Lipoxygenase stimulating effects of hydroxylated docosahexaenoates produced by human platelets.
Human platelet suspensions are capable of lipoxygenating docosahexaenoic acid (22:6n3) to an 11(S)-OH-, 14(S)-OH- or 17(S)-OH-22:6n3. The structure and stereochemical purity of these derivatives were confirmed by GC/MS and chiral phase LC analysis. The purified OH-22:6n3 positional isomers which are formed by human platelets were capable of inducing a concentration-dependent contractile response in the guinea-pig lung parenchymal strip at sub-micromolar concentrations. OH-22:6n3 may act in part through stimulation of leukotriene (LT) production as an increase in peptidyl-LT levels (LTC4, LTD4 and LTE4) occurred during the OH-22:6n3-induced contraction in this preparation. Both specific lipoxygenase inhibitors (caffeic acid, 20 uM and NDGA, 50 uM) and a LT receptor antagonist (FPL55712, 20 uM) significantly inhibited the contractile response. Moreover, the OH-22:6n3 positional isomers induced a concentration-dependent increase in LTB4 and LTC4 production in the guinea-pig chopped lung preparation. Other hydroxylated fatty acids and parent fatty acids which were tested (12-OH-20:4n6, 5-OH-20:4n6, 12-OH-20:5n3, 20:5n3 and 22:6n3) did not significantly contract this airway smooth muscle preparation or alter LT production. The hydroxylated 22:6n3 metabolites may modulate airway smooth muscle function in part through the release of peptidyl-LTs from the guinea-pig lung.
Karanian
J W
JW
Laboratory of Membrane Biochemistry and Biophysics, DICBR, NIAAA, Bethesda, MD 20892.
Kim
H Y
HY
Yergey
J A
JA
Salem
N
N
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D015777:Eicosanoids / Q000096:biosynthesis; D006168:Guinea Pigs; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000096:biosynthesis; D008084:Lipoxygenase / Q000097:blood*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology
D015777:Eicosanoids; D015289:Leukotrienes; D004281:Docosahexaenoic Acids; D008084:Lipoxygenase