Dai Da-Peng, Geng Pei-Wu, Wang Shuang-Hu, Cai Jie, Hu Li-Ming, Nie Jing-Jing, Hu Ji-Hong, Hu Guo-Xin, Cai Jian-Ping
The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
Department of Pharmacology, School of Pharmacy Wenzhou Medical University, Wenzhou, Zhejiang, China.
Basic Clin Pharmacol Toxicol. 2015 Jul;117(1):39-43. doi: 10.1111/bcpt.12363. Epub 2015 Jan 14.
Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs related to genetic polymorphisms and is responsible for one-quarter of the currently used clinical drugs. We previously detected 22 novel, non-synonymous, mutated sites in the Chinese population, but nothing is known about the functional effects of these mutations in terms of specific CYP2D6 substrates. In this study, wild-type CYP2D6, two common allelic variants and 22 newly reported CYP2D6 isoforms were transiently expressed in 293FT cells, and the enzymatic activities of these variants were systematically assessed using dextromethorphan and bufuralol as the probing substrates. Consequently, 19 and 21 allelic variants were found to exhibit significantly decreased enzymatic activities for dextromethorphan and bufuralol, respectively. Of 22 novel CYP2D6 variants, six allelic isoforms (CYP2D6.89, CYP2D6.92, CYP2D6.93, CYP2D6.96, E215K and R440C) exhibited absent or extremely reduced metabolic activities compared with those observed for the wild-type enzyme. Our in vitro functional data can be useful for CYP2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP2D6 variants in China.
细胞色素P450 2D6（CYP2D6）是与基因多态性相关且研究最为广泛的细胞色素P450之一，目前使用的临床药物中有四分之一由其代谢。我们之前在中国人群中检测到22个新的非同义突变位点，但对于这些突变对特定CYP2D6底物的功能影响尚不清楚。在本研究中，野生型CYP2D6、两种常见等位基因变体和22种新报道的CYP2D6同工型在293FT细胞中瞬时表达，并使用右美沙芬和布非洛尔作为探针底物系统评估这些变体的酶活性。结果发现，分别有19种和21种等位基因变体对右美沙芬和布非洛尔的酶活性显著降低。在22种新的CYP2D6变体中，六种等位基因同工型（CYP2D6.89、CYP2D6.92、CYP2D6.93、CYP2D6.96、E215K和R440C）与野生型酶相比，代谢活性缺失或极低。我们的体外功能数据可用于CYP2D6表型预测，并为研究中国这些新发现的CYP2D6变体的临床影响提供有价值的信息。
