Powell W S, Gravel S, Gravelle F
Department of Medicine, McGill University, Montreal, Quebec, Canada.
J Lipid Res. 1995 Dec;36(12):2590-8.
We recently showed that human neutrophils convert arachidonic acid to its 5-oxo metabolite, 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). 5-Oxo-ETE, which is synthesized by oxidation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by a highly specific microsomal dehydrogenase, is a potent stimulator of human neutrophils and eosinophils. The objective of the current investigation was to determine whether neutrophils can convert 5,8,11,14,17-eicosapentaenoic acid (EPA) to its 5-oxo metabolite, 5-oxo-6,8,11,14,17-eicosapentaenoic acid (5-oxo-EPE) and, if so, to compare the biological activities of 5-oxo-EPE and 5-oxo-ETE. The two major eicosanoids formed by neutrophils incubated with EPA in the presence of A23187 were 5-hydroxy-6,8,11,14,17-eicosapentaenoic acid (5-HEPE) and 5-oxo-EPE. Smaller amounts of LTB5 and 20-hydroxy-LTB5 were also formed. Phorbol myristate acetate stimulated the formation of 5-oxo-EPE from both EPA and 5-HEPE. 5-HEPE and 5-HETE were equally good substrates for 5-hydroxyeicosanoid dehydrogenase (Km, ca. 0.85 microM; Vmax, ca. 1.4 pmol/min per microgram protein). 5-Oxo-EPE mobilized calcium in neutrophils with an EC50 of 36 nM, about 10 times higher than that of 5-oxo-ETE. 5-Oxo-EPE was also about one-tenth as active as 5-oxo-ETE in stimulating the migration of both human neutrophils and human eosinophils. It is concluded that 5-oxo-EPE is readily formed from EPA via 5-HEPE. However, it is only about one-tenth as potent as 5-oxo-ETE in stimulating human neutrophils and eosinophils. These results support the contention that EPA can alleviate certain inflammatory diseases by reducing the contribution of arachidonate-derived eicosanoids.
我们最近发现，人类中性粒细胞可将花生四烯酸转化为其5-氧代代谢产物5-氧代-6,8,11,14-二十碳四烯酸（5-氧代-ETE）。5-氧代-ETE由5-羟基-6,8,11,14-二十碳四烯酸（5-HETE）经一种高度特异性的微粒体脱氢酶氧化合成，是人类中性粒细胞和嗜酸性粒细胞的强效刺激物。本研究的目的是确定中性粒细胞是否能将5,8,11,14,17-二十碳五烯酸（EPA）转化为其5-氧代代谢产物5-氧代-6,8,11,14,17-二十碳五烯酸（5-氧代-EPE），如果可以，比较5-氧代-EPE和5-氧代-ETE的生物学活性。在A23187存在的情况下，与EPA一起孵育的中性粒细胞形成的两种主要类二十烷酸是5-羟基-6,8,11,14,17-二十碳五烯酸（5-HEPE）和5-氧代-EPE。还形成了较少量的白三烯B5（LTB5）和20-羟基-LTB5。佛波醇肉豆蔻酸酯乙酸盐刺激了EPA和5-HEPE生成5-氧代-EPE。5-HEPE和5-HETE是5-羟基类二十烷酸脱氢酶的同等良好底物（Km约为0.85微摩尔；Vmax约为1.4皮摩尔/分钟/微克蛋白质）。5-氧代-EPE使中性粒细胞中的钙动员，其半数有效浓度（EC50）为36纳摩尔，约为5-氧代-ETE的10倍。5-氧代-EPE在刺激人类中性粒细胞和人类嗜酸性粒细胞迁移方面的活性也约为5-氧代-ETE的十分之一。得出的结论是，5-氧代-EPE可通过5-HEPE由EPA轻易形成。然而，在刺激人类中性粒细胞和嗜酸性粒细胞方面，它的效力仅约为5-氧代-ETE的十分之一。这些结果支持了EPA可通过减少花生四烯酸衍生的类二十烷酸的作用来缓解某些炎症性疾病的观点。
