Yagaloff K A, Franco L, Simko B, Burghardt B
Department of Metabolic Disease Research, Hoffmann-La Roche, Nutley, NJ 07110, USA.
Prostaglandins Leukot Essent Fatty Acids. 1995 May;52(5):293-7. doi: 10.1016/0952-3278(95)90029-2.
A series of essential fatty acids and fatty acid derivatives were evaluated for their ability to inhibit [3H] leukotriene B4 (LTB4) binding to pig neutrophil membranes. The fatty acids varied in chain length, extent of unsaturation, position of unsaturation, and isomerization. Generally, fatty acids with two or more unsaturated sites and chain lengths of 18-22 were potent inhibitors of [3H]LTB4 binding; both n-3 and n-6 fatty acids were inhibitory. The most potent compounds tested were homogammalinolenic acid and ricinelaidic acid which gave Ki values of 1 microM and 2 microM in the binding assay. Ricinelaidic acid was also tested for its ability to inhibit LTB4-mediated chemotaxis (IC50 = 10 microM) and LTB4-induced calcium fluxes (IC50 = 7 microM) in isolated human neutrophils. Ricinelaidic acid did not show agonist activity in these assays. In an in vivo model of LTB4-induced bronchoconstriction, ricinelaidic acid and homogammalinolenic acid gave 46% and 53% inhibition, respectively, at a 1 mg/kg i.v. dose. These results indicate that essential fatty acids are LTB4 receptor antagonists, which may account in part for their reported anti-inflammatory activities.
评估了一系列必需脂肪酸和脂肪酸衍生物抑制[3H]白三烯B4（LTB4）与猪中性粒细胞膜结合的能力。这些脂肪酸在链长、不饱和度、不饱和位置和异构化程度上有所不同。一般来说，具有两个或更多不饱和位点且链长为18 - 22的脂肪酸是[3H]LTB4结合的有效抑制剂；n-3和n-6脂肪酸均具有抑制作用。测试的最有效化合物是高γ-亚麻酸和蓖麻反油酸，在结合试验中其Ki值分别为1 microM和2 microM。还测试了蓖麻反油酸抑制分离的人中性粒细胞中LTB4介导的趋化作用（IC50 = 10 microM）和LTB4诱导的钙通量（IC50 = 7 microM）的能力。蓖麻反油酸在这些试验中未表现出激动剂活性。在LTB4诱导的支气管收缩的体内模型中，静脉注射1 mg/kg剂量时，蓖麻反油酸和高γ-亚麻酸分别产生46%和53%的抑制作用。这些结果表明必需脂肪酸是LTB4受体拮抗剂，这可能部分解释了它们所报道的抗炎活性。
