PGH synthase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs.
PGH synthase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs.
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DOI：
10.1016/0002-9343(93)90396-7
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发表时间：
1993-08-09
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影响因子：
--
通讯作者：
Smith, W L
中科院分区：
文献类型：
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作者：
DeWitt, D L;Meade, E A;Smith, W L
随着前列腺素内过氧化物（PGH）合成酶（环加氧酶）编码基因的克隆，哺乳动物细胞中含有两种相关但独特的PGH合成酶同工酶已经变得很明显。这两种同工酶都催化花生四烯酸转化为PGH2，从而产生具有生物活性的前列腺素。虽然第一种同工酶PGH合成酶-1 （PGHS-1）一直被认为是非甾体抗炎药（NSAIDs）的主要和唯一作用位点，但现在已知第二种同工酶PGH合成酶-2 （PGHS-2）对NSAIDs也很敏感。克隆小鼠PGHS-1和PGHS-2的互补dna，使这两种同工酶在cos-1细胞系统中单独表达，并比较了几种常见非甾体抗炎药对它们的相对抑制作用。这些研究表明，PGHS-1和PGHS-2这两种小鼠同工酶在药理学上是不同的。PGHS-1是一种组成性表达酶，早期观察表明，它是产生前列腺素的主要酶，前列腺素调节细胞内务功能，如胃细胞保护、血管稳态和肾脏功能。相比之下，PGHS-2似乎只在炎症组织或暴露于生长因子、淋巴因子或其他炎症介质后表达。抗炎糖皮质激素抑制PGHS-2的表达，进一步支持该酶产生参与炎症的前列腺素的假设。我们已经发现非甾体抗炎药优先抑制小鼠PGHS-1或PGHS-2，或同样抑制这两种同工酶。这两种同工酶可以被差异抑制的发现为鉴定更安全、更有效的非甾体抗炎药提供了可能的机制。筛选优先抑制PGHS-2的药物可以识别出减轻炎症的非甾体抗炎药，但可以减少肾脏和胃前列腺素的合成，从而减少大多数非甾体抗炎药通常伴随的不良副作用。到目前为止，纳布美酮是唯一确定的优先抑制小鼠PGHS-2的非甾体抗炎药。
With the recent cloning of a second gene coding for the prostaglandin endoperoxide (PGH) synthase (cyclooxygenase), it has become obvious that mammalian cells contain two related, but unique, isozymes of PGH synthase. Both of these isozymes catalyze the conversion of arachidonic acid to PGH2, leading to production of biologically active prostaglandins. Although the first of these isozymes, PGH synthase-1 (PGHS-1), has long been thought to be the primary and sole site of action of nonsteroidal antiinflammatory drugs (NSAIDs), it is now known that the second isozyme, PGH synthase-2 (PGHS-2), is also sensitive to NSAIDs. Cloning of complementary DNAs for murine PGHS-1 and PGHS-2 has permitted individual expression of these two isozymes in the cos-1 cell system and comparison of their relative inhibition by several common NSAIDs in vitro. These studies have demonstrated that the two mouse isozymes, PGHS-1 and PGHS-2, are pharmacologically distinct. PGHS-1 is a constitutively expressed enzyme that early observations indicate is the principal enzyme involved in producing prostaglandins that regulate cellular housekeeping functions, such as gastric cytoprotection, vascular homeostasis, and kidney function. In contrast, PGHS-2 appears only to be expressed in inflamed tissue or following exposure to growth factors, lymphokines, or other mediators of inflammation. Expression of PGHS-2 is inhibited by antiinflammatory glucocorticoids, lending further support to the hypothesis that this enzyme produces prostaglandins involved in inflammation. We have identified NSAIDs that preferentially inhibit murine PGHS-1 or PGHS-2 or inhibit both isozymes equally. The finding that the two isozymes can be differentially inhibited provides a possible mechanism for identifying safer, more effective NSAIDs. Screening for drugs that preferentially inhibit PGHS-2 may allow identification of NSAIDs that reduce inflammation, but spare renal and gastric prostaglandin synthesis, thus reducing the untoward side effects commonly associated with most NSAIDs. Thus far, nabumetone is the only NSAID identified that preferentially inhibits murine PGHS-2.