INHIBITION OF LEUKOTRIENE SYNTHESIS BY AZELASTINE

Background: Azelastine, oxatomide, and ketotifen are used for patients with allergic diseases. These drugs inhibit the release of chemical m ediators including the leukotrienes; however, the mechanism involved i s unclear. Objective: To clarify the mechanism of inhibition, we inves tigated the effects of three drugs on the function of phospholipase A( 2), 5-lipoxygenase, leukotriene C-4 synthase, and leukotriene A(4) hyd rolase, which are all catabolic enzymes involved in synthesizing leuko triene C-4 and leukotriene B-4 in rat basophilic leukemia (RBL)-1 cell s. Methods and Results: The production of leukotriene C-4 and leukotri ene B-4 was measured by high performance liquid chromatography (HPLC). All three drugs inhibited the production of leukotriene C-4 and leuko triene Bq when cells were stimulated with A23187. All three drugs also inhibited the A23187-stimulated release of H-3-arachidonic acid from membrane phospholipids. Azelastine inhibited the production of leukotr iene C-4, but not leukotriene B-4, when either arachidonic acid or leu kotriene A(4) free acid was used as the substrate in our cell free sys tem. Oxatomide and ketotifen did not inhibit the synthesis of either l eukotriene C-4 or leukotriene B-4 in the same cell free study. Conclus ion: Results indicated that oxatomide and ketotifen inhibit the produc tion of leukotriene C-4 and leukotriene B-4 by inhibiting phospholipas e A(2) activity, whereas, azelastine inhibits the leukotriene C-4 prod uction by inhibiting phospholipase A(2) and leukotriene C-4 synthase.