Evidence for inhibition of leukotriene A4 synthesis by 5,8,11,14-eicosatetraynoic acid in guinea pig polymorphonuclear leukocytes.
The sensitivity of the 5-lipoxygenase to inhibition by 5,8,11,14-eicosatetraynoic acid (ETYA) is species- and/or tissue-dependent. Guinea pig peritoneal polymorphonuclear leukocytes prelabeled with [3H]arachidonic acid and stimulated with ionophore A23187 formed 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), as well as several dihydroxy fatty acids, including 5(S),12(R)-dihydroxy-6,8,10-(cis/trans/trans)-14-(cis)-eicosatetraenoic acid. ETYA (40 microM) did not inhibit, but, rather, increased the incorporation of 3H label into 5-HETE. In contrast, ETYA markedly inhibited the formation of radiolabeled dihydroxy acid metabolites by the A23187-stimulated cells. Assay of products from polymorphonuclear leukocytes incubated with exogenous arachidonic acid plus A23187, by reverse phase high performance liquid chromatography combined with ultraviolet absorption, showed a concentration-dependent inhibition of the formation of dihydroxy acid metabolite by ETYA (1-50 microM) and an increase in 5-HETE levels (maximum of 2- to 3-fold). The latter finding was verified by stable isotope dilution assay with deuterated 5-HETE as the internal standard. Another lipoxygenase inhibitor, nordihydroguaiaretic acid, potently inhibited the formation of both 5-HETE and dihydroxy acids, with an IC50 of 2 microM. The data suggest that ETYA can inhibit the enzymatic step whereby 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid is converted to leukotriene A4 in guinea pig polymorphonuclear leukocytes.
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000096:biosynthesis*; D002396:Catechols / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006168:Guinea Pigs; D007700:Kinetics; D017572:Leukotriene A4; D009637:Masoprocol; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*
D000975:Antioxidants; D001095:Arachidonic Acids; D002396:Catechols; D005231:Fatty Acids, Unsaturated; D017572:Leukotriene A4; D015117:5,8,11,14-Eicosatetraynoic Acid; D009637:Masoprocol