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首页> 外文期刊>Biochemical Pharmacology >Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-alpha.
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Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-alpha.

机译：多氯联苯通过激活IVA胞质磷脂酶A2-α，以他莫昔芬敏感的方式诱导花生四烯酸在人血小板中释放。

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摘要

Polychlorinated biphenyls (PCBs) are stable compounds commonly found in nature as environmental pollutants. PCBs can affect the endocrine function of hormones such as steroid-hormones. Also, PCBs are known to be inducers of arachidonic acid release in various cells. We report, here, the effects of PCBs on eicosanoid formation, arachidonic acid release and cytosolic phospholipase A2-alpha (cPLA2-alpha) activation in human platelets. Ortho-substituted PCBs induced a time and dose-dependent release of arachidonic acid and the concomitant formation of 12(S)-hydroxy-5,8-cis-10-trans-14-cis-eicosatetraenoic acid (12-HETE) and 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid (12-HHT) in human platelets. The release of arachidonic acid and the formation of 12-HETE was completely blocked by the cPLA2-alpha inhibitors AACOCF3 or pyrrolidine-1. PCB-treatment of platelets demonstrated that the cPLA2-alpha protein as well as PLA2 activity translocated to the membrane fraction, independent of a rise in intracellular Ca2+. Furthermore, electrophoretic gel mobility shift analysis of cPLA2-alpha on SDS-PAGE demonstrated a PCB-dependent phosphorylation of cPLA2-alpha. The effects of 17beta-estradiol and two structurally unrelated anti-estrogens, nafoxidin and tamoxifen on PCB-induced arachidonic acid release in platelets were also investigated. Both nafoxidin and tamoxifen inhibited PCB-induced arachidonic acid release as well as 12-HETE and 12-HHT formation. Interestingly, platelets incubated with PCBs did not aggregate despite the fact that robust release of arachidonic acid was observed. In summary, these results demonstrate that certain PCBs induce activation of cPLA2-alpha independent of a rise in intracellular calcium and a robust release of arachidonic acid release with resulting eicosanoid formation in human platelets.
机译：多氯联苯（PCB）是稳定的化合物，通常在自然界中被发现为环境污染物。多氯联苯可影响激素（如类固醇激素）的内分泌功能。而且，已知PCB是各种细胞中花生四烯酸释放的诱导剂。我们在这里报告了多氯联苯对类花生酸形成，花生四烯酸释放和人类血小板中胞质磷脂酶A2-α（cPLA2-α）活化的影响。邻位取代的PCBs诱导花生四烯酸的时间和剂量依赖性释放以及12（S）-羟基-5,8-顺式-10-反式-14-顺式二十碳四烯酸（12-HETE）和12的伴随形成人血小板中的（S）-羟基-5-顺-8,10-反十七碳三烯酸（12-HHT）花生四烯酸的释放和12-HETE的形成被cPLA2-α抑制剂AACOCF3或吡咯烷-1完全阻断。血小板的PCB处理表明cPLA2-α蛋白以及PLA2活性易位到膜部分，而与细胞内Ca2 +的升高无关。此外，在SDS-PAGE上对cPLA2-alpha的电泳迁移率分析表明，PCB依赖的cPLA2-alpha磷酸化。还研究了17β-雌二醇和两种结构上不相关的抗雌激素，nafoxidin和他莫昔芬对PCB诱导的花生四烯酸释放的影响。 nafoxidin和他莫昔芬均抑制PCB诱导的花生四烯酸释放以及12-HETE和12-HHT的形成。有趣的是，尽管观察到花生四烯酸的强烈释放，但与PCB一起孵育的血小板并未聚集。总而言之，这些结果表明，某些PCB诱导cPLA2-α的活化，而与细胞内钙的升高和花生四烯酸释放的强劲释放无关，从而在人体血小板中形成类花生酸。

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