Essential fatty acids are antagonists of the leukotriene B4 receptor.
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.
Yagaloff
K A
KA
Department of Metabolic Disease Research, Hoffmann-La Roche, Nutley, NJ 07110, USA.
Franco
L
L
Simko
B
B
Burghardt
B
B
D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005228:Fatty Acids, Essential / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D012277:Ricinoleic Acids / Q000494:pharmacology; D013552:Swine; D014316:Tritium
D005228:Fatty Acids, Essential; D005231:Fatty Acids, Unsaturated; D018102:Receptors, Leukotriene B4; D012277:Ricinoleic Acids; D014316:Tritium; D007975:Leukotriene B4; D015126:8,11,14-Eicosatrienoic Acid; C030521:ricinoleic acid; D002118:Calcium