Hamasaki Y, Shafigeh M, Yamamoto S, Sato R, Zaitu M, Muro E, Kobayashi I, Ichimaru T, Tasaki H, Miyazaki S
Department of Pediatrics, Saga Medical School, Japan.
Ann Allergy Asthma Immunol. 1996 May;76(5):469-75. doi: 10.1016/S1081-1206(10)63465-5.
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.
To clarify the mechanism of inhibition, we investigated the effects of three drugs on the function of phospholipase A2, 5-lipoxygenase, leukotriene C4 synthase, and leukotriene A4 hydrolase, which are all catabolic enzymes involved in synthesizing leukotriene C4 and leukotriene B4 in rat basophilic leukemia (RBL)-1 cells.
The production of leukotriene C4 and leukotriene B4 was measured by high performance liquid chromatography (HPLC). All three drugs inhibited the production of leukotriene C4 and leukotriene B4 when cells were stimulated with A23187. All three drugs also inhibited the A23187-stimulated release of 3H-arachidonic acid from membrane phospholipids. Azelastine inhibited the production of leukotriene C4, but not leukotriene B4, when either arachidonic acid or leukotriene A4 free acid was used as the substrate in our cell free system. Oxatomide and ketotifen did not inhibit the synthesis of either leukotriene C4 or leukotriene B4 in the same cell free study.
Results indicated that oxatomide and ketotifen inhibit the production of leukotriene C4 and leukotriene B4 by inhibiting phospholipase A2 activity, whereas, azelastine inhibits the leukotriene C4 production by inhibiting phospholipase A2 and leukotriene C4 synthase.
氮卓斯汀、奥沙米特和酮替芬用于治疗过敏性疾病患者。这些药物可抑制包括白三烯在内的化学介质的释放；然而，其作用机制尚不清楚。
为阐明抑制机制，我们研究了这三种药物对磷脂酶A2、5-脂氧合酶、白三烯C4合酶和白三烯A4水解酶功能的影响，这些都是参与大鼠嗜碱性白血病（RBL）-1细胞中白三烯C4和白三烯B4合成的分解代谢酶。
采用高效液相色谱法（HPLC）测定白三烯C4和白三烯B4的生成量。当用A23187刺激细胞时，这三种药物均抑制白三烯C4和白三烯B4的生成。这三种药物还抑制A23187刺激的膜磷脂中3H-花生四烯酸的释放。在我们的无细胞体系中，当以花生四烯酸或白三烯A4游离酸作为底物时，氮卓斯汀抑制白三烯C4的生成，但不抑制白三烯B4的生成。在相同的无细胞研究中，奥沙米特和酮替芬均不抑制白三烯C4或白三烯B4的合成。
结果表明，奥沙米特和酮替芬通过抑制磷脂酶A2活性来抑制白三烯C4和白三烯B4的生成，而氮卓斯汀通过抑制磷脂酶A2和白三烯C4合酶来抑制白三烯C4的生成。
