CYP2C19基因变异对氟西汀体外代谢的影响。
Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro.
作者信息
Fang Ping, He Jia-Yang, Han Ai-Xia, Lan Tian, Dai Da-Peng, Cai Jian-Ping, Hu Guo-Xin
机构信息
School of Pharmacy, Wenzhou Medical University, Wenzhou, China.
出版信息
Pharmacology. 2017;100(1-2):91-97. doi: 10.1159/000475598. Epub 2017 May 12.
AIMS
CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31 CYP2C19 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of fluoxetine in vitro.
METHODS
The wild-type and 30 CYP2C19 variants were expressed in insect cells and each variant was characterized using fluoxetine as the substrate. Reactions were performed at 37°C with 20-1,000 µmol/L substrate for 30 min. By using ultra-high performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of norfluoxetine were determined.
RESULTS
Among the CYP2C19 variants tested, T130M showed similar intrinsic clearance (Vmax/Km) values with CYP2C191, while the intrinsic clearance values of other variants were significantly decreased (from 9.56 to 77.77%). In addition, CYP2C193 and *35FS could not be detected because they have no detectable enzyme activity.
CONCLUSION
In China, the assessment of CYP2C19 variants in vitro offers valuable information relevant to the personalized medicine for CYP2C19-metabolized drug.
目的
细胞色素P450酶超家族的一个重要成员是CYP2C19。我们最近在中国汉族人群中鉴定出31种CYP2C19等位基因。本研究的目的是评估这些等位基因亚型的催化活性及其在体外对氟西汀代谢的影响。
方法
野生型和30种CYP2C19变体在昆虫细胞中表达，每种变体以氟西汀为底物进行表征。反应在37°C下进行，底物浓度为20 - 1000 μmol/L，反应30分钟。通过超高效液相色谱 - 质谱法检测产物，测定去甲氟西汀的动力学参数Km、Vmax和内在清除率（Vmax/Km）。
结果
在所测试的CYP2C19变体中，T130M的内在清除率（Vmax/Km）值与CYP2C191相似，而其他变体的内在清除率值显著降低（从9.56%降至77.77%）。此外，无法检测到CYP2C193和*35FS，因为它们没有可检测的酶活性。
结论
在中国，体外评估CYP2C19变体为CYP2C19代谢药物的个体化医疗提供了有价值的信息。
Zotero 插件