SELECTIVITY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS AS INHIBITORS OF CONSTITUTIVE AND INDUCIBLE CYCLOOXYGENASE

Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthas e, EC 1.14.99.1) is present in cells under physiological conditions, w hereas COX-2 is induced by some cytokines, mitogens, and endotoxin pre sumably in pathological conditions, such as inflammation. Therefore, w e have assessed the relative inhibitory effects of some nonsteroidal a ntiinflammatory drugs on the activities of COX-1 (in bovine aortic end othelial 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 potencie s of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspiri n, indomethacin, and ibuprofen were more potent inhibitors of COX-1 th an COX-2 in all models used. The relative potencies of aspirin and ind omethacin varied only slightly between models, although the IC50 value s were different. lbuprofen was more potent as an inhibitor of COX-2 i n 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 a pproximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was th e most potent and most selective inhibitor of COX-2 in intact cells. T hus, there are clear pharmacological differences between the two enzym es. The use of such models of COX-1 and COX-2 activity will lead to th e identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activ ity in intact cells than against purified enzymes, suggesting that pur e enzyme preparations may not be predictive of therapeutic action.