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Boswellic Acids Stimulate Arachidonic Acid Release and 12-Lipoxygenase Activity in Human Platelets Independent of Ca²⁺ and Differentially Interact with Platelet-Type 12-Lipoxygenase

Department of Pharmaceutical Analytics, Institute of Pharmacy, Eberhard-Karls-University Tubingen, Tubingen, Germany (D.P., O.W.); Institute of Pharmaceutical Chemistry, University of Frankfurt, Frankfurt, Germany (L.T.); and Institute of Organic Chemistry, University of Saarland, Saarbruecken, Germany (N.K., J.J.)

Boswellic acids inhibit the transformation of arachidonic acid to leukotrienes via 5-lipoxygenase but can also enhance the liberation of arachidonic acid in human leukocytes and platelets. Using human platelets, we explored the molecular mechanisms underlying the boswellic acid-induced release of arachidonic acid and the subsequent metabolism by platelet-type 12-li-poxygenase (p12-LO). Both -boswellic acid and 3-O-acetyl-11-keto-boswellic acid (AKBA) markedly enhanced the release of arachidonic acid via cytosolic phospholipase A₂ (cPLA₂), whereas for generation of 12-hydro(pero)xyeicosatetraenoic acid [12-H(P)ETE], AKBA was less potent than -boswellic acid and was without effect at higher concentrations (30 µM). In contrast to thrombin, -boswellic acid-induced release of ara-chidonic acid and formation of 12-H(P)ETE was more rapid and occurred in the absence of Ca²⁺. The Ca²⁺-independent release of arachidonic acid and 12-H(P)ETE production elicited by -boswellic acid was not affected by pharmacological inhibitors of signaling molecules relevant for agonist-induced arachidonic acid liberation and metabolism. It is noteworthy that in cell-free assays, -boswellic acid increased p12-LO catalysis approximately 2-fold in the absence but not in the presence of Ca²⁺, whereas AKBA inhibited p12-LO activity. No direct modulatory effects of boswellic acids on cPLA₂ activity in cell-free assays were evident. Therefore, immobilized KBA (linked to Sepharose beads) selectively precipitated p12-LO from platelet lysates but failed to bind cPLA₂. Taken together, we show that boswellic acids induce the release of arachidonic acid and the synthesis of 12-H(P)ETE in human platelets by unique Ca²⁺-independent routes, and we identified p12-LO as a selective molecular target of boswellic acids.

Address correspondence to: Dr. Oliver Werz, Department of Pharmaceutical Analytics, Institute of Pharmacy, Eberhard-Karls-University Tubingen, Auf der Morgenstelle 8, D-72076 Tubingen, Germany. E-mail: oliver.werz{at}uni-tuebingen.de