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 mediators including the leukotrienes; however, the mechanism involved is unclear. Objective: To clarify the mechanism of inhibition, we investigated the effects of three drugs on the function of phospholipase A(2), 5-lipoxygenase, leukotriene C-4 synthase, and leukotriene A(4) hydrolase, which are all catabolic enzymes involved in synthesizing leukotriene C-4 and leukotriene B-4 in rat basophilic leukemia (RBL)-1 cells. Methods and Results: The production of leukotriene C-4 and leukotriene B-4 was measured by high performance liquid chromatography (HPLC). All three drugs inhibited the production of leukotriene C-4 and leukotriene 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 leukotriene C-4, but not leukotriene B-4, when either arachidonic acid or leukotriene A(4) free acid was used as the substrate in our cell free system. Oxatomide and ketotifen did not inhibit the synthesis of either leukotriene C-4 or leukotriene B-4 in the same cell free study. Conclusion: Results indicated that oxatomide and ketotifen inhibit the production of leukotriene C-4 and leukotriene B-4 by inhibiting phospholipase A(2) activity, whereas, azelastine inhibits the leukotriene C-4 production by inhibiting phospholipase A(2) and leukotriene C-4 synthase.