SUPPRESSION OF INFLAMMATORY RESPONSES TO 12-O-TETRADECANOYLPHORBOL-13-ACETATE AND CARRAGEENAN BY YM-26734, A SELECTIVE INHIBITOR OF EXTRACELLULAR GROUP-II PHOSPHOLIPASE-A(2)
SUPPRESSION OF INFLAMMATORY RESPONSES TO 12-O-TETRADECANOYLPHORBOL-13-ACETATE AND CARRAGEENAN BY YM-26734, A SELECTIVE INHIBITOR OF EXTRACELLULAR GROUP-II PHOSPHOLIPASE-A(2)
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DOI：
10.1111/j.1476-5381.1993.tb13831.x
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发表时间：
1993-09-01
影响因子：
7.3
通讯作者：
KAWASHIMA, H
中科院分区：
文献类型：
--
作者：
MIYAKE, A;YAMAMOTO, H;KAWASHIMA, H
1 YM-26734 14（3，5-双十二烷酰基-2，4，6-三羟基苯基）-7-羟基-2-（4-羟基苯基）苯并二氢吡喃]剂量依赖性地抑制细胞外磷脂酶A2（PLA 2）的活性：兔血小板衍生的II组和猪胰腺衍生的I组PLA 2，IC 50值为0.085（0.056-0.129，n = 5）和6.8（5.0-9.6，n = 5）μ m。2相反，YM-26734没有降低从小鼠巨噬细胞制备的细胞内PLA 2的活性，其在高达50 μ m的浓度下优先水解花生四烯酸磷脂。YM-26734对绵羊精囊环氧合酶或大鼠白细胞5-脂氧合酶也没有作用。3 Lineweaver-Burk分析表明，YM-26567-1表现为兔血小板衍生的II组PLA 2的竞争性抑制剂，K（i）值为48 nm。4在小鼠中，YM-26734抑制12-0-十四酰基佛波醇-13-乙酸酯（TPA，1 μ g/耳）以剂量依赖性方式诱导耳水肿，ED 50值为45（30-67）μ g/耳（n=5）和11（4- 32）mg kg-1，i. v.（n = 5），但未降低花生四烯酸1 mg/耳和30 mg kg-1（4 mg/耳）诱导的耳水肿，i.v.5在大鼠中，在用YM-26734治疗的组中，响应于角叉菜胶注射（2 mg）的渗出液和白细胞在胸膜腔中的积聚显著较少（20 mg kg-1，i.v.）较对照组（每腔分别为0.43 +/- 0.02 vs 0.59 +/- 0.03 g和3.8 +/- 0.2 vs 4.9 +/- 0.3 x 10（7）个细胞; n = 5）。6这些结果表明YM-26734是一种有效的和竞争性的细胞外PLA 2抑制剂，对II组PLA 2具有选择性，并且II组酶活性的抑制可导致对TPA和角叉菜胶的炎症反应的抑制。
1 YM-26734 14-(3,5-didodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyphenyl)chroman] dose-dependently inhibited the activities of extracellular phospholipase A2 (PLA2): rabbit platelet-derived group II and porcine pancreas-derived group I PLA2, with IC50 values of 0.085 (0.056-0.129, n = 5) and 6.8 (5.0-9.6, n = 5) mum, respectively.2 In contrast, YM-26734 did not reduce the activity of intracellular PLA2 prepared from mouse macrophages, which preferentially hydrolyzed arachidonoyl phospholipids at concentrations up to 50 mum. YM-26734 also showed no effect against either sheep seminal vesicle cyclo-oxygenase or rat leukocyte 5-lipoxygenase.3 Lineweaver-Burk analysis showed that YM-26567-1 behaved as a competitive inhibitor of group II PLA2 derived from rabbit platelets, with a K(i) value of 48 nm.4 In mice, YM-26734 inhibited 12-0-tetradecanoylphorbol-13-acetate (TPA, 1 mug/ear)-induced ear oedema in a dose-dependent manner, with ED50 values of 45 (30-67) mug/ear (n=5) and 11 (4- 32) mg kg-1, i.v. (n = 5), but did not decrease arachidonic acid (4 mg/ear)-induced ear oedema at 1 mg/ear and 30 mg kg-1, i.v.5 In rats, the accumulation of exudate fluids and leukocytes in the pleural cavity in response to carrageenin injection (2 mg) was significantly less in a group treated with YM-26734 (20 mg kg-1, i.v.) than in the control group (0.43 +/- 0.02 vs 0.59 +/- 0.03 g per cavity and 3.8 +/- 0.2 vs 4.9 +/- 0.3 x 10(7) cells per cavity, respectively; n = 5).6 These results suggest that YM-26734 is a potent and competitive inhibitor of extracellular PLA2 with selectivity for group II PLA2, and that the inhibition of group II enzymes activity may cause the suppression of inflammatory responses to TPA and carrageenin.