Smith W L, Meade E A, DeWitt D L
Department of Biochemistry, Michigan State University, East Lansing 48824.
Ann N Y Acad Sci. 1994 Nov 15;744:50-7. doi: 10.1111/j.1749-6632.1994.tb52723.x.
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 same two reactions: oxygenation of arachidonate to yield PGG2 and reduction of PGG2 to PGH2. PGH synthase-1 is expressed constitutively and is found in most tissues. PGH synthase-2 is undetectable in most cells but can be induced in fibroblasts, endothelial cells, ovarian follicles, and macrophages by various mitogens, cytokines, and tumor promoters. PGH synthase-1 (PGHS-1) has been presumed to be the site of action of nonsteroidal antiinflammatory drugs (NSAIDs). However, the discovery of the second isozyme, PGH synthase-2 (PGHS-2), and its association with inflammation has suggested that this latter enzyme may be the therapeutic target of NSAIDs functioning in their antiinflammatory capacities. We have cloned cDNAs for murine PGHS-1 and PGHS-2, expressed these enzymes in cos-1 cells, and compared the relative sensitivities of the two isozymes to some common NSAIDs. Indomethacin, piroxicam, and sulindac sulfide were found to 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 PGH2 or any other oxygenated 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. Our results indicate mouse PGHS-1 and PGHS-2 are pharmacologically distinct. Thus, it should be possible to develop agents highly selective for each PGHS isozyme. PGHS-2 is not expressed in stomach but is increased by inflammatory cytokines in cells such as macrophages. Thus, a selective inhibitor of PGHS-2 could be an antiinflammatory agent but without being ulcerogenic.
前列腺素内过氧化物（PGH）合酶（环氧化酶）有两种同工酶，分别称为PGH合酶-1和-2或COX I和COX II。这两种同工酶催化相同的两个反应：花生四烯酸的氧化生成PGG2以及PGG2还原为PGH2。PGH合酶-1组成性表达，存在于大多数组织中。PGH合酶-2在大多数细胞中检测不到，但可被各种促有丝分裂原、细胞因子和肿瘤启动子在成纤维细胞、内皮细胞、卵巢卵泡和巨噬细胞中诱导表达。PGH合酶-1（PGHS-1）一直被认为是非甾体抗炎药（NSAIDs）的作用位点。然而，第二种同工酶PGH合酶-2（PGHS-2）的发现及其与炎症的关联表明，后一种酶可能是NSAIDs发挥抗炎作用的治疗靶点。我们克隆了小鼠PGHS-1和PGHS-2的cDNA，在cos-1细胞中表达了这些酶，并比较了这两种同工酶对一些常见NSAIDs的相对敏感性。发现吲哚美辛、吡罗昔康和舒林酸硫化物优先抑制PGHS-1。布洛芬和甲氯芬那酸以相当的效力抑制这两种酶。Relafen的活性代谢物6-甲氧基-2-萘乙酸优先抑制小鼠PGHS-2。阿司匹林不可逆地抑制PGHS-1，阻止该同工酶形成PGH2或任何其他氧化产物；相反，用阿司匹林处理PGHS-2会使该酶形成15-羟基-5c,8c,11c,13t-二十碳四烯酸（15-HETE）而不是PGH2。我们的结果表明小鼠PGHS-1和PGHS-2在药理学上是不同的。因此，应该有可能开发出对每种PGHS同工酶具有高度选择性的药物。PGHS-2在胃中不表达，但在巨噬细胞等细胞中可被炎性细胞因子上调。因此，PGHS-2的选择性抑制剂可能是一种抗炎药，但不会引起溃疡。
