CYP2C19*10 等位基因对氯吡格雷激活和 CYP2C19*2 基因分型的影响。
The influence of the CYP2C19*10 allele on clopidogrel activation and CYP2C19*2 genotyping.
机构信息
aDepartment of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, Florida bDepartment of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA cKey Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People's Republic of China dNational Institute of Environmental Health Science, Research Triangle Park, North Carolina, USA.
出版信息
Pharmacogenet Genomics. 2014 Aug;24(8):381-6. doi: 10.1097/FPC.0000000000000068.
BACKGROUND/OBJECTIVES: The polymorphic hepatic enzyme CYP2C19 catalyzes the metabolism of clinically important drugs such as clopidogrel, proton-pump inhibitors, and others and clinical pharmacogenetic testing for clopidogrel is increasingly common. The CYP2C1910 single-nucleotide polymorphism (SNP) is located 1 bp upstream the CYP2C192 SNP. Despite the low frequency of the CYP2C1910 allele, its impact on metabolism of CYP2C19 substrates and CYP2C192 genotyping makes it an important SNP to consider for pharmacogenetic testing of CYP2C19. However, the effect of the CYP2C19*10 allele on clopidogrel metabolism has not been explored to date.
METHODS
We measured the enzymatic activity of the CYP2C19.10 protein against clopidogrel. DNA samples from two clinical studies were genotyped for CYP2C19*2 and *10 by pyrosequencing genotyping method.
RESULTS
The catalytic activity of CYP2C19.10 in the biotransformation of clopidogrel and 2-oxo-clopidogrel was significantly decreased relative to the wild-type CYP2C19.1B. We also reported that the CYP2C1910 SNP interferes with the CYP2C192 TaqMan genotyping assay, resulting in miscalling of CYP2C19*10/2 as CYP2C192/*2.
CONCLUSIONS
Our data provide evidence that CYP2C19.10 variant partially metabolizes clopidogrel and 2-oxo-clopidogrel, and the presence of CYP2C1910 allele affects the CY2C192 TaqMan genotyping assay and results in misclassification of CYP2C19*10/2 as CYP2C192/*2.
背景/目的：多态性肝酶 CYP2C19 催化氯吡格雷、质子泵抑制剂等临床重要药物的代谢，临床药物遗传学检测氯吡格雷越来越普遍。CYP2C1910 单核苷酸多态性（SNP）位于 CYP2C192 SNP 的上游 1bp。尽管 CYP2C1910 等位基因的频率较低，但它对 CYP2C19 底物代谢和 CYP2C192 基因分型的影响使其成为 CYP2C19 药物遗传学检测中需要考虑的重要 SNP。然而，迄今为止，CYP2C19*10 等位基因对氯吡格雷代谢的影响尚未得到探索。
方法
我们测量了 CYP2C19.10 蛋白对氯吡格雷的酶活性。通过焦磷酸测序基因分型方法对来自两项临床研究的 DNA 样本进行 CYP2C19*2 和 *10 基因分型。
结果
CYP2C19.10 在氯吡格雷和 2-氧代-氯吡格雷生物转化中的催化活性明显低于野生型 CYP2C19.1B。我们还报告称，CYP2C1910 SNP 干扰 CYP2C192 TaqMan 基因分型检测，导致 CYP2C19*10/2 误判为 CYP2C192/*2。
结论
我们的数据提供了证据表明 CYP2C19.10 变体部分代谢氯吡格雷和 2-氧代-氯吡格雷，并且 CYP2C1910 等位基因的存在影响 CYP2C192 TaqMan 基因分型检测，导致 CYP2C19*10/2 误判为 CYP2C192/*2。
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