Sakuyama Kanako, Sasaki Takamitsu, Ujiie Shuta, Obata Kanako, Mizugaki Michinao, Ishikawa Masaaki, Hiratsuka Masahiro
Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Drug Metab Dispos. 2008 Dec;36(12):2460-7. doi: 10.1124/dmd.108.023242. Epub 2008 Sep 10.
Cytochrome P450 2D6 (CYP2D6) is an enzyme of potential importance for the metabolism of drugs used clinically, and it exhibits genetic polymorphism with interindividual differences in metabolic activity. To date, 21 CYP2D6 allelic variants have been identified in the Japanese population. The aim of this study was to investigate the functional characterization of CYP2D6 variants identified in Japanese subjects. Wild-type CYP2D6 and its variants, namely, CYP2D6.2, CYP2D6.10, CYP2D6.14A, CYP2D6.14B, CYP2D6.18, CYP2D6.27, CYP2D6.36, CYP2D6.39, CYP2D6.47, CYP2D6.48, CYP2D6.49, CYP2D6.50, CYP2D6.51, CYP2D6.53, CYP2D6.54, CYP2D6.55, and CYP2D6.57 were transiently expressed in COS-7 cells, and enzymatic activities of the CYP2D6 variant proteins were characterized using bufuralol and dextromethorphan. Functional characterization of 17 CYP2D6 variants revealed an absence of enzyme activity in four (CYP2D6.14A, CYP2D6.36, CYP2D6.47, and CYP2D6.57), low activity in eight (CYP2D6.10, CYP2D6.14B, CYP2D6.18, CYP2D6.49, CYP2D6.50, CYP2D6.51, CYP2D6.54, and CYP2D6.55), and high activity in one (CYP2D6.53) compared with the wild type. Analysis of CYP2D6 variant proteins can be useful for predicting CYP2D6 phenotypes and could be applied to personalized drug therapy.
细胞色素P450 2D6（CYP2D6）是一种对临床使用药物的代谢具有潜在重要性的酶，它表现出遗传多态性，个体间代谢活性存在差异。迄今为止，在日本人群中已鉴定出21种CYP2D6等位基因变体。本研究的目的是调查在日本受试者中鉴定出的CYP2D6变体的功能特征。野生型CYP2D6及其变体，即CYP2D6.2、CYP2D6.10、CYP2D6.14A、CYP2D6.14B、CYP2D6.18、CYP2D6.27、CYP2D6.36、CYP2D6.39、CYP2D6.47、CYP2D6.48、CYP2D6.49、CYP2D6.50、CYP2D6.51、CYP2D6.53、CYP2D6.54、CYP2D6.55和CYP2D6.57在COS-7细胞中瞬时表达，并使用布非洛尔和右美沙芬对CYP2D6变体蛋白的酶活性进行表征。17种CYP2D6变体的功能特征显示，四种变体（CYP2D6.14A、CYP2D6.36、CYP2D6.47和CYP2D6.57）缺乏酶活性，八种变体（CYP2D6.10、CYP2D6.14B、CYP2D6.18、CYP2D6.49、CYP2D6.50、CYP2D6.51、CYP2D6.54和CYP2D6.55）活性较低，一种变体（CYP2D6.53）与野生型相比活性较高。对CYP2D6变体蛋白的分析有助于预测CYP2D6表型，并可应用于个性化药物治疗。
