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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1
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Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

机译:考昔布通过与环氧合酶1的一种单体紧密结合而干扰阿司匹林的作用。

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摘要

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 antiinflam-matory 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.
机译:与炎症相关的疼痛涉及由花生四烯酸(AA)通过环氧合酶2(COX-2)途径合成的前列腺素,而由血小板通过环氧合酶1(COX-1)形成的血栓烷A_2介导了血栓形成。 COX-1和COX-2都是包括阿司匹林在内的非选择性非甾体抗炎药(nsNSAIDs)的靶标,而COX-2活性优先被称为coxibs的COX-2抑制剂阻断。 COXs是由相同亚基组成的同型二聚体,但我们已经表明在催化过程中一次仅一个亚基是有活性的。此外,许多nsNSAIDS与COX二聚体的单个亚基结合以抑制整个二聚体的COX活性。在这里,我们报告了令人惊讶的观察结果,塞来昔布和其他coxib与COX-1的一个亚基紧密结合。尽管塞来昔布与COX-1的一个单体结合不会影响第二个伴侣亚基对AA的正常催化作用,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celecoxib / COX-1复合物获得的X射线晶体学结果表明,celecoxib如何结合到COX-1二聚体的两个可用COX位点之一。最后,我们发现向犬施用塞来昔布会干扰低剂量阿司匹林抑制AA诱导的离体血小板聚集的能力。 COX-2抑制剂(如塞来昔布)被广泛用于缓解疼痛。由于考昔布具有心血管副作用,因此经常与低剂量阿司匹林联用以预防血栓形成。我们的研究预测,小剂量阿司匹林与coxibs联合使用可能对心血管的保护作用减弱。

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