Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo
Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo
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DOI：
10.1007/s00018-009-0078-3
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发表时间：
2009-08-01
影响因子：
8
通讯作者：
Werz, Oliver
中科院分区：
文献类型：
--
作者：
Feisst, Christian;Pergola, Carlo;Werz, Oliver
我们先前的研究表明，在体外，贯叶连翘中的金丝桃素可以抑制白三烯生物合成的关键酶--5-脂氧合酶(5-LO)。在这里，我们证明了金丝桃素作为5-LO抑制剂具有新颖而独特的分子药理学特征，在体内具有显著的疗效。金丝桃素(4 mg/kg，ip)显著抑制角叉菜胶处理的大鼠胸腔渗出液中白三烯B-4的形成，这与有效的抗炎效果有关。在磷脂酰胆碱存在下，金丝桃素对5-LO的抑制作用被取消，而铁配位型5-LO抑制剂BWA4C或非氧化还原类型抑制剂ZM230487对5-LO的抑制作用被取消，并被5-LO C2样结构域的突变(W13A-W75A-W102A)强烈减少。此外，金丝桃素削弱了5-LO与Coactosin样蛋白的相互作用，并取消了离子霉素刺激的中性粒细胞中的5-LO核膜转位，这一过程通常是通过调节5-LO C2样结构域来介导的。综上所述，金丝桃素是一种新型的5-LO抑制剂，显然是通过干扰C2样结构域发挥作用的，在体内具有高效的作用。
We previously showed that, in vitro, hyperforin from St. John's wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO), the key enzyme in leukotriene biosynthesis. Here, we demonstrate that hyperforin possesses a novel and unique molecular pharmacological profile as a 5-LO inhibitor with remarkable efficacy in vivo. Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B-4 formation in pleural exudates of carrageenan-treated rats associated with potent anti-inflammatory effectiveness. Inhibition of 5-LO by hyperforin, but not by the iron-ligand type 5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was abolished in the presence of phosphatidylcholine and strongly reduced by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain. Moreover, hyperforin impaired the interaction of 5-LO with coactosin-like protein and abrogated 5-LO nuclear membrane translocation in ionomycin-stimulated neutrophils, processes that are typically mediated via the regulatory 5-LO C2-like domain. Together, hyperforin is a novel type of 5-LO inhibitor apparently acting by interference with the C2-like domain, with high effectiveness in vivo.