Powell W S, MacLeod R J, Gravel S, Gravelle F, Bhakar A
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
J Immunol. 1996 Jan 1;156(1):336-42.
5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a recently discovered metabolite of arachidonic acid that activates human neutrophils by a mechanism independent of the receptor for leukotriene B4 (LTB4). The objectives of this study were to identify the major metabolites of 5-oxo-ETE in neutrophils and to compare the biologic activities of 5-oxo-ETE with those of its metabolites and other 5-oxoeicosanoids. Neutrophils rapidly converted 5-oxo-ETE to its omega-oxidation product, 5-oxo-20-hydroxy-6E,8Z,11Z,14Z- eicosatetraenoic acid. This compound was nearly 100 times less potent than 5-oxo-ETE in elevating cytosolic calcium levels in neutrophils. Methylation of the carboxyl group of 5-oxo-ETE resulted in a 20-fold loss of potency, whereas replacement of the 8,9-cis double bond by a trans double bond reduced potency by about sixfold. Similar results were obtained for the effects of the above compounds on neutrophil migration. 5-Oxo-20-hydroxy-6E,8Z,11Z,14Z- eicosatetraenoic acid, 5-oxo-8-trans-ETE, and 5-oxo-ETE methyl ester desensitized neutrophils to 5-oxo-ETE. 5-Oxo-ETE-induced calcium mobilization was inhibited by pretreatment of the cells with pertussis toxin. 5-Oxo metabolites of 6-trans-LTB4 and 12-epi-6-trans-LTB4 had weak stimulatory effects on calcium levels and migration that appeared to be mediated primarily by stimulation of LTB4 receptors. These studies indicate that the 5-oxo group, the omega-end of the molecule, and the carboxyl group are all important for the biologic activity of 5-oxo-ETE, which may be mediated by a G protein-linked receptor. The biologic activity of 5-oxo-ETE can be terminated by omega-oxidation.
5-氧代-6,8,11,14-二十碳四烯酸（5-氧代-ETE）是一种最近发现的花生四烯酸代谢产物，它通过一种独立于白三烯B4（LTB4）受体的机制激活人类中性粒细胞。本研究的目的是鉴定中性粒细胞中5-氧代-ETE的主要代谢产物，并比较5-氧代-ETE与其代谢产物及其他5-氧代二十碳类化合物的生物活性。中性粒细胞迅速将5-氧代-ETE转化为其ω-氧化产物5-氧代-20-羟基-6E,8Z,11Z,14Z-二十碳四烯酸。该化合物在提高中性粒细胞胞质钙水平方面的效力比5-氧代-ETE低近100倍。5-氧代-ETE羧基的甲基化导致效力丧失20倍，而将8,9-顺式双键替换为反式双键则使效力降低约6倍。上述化合物对中性粒细胞迁移的影响也得到了类似结果。5-氧代-20-羟基-6E,8Z,11Z,14Z-二十碳四烯酸、5-氧代-8-反式-ETE和5-氧代-ETE甲酯使中性粒细胞对5-氧代-ETE脱敏。用百日咳毒素预处理细胞可抑制5-氧代-ETE诱导的钙动员。6-反式-LTB4和12-表-6-反式-LTB4的5-氧代代谢产物对钙水平和迁移有微弱的刺激作用，这似乎主要是通过刺激LTB4受体介导的。这些研究表明，5-氧代基团、分子的ω-末端和羧基对5-氧代-ETE的生物活性都很重要，其生物活性可能由G蛋白偶联受体介导。5-氧代-ETE的生物活性可通过ω-氧化终止。
