PHARMACOLOGY OF PROSTAGLANDIN ENDOPEROXIDE SYNTHASE ISOZYME-1 AND ISOZYME-2
PHARMACOLOGY OF PROSTAGLANDIN ENDOPEROXIDE SYNTHASE ISOZYME-1 AND ISOZYME-2
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DOI：
10.1111/j.1749-6632.1994.tb12037.x
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发表时间：
1994-01-01
期刊：
影响因子：
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通讯作者：
DEWITT, DL
中科院分区：
文献类型：
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作者：
SMITH, WL;MEADE, EA;DEWITT, DL
现在前列腺素内过氧化物（PGH）合酶（环氧合酶）有两种同工酶，称为PGH合酶-1和-2或COX I和II。两种同工酶均可催化花生四烯酸转化为 PGH2，这是形成前列环素和血栓素 A2 的关键步骤。 PGH 合酶-1 存在于血小板和内皮细胞中，而 PGH 合酶-2 已在用细胞因子和佛波酯处理的内皮细胞中检测到。 PGH 合酶-1 (PGHS-1) 长期以来被认为是非甾体类抗炎药 (NSAID) 的作用位点。然而，现在已经清楚，第二种同工酶 PGH 合成酶 2 (PGHS-2) 也受到这些化合物的抑制。小鼠 PGHS-1 和 PGHS-2 cDNA 的克隆使我们能够在 cos-1 细胞中表达这两种酶，并使用一系列常见的 NSAID 在体外比较这些酶的相对敏感性。 NSAIDs，例如吲哚美辛、吡罗昔康和硫化舒林酸优先抑制 PGHS-1。布洛芬和甲氯芬那酯对这两种酶的抑制作用相当。 6-Methoxy-2-naphthylacetacid 是 Relafen 的活性代谢物，优先抑制小鼠 PGHS-2。阿司匹林不可逆地抑制 PGHS-1，阻止该同工酶形成任何产物；相比之下，阿司匹林处理 PGHS-2 会导致该酶形成 15-羟基-5c、8c、11c、13t-二十碳四烯酸 (15-HETE)，而不是 PGH2。这些结果表明，这两种小鼠酶在药理学上是不同的，并表明有可能鉴定或设计对每种 PGHS 同工酶具有完全选择性的化合物。由于 PGHS-2 通常仅在发炎组织中或暴露于炎症介质后表达，因此该同工酶的选择性抑制剂可能表现出抗炎活性，而不影响血小板的 PGHS-1，并且可能不会产生与常用 NSAID 相关的溃疡作用。
It is now that there are two isozymes of prostaglandin endoperoxide (PGH) synthase (cyclooxygenase) called PGH synthase-1 and-2 or COX I and II. Both isozymes catalyze the conversion of arachidonate to PGH2, the committed step in the formation of both prostacyclin and thromboxane A2. PGH synthase-1 is present in platelets and endothelial cells whereas PGH synthase-2 has been detected in endothelial cells treated with cytokines and phorbol esters. PGH synthase-1 (PGHS-1) has long been thought to be the site of action of nonsteroidal anti-inflammatory drugs (NSAIDs). However, it is now clear that the second isozyme, PGH synthase-2 (PGHS-2), is also inhibited by these compounds. Cloning of the cDNAs for murine PGHS-1 and PGHS-2 has allowed us to express these two enzymes in cos-1 cells and to compare the relative sensitivities of these enzymes in vitro using a series of common NSAIDs. NSAIDs such as indomethacin, piroxicam, and sulindac sulfide preferentially inhibit PGHS-1. Ibuprofen and meclofenamate inhibit both enzymes with comparable potencies. 6-Methoxy-2-naphthylacetic acid, the active metabolite of Relafen, inhibits murine PGHS-2 preferentially. Aspirin irreversibly inhibits PGHS-1, preventing this isozyme from forming any product; in contrast, aspirin treatment of PGHS-2 causes this enzyme to form 15-hydroxy-5c, 8c, 11c, 13t-eicosatetraenoic acid (15-HETE) instead of PGH2. These results establish that the two mouse enzymes are pharmacologically distinct and suggest that it will be possible to identify or design compounds that are completely selective for each PGHS isozyme. Because PGHS-2 is usually only expressed in inflamed tissue or after exposure to mediators of inflammation, a selective inhibitor of this isoenzyme may exhibit anti-inflammatory activity without effects on PGHS-1 of platelets and perhaps without ulcerogenic effects associated with commonly available NSAIDs.