SELECTIVITY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS AS INHIBITORS OF CONSTITUTIVE AND INDUCIBLE CYCLOOXYGENASE
SELECTIVITY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS AS INHIBITORS OF CONSTITUTIVE AND INDUCIBLE CYCLOOXYGENASE
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DOI：
10.1073/pnas.90.24.11693
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发表时间：
1993-12-15
影响因子：
11.1
通讯作者：
VANE, JR
中科院分区：
文献类型：
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作者：
MITCHELL, JA;AKARASEREENONT, P;VANE, JR
组成型环氧合酶（COX-1；前列腺素内过氧化物合酶，EC 1.14.99.1）在生理条件下存在于细胞中，而COX-2则可能在病理条件下（如炎症）由一些细胞因子、丝裂原和内毒素诱导产生。因此，我们评估了一些非甾体类抗炎药对完整细胞、破碎细胞和纯化酶制剂（羊精囊中的COX-1；羊胎盘中的COX-2）中COX-1（牛主动脉内皮细胞）和COX-2（内毒素活化的J774.2巨噬细胞）活性的相对抑制作用。阿司匹林、吲哚美辛和布洛芬对破碎细胞和纯化酶制剂的类似效力表明没有物种的影响。在所有使用的模型中，阿司匹林、吲哚美辛和布洛芬是COX-1比COX-2更有效的抑制剂。虽然IC50值不同，但阿司匹林和吲哚美辛的相对效力在不同模型之间的差异很小。与破碎细胞或纯化酶相比，布洛芬在完整细胞中作为COX-2的抑制剂更有效。在完整细胞中，水杨酸钠是两种COX亚型的弱抑制剂，在破碎细胞或纯化酶制剂中对COX无活性。双氯芬酸、BW 755C、对乙酰氨基酚和萘普生在完整细胞中是COX-1和COX-2的近似等效抑制剂。BF 389是一种目前正在人体试验的实验性药物，在完整细胞中是最有效和最具选择性的COX-2抑制剂。因此，两种酶之间存在明显的药理学差异。使用这种COX-1和COX-2活性模型将导致鉴定COX-2的选择性抑制剂，其副作用可能比目前的治疗方法要小。一些抑制剂在完整细胞中的活性高于对纯化酶的活性，这表明纯酶制剂可能不能预测治疗作用。
Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxin-activated J774.2 macrophages) in intact cells, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different. lbuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW 755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action.