Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase ( cytokines / arachidonic add / prostanoids / inflammation / mitogen / aspirin - like drugs )

نویسندگان

  • RODERICK J. FLOWER
  • JOHN R. VANE
چکیده

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 endotoxinactivated J774.2 macrophages) in intact ceils, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspfrin, 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. Ibuprofen 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 purifiedenzyme preparations. Diclofenac, BW755C, 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. Cyclo-oxygenase (COX; prostaglandin-endoperoxide synthase, EC 1.14.99.1) converts arachidonic acid to prostaglandin (PG) H2, which is then further metabolized by other enzymes to various PGs, prostacyclin, and thromboxanes (1). COX exists in at least two isoforms with similar molecular weights ("'70 kDa). COX-1 is expressed constitutively and was first characterized, purified, and cloned from sheep vesicular glands (2-7). Activation of COX-1 leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic (8) and by the gastric mucosa is cytoprotective (9). COX-2 is induced in cells exposed to proinflammatory agents, including cytokines (10), mitogens (11) and endotoxin (12, 13). Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the activity of COX, a property that accounts for their shared therapeutic and side effects (14). Thus, the ability of NSAIDs to inhibit The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. COX-2 may well explain their therapeutic utility as antiinflammatory drugs, whereas inhibition of COX-1 may explain their unwanted side effects, such as gastric and renal damage. After establishing that bovine aortic endothelial cells in culture contain COX-1 and that endotoxin-activated J774.2 macrophages contain COX-2, we have investigated the inhibitory effects of some NSAIDs on the activity of COX-1 and COX-2 in whole cells and broken cells and in purified enzyme preparations. Our results show that NSAIDs have different profiles ofinhibition ofCOX-1 and COX-2 in a range

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تاریخ انتشار 2005