The antiinflammatory activity of analogs of indomethacin correlates with their inhibitory effects on phospholipase A 2 of rabbit polymorphonuclear leukocytes

Abstract

The effect of the antiinflammatory agent sulindac sulfide, a sulfated analog of indomethacin and an inhibitor of prostaglandin synthesis in vitro, on the action of partially purified rabbit polymorphonuclear leukocyte phospholipase A 2 (EC 3.1.1.4) was examined. Sulindac sulfide produces a dose-dependent inhibition of this phospholipase A 2 ( I 50 = 10 μM) that is still recognizable at 1 μM. This inhibition is of the noncompetitive type with an apparent K of 5 μM and in all aspects examined cannot be distinguished from the effects, recently reported (Kaplan, L., Weiss, J. and Elsbach, P. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 2955–2958), of indomethacin on the enzyme. In contrast, the pharmacologically inactive analogs sulindac sulfoxide and sulindac sulfone are without any inhibitory effect at 100 μM. Other antiinflammatory agents, including the steroids dexamethasone and hydrocortisone hemisuccinate, and the non-steroids acetylsalicyclic acid, sodium salicylate, sulfinpyrazone and quinacrine also do not inhibit the leukocyte phospholipase A 2 at concentrations as high as 100 μM. Meclofenamic acid and flufenamic acid are weakly inhibitory ( I 50 = 100–500 μM). The apparent specificity of the inhibition of leukocyte phospholipase A 2 by low concentrations of pharmacologically active analogs of indomethacin supports our contention that this effect may contribute to the effects of these agents on prostaglandin synthesis.