Kusner E J, Marks R L, Aharony D, Krell R D
Department of Pharmacology, ICI Pharmaceuticals, Wilmington, DE 19897.
Biochem Pharmacol. 1989 Dec 1;38(23):4183-9. doi: 10.1016/0006-2952(89)90513-3.
The 5-lipoxygenase inhibitor REV-5901 [alpha-pentyl-3-(2-quinolinylmethoxy)benzene-methanol] was evaluated for effects on mediator release in vitro from fragmented guinea-pig and human lung. In guinea-pig lung, REV-5901 inhibited the antigen-induced release of immunoreactive leukotriene D4 (iLTD4) with an IC50 of 9.6 +/- 2.9 microM and immunoreactive leukotriene B4 (iLTB4) with an IC50 of 13.5 +/- 2.2 microM. REV-5901 also inhibited the calcium ionophore-induced release of immunoreactive leukotrienes from human lung in vitro with IC50 values of 11.7 +/- 2.2 MicroM versus peptide leukotrienes and 10.0 +/- 1.1 microM versus iLTB4. The inhibition of release of iLTD4 and iLTB4 with similar IC50 values suggests that REV-5901 acts by inhibiting 5-lipoxygenase in this system. At concentrations as high as 50 microM, REV-5901 did not inhibit the release of thromboxane B2 (TxB2), 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha), or histamine from either lung. The lack of effect on TxB2 and 6-keto-PGF1 alpha indicates that REV-5901 did not inhibit phospholipase A2, cyclooxygenase, or thromboxane synthetase. Inhibition of leukotriene release by REV-5901 could not be reversed by washing. Among various 5-lipoxygenase inhibitors, the order of potency for inhibition of iLTD4 release from guinea-pig lung was AA-861 greater than REV-5901 greater than phenidone greater than nafazatrom greater than NDGA greater than BW755C. These findings suggest that REV-5901 is a selective and relatively potent inhibitor of leukotriene release from lung tissue in vitro.
对5-脂氧合酶抑制剂REV-5901 [α-戊基-3-(2-喹啉甲氧基)苯甲醇] 进行了评估，观察其对豚鼠和人肺组织碎片体外介质释放的影响。在豚鼠肺中，REV-5901抑制抗原诱导的免疫反应性白三烯D4（iLTD4）释放，IC50为9.6±2.9微摩尔，抑制免疫反应性白三烯B4（iLTB4）释放，IC50为13.5±2.2微摩尔。REV-5901还在体外抑制钙离子载体诱导的人肺免疫反应性白三烯释放，对肽白三烯的IC50值为11.7±2.2微摩尔，对iLTB4的IC50值为10.0±1.1微摩尔。以相似的IC50值抑制iLTD4和iLTB4释放表明，REV-5901在该系统中通过抑制5-脂氧合酶发挥作用。在浓度高达50微摩尔时，REV-5901不抑制来自任何一种肺组织的血栓素B2（TxB2）、6-酮-前列腺素-F1α（6-酮-PGF1α）或组胺的释放。对TxB2和6-酮-PGF1α无影响表明REV-5901不抑制磷脂酶A2、环氧化酶或血栓素合成酶。洗涤不能逆转REV-5901对白三烯释放的抑制作用。在各种5-脂氧合酶抑制剂中，抑制豚鼠肺iLTD4释放的效力顺序为AA-861＞REV-5901＞非那吡啶＞萘呋胺酯＞去甲二氢愈创木酸＞BW755C。这些发现表明，REV-5901是体外肺组织白三烯释放的一种选择性且相对强效的抑制剂。
