Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 4810, USA.
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):28-33. doi: 10.1073/pnas.0909765106. Epub 2009 Dec 1.
Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.
与炎症相关的疼痛涉及通过环氧化酶-2 (COX-2) 途径从花生四烯酸 (AA) 合成的前列腺素，而血小板通过环氧化酶-1 (COX-1) 从 AA 形成的血栓素 A(2)介导血栓形成。COX-1 和 COX-2 都是非选择性非甾体抗炎药 (nsNSAIDs) 的靶标，包括阿司匹林，而 COX-2 活性则被称为 COX-2 抑制剂的 COX-2 抑制剂优先阻断。COX 是由相同亚基组成的同源二聚体，但我们已经表明，在催化过程中一次只有一个亚基是活跃的；此外，许多 nsNSAIDs 结合 COX 二聚体的一个亚基以抑制整个二聚体的 COX 活性。在这里，我们报告了一个令人惊讶的观察结果，即塞来昔布和其他 COX-2 抑制剂紧密结合 COX-1 的一个亚基。尽管塞来昔布结合 COX-1 的一个单体不会影响第二个亚基对 AA 的正常催化处理，但塞来昔布确实会干扰阿司匹林在体外对 COX-1 的抑制作用。用塞来昔布/COX-1 复合物获得的 X 射线晶体学结果显示了塞来昔布如何能够结合 COX-1 二聚体的两个可用 COX 位点之一。最后，我们发现给狗服用塞来昔布会干扰低剂量阿司匹林抑制 AA 诱导的体外血小板聚集的能力。塞来昔布等 COX-2 抑制剂被广泛用于缓解疼痛。由于 COX-2 抑制剂具有心血管副作用，因此通常与低剂量阿司匹林一起开处方以预防血栓形成。我们的研究预测，当与 COX-2 抑制剂一起服用时，低剂量阿司匹林对 COX-1 的心脏保护作用可能会减弱。
