Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals.
Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals.
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DOI：
10.3390/jpm11020094
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发表时间：
2021-02-02
影响因子：
--
通讯作者：
Hiratsuka M
中科院分区：
文献类型：
--
作者：
Kumondai M;Ito A;Gutiérrez Rico EM;Hishinuma E;Ueda A;Saito S;Nakayoshi T;Oda A;Tadaka S;Kinoshita K;Maekawa M;Mano N;Hirasawa N;Hiratsuka M
细胞色素P450 2C 9（CYP 2C 9）是一种重要的药物代谢酶，约15%的临床使用的药物（包括华法林）的代谢都是由CYP 2C 9所引起的，华法林的治疗窗较窄。CYP 2C 9基因多态性引起的CYP 2C 9酶活性的个体间差异导致患者的治疗反应不一致。因此，在本研究中，我们描述了CYP 2C 9野生型（CYP2C9.1）、CYP2C9.2、CYP2C9.3和在4773名日本个体中鉴定的12种罕见新变体的功能差异。这些CYP 2C 9变体在293 FT细胞中异源表达，并估计了（S）-华法林7-羟基化和甲苯磺丁脲4-羟基化的动力学参数（Km、kcat、Vmax、催化效率和克林特）。根据该分析，与CYP 2C 9野生型相比，几乎所有新型CYP 2C 9变体均显示酶活性显著降低或无效。在所有研究的CYP 2C 9变体中，发现（S）-华法林7-羟基化和甲苯磺丁脲4-羟基化之间的催化效率具有很强的相关性。观察到的扰动酶活性的原因进行了评估，通过三维结构建模。我们的研究结果可以澄清基于新型CYP 2C 9罕见等位基因变异的基因型-表型关联之间的部分差异，因此可以改善个性化药物，包括选择适当的华法林剂量。
Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (Km, kcat, Vmax, catalytic efficiency, and CLint) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose.
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影响因子：
6.7
作者：
Johnson JA;Caudle KE;Gong L;Whirl-Carrillo M;Stein CM;Scott SA;Lee MT;Gage BF;Kimmel SE;Perera MA;Anderson JL;Pirmohamed M;Klein TE;Limdi NA;Cavallari LH;Wadelius M
通讯作者：
Wadelius M
影响因子：
14.8
作者：
通讯作者：
--
中国人群中发现的 36 个 CYP2C9 等位基因亚型对格列美脲代谢的体外评估
影响因子：
3.1
作者：
Dai, Da-Peng;Wang, Shuang-Hu;Cai, Jian-Ping
通讯作者：
Cai, Jian-Ping
影响因子：
5.6
作者：
Claudio-Campos K;Labastida A;Ramos A;Gaedigk A;Renta-Torres J;Padilla D;Rivera-Miranda G;Scott SA;Ruaño G;Cadilla CL;Duconge-Soler J
通讯作者：
Duconge-Soler J
中国汉族人群中发现的 13 个 CYP2C9 等位基因变异体的体外和体内特征
影响因子：
3.9
作者：
Hu, Guo-Xin;Pan, Pei-Pei;Cai, Jian-Ping
通讯作者：
Cai, Jian-Ping