Low concentrations of indomethacin inhibit phospholipase A2 of rabbit polymorphonuclear leukocytes

Inhibition of prostaglandin synthesis by indomethacin, a drug with anti-inflammatory properties, has been attributed to its action on fatty acid cyclooxygenase. However, prostaglandin synthesis would also be inhibited if precursor fatty acids were not supplied. We find that indomethacin inhibits phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) of rabbit polymorphonuclear leukocytes in dose-dependent fashion. Inhibition is immediate and readily detected at 1 micrometer. The extent of inhibition is the same over a 10-fold range of substrate concentration and over a 500-fold range of enzyme purification. Inhibition is of the noncompetitive type, with an apparent Ki of 12 micrometer. Four other phospholipases A2--from venoms of Russell viper, Crotalus adamanteus, and bee, and from pig pancreas--are unaffected by 50 micrometer indomethacin, which inhibits leukocyte phospholipase A2 by 70%. This inhibition at low concentrations may well be important in the effects of the drug on protaglandin synthesis and inflammatory responses.