Luo Huai-Rong, Aloumanis Vasileios, Lin Keh-Ming, Gurwitz David, Wan Yu-Jui Yvonne
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7417, USA.
Am J Pharmacogenomics. 2004;4(6):395-401. doi: 10.2165/00129785-200404060-00006.
The cytochrome P450 isoenzymes CYP2C19 and CYP2D6 catalyze reactions involved in the metabolism of many widely used drugs. Their polymorphisms give rise to important interindividual and interethnic variability in the metabolism and disposition of several therapeutic agents and may cause differences in clinical response to some drugs. Individuals who carry two null alleles of either gene are known as poor metabolizers (PMs), while those who carry more than two copies of the functional CYP2D6 gene are ultrarapid metabolizers (UMs).
The aim of the current study was to genotype Israelis from four different ethnic backgrounds with respect to CYP2C19 and CYP2D6.
Polymorphisms of the CYP2C19 and CYP2D6 genes were determined by genotyping the four ethnic groups using PCR and/or restriction fragment length polymorphism (RFLP) analysis. The groups consisted of three Jewish communities, Yemenite Jews (n = 36), Sephardic Jews (n = 47), Ethiopian Jews (n = 28), and one Arabian population, Bedouins (n = 50).
CYP2C192 allele frequencies ranged from 12.0 to 19.6% among the four ethnic groups. Within the study population, the CYP2C193 gene was only found in one Bedouin individual, in the heterozygous state (CYP2C191/3). In each group, one individual was homozygous for CYP2C192, and were predicted to be PMs. The data revealed a high prevalence of CYP2D62, *4, *10, *41, and gene duplication, followed by *5 and *17, while 3 was very rare. The frequencies of the CYP2D64, *10, and 17 alleles and CYP2D6 gene duplication were significantly different among the four groups. However, the CYP2D62, *3, and *5 and 41 alleles showed similar frequencies in the four groups. Four (8.5%) Sephardic Jews and one (2.0%) Bedouin were found with the genotype CYP2D64/*4 (two null alleles), and were thus presumably PMs. A total of 15 individuals, distributed in all groups, were found with functional CYP2D6 gene duplications. The frequencies of predicted UMs (duplication of CYP2D6) were 17.8% (5/28) and 12.8% (6/47) in Ethiopian Jews and Sephardic Jews, respectively, which were higher than that of Yemenite Jews (5.6%, 2/36) and Bedouins (4.0%, 2/50).
This is the first study of the CYP2D6 gene polymorphism in Israeli ethnic groups, either Jewish or Arab. Furthermore, this is also the first study of the CYP2C19 gene polymorphism in Jewish or Arab subgroups living in Israel. The frequencies of various alleles for the CYP2D6 gene are significantly different among the ethnic groups in Israel. These new findings may have important clinical implications in administrating drugs metabolized by CYP2D6 and for CYP2D6-related adverse drug reactions in the Israeli population.
细胞色素P450同工酶CYP2C19和CYP2D6催化许多广泛使用药物的代谢反应。它们的多态性导致几种治疗药物在代谢和处置方面存在重要的个体间和种族间差异，并可能引起对某些药物临床反应的差异。携带这两个基因中任一基因两个无效等位基因的个体被称为慢代谢者（PMs），而携带超过两个功能性CYP2D6基因拷贝的个体是超快代谢者（UMs）。
本研究的目的是对来自四个不同种族背景的以色列人进行CYP2C19和CYP2D6基因分型。
通过使用聚合酶链反应（PCR）和/或限制性片段长度多态性（RFLP）分析对四个种族群体进行基因分型，来确定CYP2C19和CYP2D6基因的多态性。这些群体包括三个犹太社区，也门犹太人（n = 36）、西班牙裔犹太人（n = 47）、埃塞俄比亚犹太人（n = 28），以及一个阿拉伯人群体贝都因人（n = 50）。
在四个种族群体中，CYP2C192等位基因频率在12.0%至19.6%之间。在研究人群中，CYP2C193基因仅在一名贝都因人个体中被发现，处于杂合状态（CYP2C191/3）。在每个群体中，有一名个体为CYP2C192纯合子，预计为慢代谢者。数据显示CYP2D62、4、10、41和基因重复的发生率较高，其次是5和17，而3非常罕见。CYP2D64、10和17等位基因以及CYP2D6基因重复的频率在四个群体中存在显著差异。然而，CYP2D62、3、5和41等位基因在四个群体中的频率相似。发现四名（8.5%）西班牙裔犹太人和一名（2.0%）贝都因人具有CYP2D64/*4基因型（两个无效等位基因），因此推测为慢代谢者。共有1名5个体分布在所有群体中，被发现具有功能性CYP2D6基因重复。预计超快代谢者（CYP2D6重复）的频率在埃塞俄比亚犹太人中为17.8%（5/28），在西班牙裔犹太人中为12.8%（6/47），高于也门犹太人（5.6%，2/36）和贝都因人（4.0%，2/50）。
这是对以色列犹太或阿拉伯种族群体中CYP2D6基因多态性的首次研究。此外，这也是对生活在以色列的犹太或阿拉伯亚群体中CYP2C19基因多态性的首次研究。以色列不同种族群体中CYP2D6基因各种等位基因的频率存在显著差异。这些新发现可能对以色列人群中由CYP2D6代谢的药物给药以及与CYP2D6相关的药物不良反应具有重要的临床意义。
