人類羧酸酯酶 (carboxylesterase, CES) 是一種絲氨酸酯解酶，其按序列同源性可 分為CES1、CES2、CES3、CES4 和 CES5 等型態，主要針對許多藥物結構中的酯 鍵和醯胺鍵進行化學鍵的水解。近年來，藥物基因體學研究已證實CES1 和 CES2 之 相關基因變異會影響藥物代謝和臨床治療結果。目前研究發現受CES1 的基因多型 性影響的藥物有dabigatran etexilate、methylphenidate、oseltamivir、imidapril，以 及 clopidogrel，而受CES2 基因多型性影響的則有aspirin 與 irinotecan 兩種藥物。 其中clopidogrel 廣泛應用於心血管疾病治療中，是一種強而專一的血小板凝集抑制 劑，為前驅藥 (prodrug) 需透過 cytochrome P450 2C19 (CYP2C19) 氧化成活性代謝物 (active metabolite)。作用機轉為其活性代謝物不可逆的結合在adenosine diphosphate (ADP) 受體purinergic receptor P2Y, G-protein coupled 12 (P2Y12) 上，達到抗血小板 的作用。臨床使用於有栓塞病史的病人，可降低中風、心肌梗塞或周邊血管粥狀動脈 硬化而導致死亡的發生率，而且對於非ST 段上升之急性冠狀動脈症 (acute coronary syndrome)，以及動脈繞道介入治療 (percutaneous coronary intervention) 的患者能顯著降低粥狀動脈硬化血栓形成的再發生率。然而不樂見的復發血栓事件依然存在，推 測 CES1 基因多型性 (rs71647871; NM_001025194.1: c.428G>A) 影響了clopidogrel 的代謝，造成clopidogrel 的治療濃度不穩定，因而干擾其抗血小板的作用。在這篇 綜述中，我們同時概述了CES 的分子功能和基因多型性特性，運用分子模擬來呈現 CES1 c.428G>A 結構上的差異，並藉由相關研究來闡述CES1 變異與clopidogrel 藥 物代謝之間的關係。

ABSTRACT

Human carboxylesterases (CES), including the CES1, CES2, CES3, CES4, and CES5, are the serine esterase that mainly hydrolyzes chemical bonds in many pharmaceutical ingredients such as the ester and amide bonds. Among all carboxylesterases, the two most common types, the CES1 and CES2, are involved in affecting drug metabolism and clinical outcomes. Studies so far have found that the polymorphism of CES1 gene affects the metabolic activities of several medications, including dabigatran etexilate, methylphenidate, oseltamivir, imidapril, and clopidogrel. On the other hand, the polymorphism of CES2 gene mainly affects both aspirin and irinotecan. Of the aforementioned medications, clopidogrel, the platelet purinergic receptor P2Y, G-protein coupled 12 (P2Y12) inhibitor, is a second-generation thienopyridine derivative extensively used as an orally administered antiplatelet agent to reduce ischemic and thrombotic complications. However, recurring events persist in some patients with acute coronary syndrome and percutaneous coronary intervention, probably due in part to the insufficient platelet inhibition by biased treatment concentrations of clopidogrel related to the CES1 gene polymorphism (rs71647871; NM_001025194.1: c.428G>A) influencing the absorption, metabolism, and P2Y12 receptor action of clopidogrel. In this article, we outline the molecular and genetic polymorphisms of CES1, using molecular simulations, to present differences in CES1 c.428G>A structure and illustrate the binding affinity between the CES1 mutations and clopidogrel. Key words: Clopidogrel, Carboxylesterase, Pharmacogenomics, Single Nucleotide Polymorphism