Fatty acid binding proteins stabilize leukotriene A4: competition with arachidonic acid but not other lipoxygenase products.
Leukotriene A(4) (LTA(4)) is a chemically reactive conjugated triene epoxide product derived from 5-lipoxygenase oxygenation of arachidonic acid. At physiological pH, this reactive compound has a half-life of less than 3 s at 37 degrees C and approximately 40 s at 4 degrees C. Regardless of this aqueous instability, LTA(4) is an intermediate in the formation of biologically active leukotrienes, which can be formed through either intracellular or transcellular biosynthesis. Previously, epithelial fatty acid binding protein (E-FABP) present in RBL-1 cells was shown to increase the half-life of LTA(4) to approximately 20 min at 4 degrees C. Five FABPs (adipocyte FABP, intestinal FABP, E-FABP, heart/muscle FABP, and liver FABP) have now been examined and also found to increase the half-life of LTA(4) at 4 degrees C to approximately 20 min with protein present. Stabilization of LTA(4) was examined when arachidonic acid was present to compete with LTA(4) for the binding site on E-FABP. Arachidonate has an apparent higher affinity for E-FABP than LTA(4) and was able to completely block stabilization of the latter. When E-FABP is not saturated with arachidonate, FABP can still stabilize LTA(4). Several lipoxygenase products, including 5-hydroxyeicosatetraenoic acid, 5,6-dihydroxyeicosatetraenoic acid, and leukotriene B(4), were found to have no effect on the stability of LTA(4) induced by E-FABP even when present at concentrations 3-fold higher than LTA(4).
Zimmer
Jennifer S Dickinson
JS
Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
Dyckes
Douglas F
DF
Bernlohr
David A
DA
Murphy
Robert C
RC
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D001669:Biochemical Phenomena; D001671:Biochemistry; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D050556:Fatty Acid-Binding Proteins; D006863:Hydrogen-Ion Concentration; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D017572:Leukotriene A4 / Q000737:chemistry / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism*; D013058:Mass Spectrometry; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D013696:Temperature; D013997:Time Factors
D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D006893:Hydroxyeicosatetraenoic Acids; D017572:Leukotriene A4; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C048698:5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid; D008084:Lipoxygenase