁比值作为尼古丁代谢指标，在白人受试者（范围为0.6 - 36.5）和黑人受试者（范围为0.9 - 30.4）中均观察到个体间存在较大差异。白人受试者（平均值为7.2±5.0）、黑人受试者（平均值为7.1±4.7）和韩国受试者（平均值为8.7±11.9）之间未观察到代谢比值的种族差异，而与其他人群相比，日本受试者的代谢比值显著较低（P <.005）（平均值为3.8±3.1）。在黑人人群中，女性显示出比男性显著更高（P <.05）的代谢比值（8.0±5.3对6.0±3.7）。在这4个人群中观察到CYP2A6等位基因存在明显的种族差异。缺乏或显示酶活性降低的等位基因（CYP2A62、CYP2A64、CYP2A65、CYP2A67、CYP2A69、CYP2A610、CYP2A611、CYP2A617、CYP2A619和CYP2A620）的合并频率在白人、黑人、韩国人和日本受试者中分别为9.1%、21.9%、42.9%和50.5%。这些CYP2A6等位基因与尼古丁代谢降低有关。在CYP2A6*1纯合子中，仍观察到代谢比值存在个体间和种族差异。因此除了遗传因素外，一些其他因素可能也导致了个体间和种族差异。这项对4个人群的综合研究扩展了我们对尼古丁代谢以及CYP2A6基因遗传多态性影响的理解。
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