Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender
Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender
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DOI：
10.1016/j.bcp.2016.09.003
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发表时间：
2016-11-01
影响因子：
5.8
通讯作者：
Zhu, Hao-Jie
中科院分区：
文献类型：
--
作者：
Shi, Jian;Wang, Xinwen;Zhu, Hao-Jie
口服抗凝前体药达比卡特兰乙酯(DABE)在肠道羧酸酯酶2(CES2)和肝羧酸酯酶1(CES1)作用下依次代谢，形成其活性代谢物达比卡特兰(DAB)。最近的全基因组关联研究报告了CES1单核苷酸多态(SNPs)rs2244613和rs8192935与长期抗凝治疗随机评估(RE-LY)研究参与者中较低的DAB血浆浓度相关。此外，在临床研究中观察到接触DAB的性别差异。这项研究的目的是用几种体外方法检测CES1基因多态和性别对DABE激活的影响。检测了104例正常人肝组织中CES1 SNPs rs2244613、rs8192935和已知的CES1功能缺失突变体rs71647871(G143E)的基因分型，以及DABE及其中间代谢产物M1和M2的活性。在携带G143E变体的人肝脏中，发现DABE、M1和M2的激活受到损害。然而，rs2244613和rs8192935都与人体肝脏中的激活无关。G143E转基因细胞的上清液(S9)与DABE的孵育研究表明，G143E是DABE代谢的功能缺失突变体。此外，女性肝脏组织中CES1活性对M2活性的影响显著高于男性。我们的数据表明，CES1基因变异和性别是人类DABE激活可变性的重要贡献因素。基于患者特定CES1基因型别和性别的个性化DABE治疗方法可能有可能提高DABE药物治疗的有效性和安全性。(C)2016 Elsevier Inc.保留所有权利。
The oral anticoagulant prodrug dabigatran etexilate (DABE) is sequentially metabolized by intestinal carboxylesterase 2 (CES2) and hepatic carboxylesterase 1 (CES1) to form its active metabolite dabigatran (DAB). A recent genome-wide association study reported that the CES1 single nucleotide polymorphisms (SNPs) rs2244613 and rs8192935 were associated with lower DAB plasma concentrations in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study participants. In addition, gender differences in exposure to DAB were observed in clinical studies. The aim of this study was to examine the effect of CES1 genetic polymorphisms and gender on DABE activation using several in vitro approaches. The genotypes of the CES1 SNPs rs2244613, rs8192935, and the known loss-of-function CES1 variant rs71647871 (G143E), and the activation of DABE and its intermediate metabolites M1 and M2 were determined in 104 normal human liver samples. DABE, M1, and M2 activations were found to be impaired in human livers carrying the G143E variant. However, neither rs2244613 nor rs8192935 was associated with the activation in human livers. The incubation study of DABE with supernatant fractions (S9) prepared from the G143E-transfected cells showed that the G143E is a loss-of-function variant for DABE metabolism. Moreover, hepatic CES1 activity on M2 activation was significantly higher in female liver samples than male. Our data suggest that CES1 genetic variants and gender are important contributing factors to variability in DABE activation in humans. A personalized DABE treatment approach based on patient-specific CES1 genotypes and sex may have the potential to improve the efficacy and safety of DABE pharmacotherapy. (C) 2016 Elsevier Inc. All rights reserved.