Doucet 2018 Mol Pharmacol
|Doucet MS, Jougleux JL, Poirier SJ, Cormier M, Leger JL, Surette ME, Pichaud N, Touaibia M, Boudreau LH (2018) Identification of peracetylated quercetin as a selective 12-lipoxygenase pathway inhibitor in human platelets. Mol Pharmacol 95:139-50.|
Abstract: The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12-hydroxyeicosatetraenoic acid (12(S)-HETE) lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12(S)-lipoxygenase (12-LO) pathway. The abundance of 12(S)-HETE and its contribution to several chronic inflammatory diseases have been well studied over the last few years. While most developed compounds primarily target the 5-lipoxygenase (5-LO) or the cyclooxygenase (COX) pathways, very few compounds selectively inhibiting the 12-LO pathway are known. In this study, we examined whether the distribution of hydroxyl groups among flavones could influence their potency as 12-LO inhibitors. Using human platelets, HEK293 cell line expressing 5-LO and human polymorphonuclear leukocytes we investigated the effects of these compounds on several inflammatory pathways, namely the 12-LO, 5-LO and COX. Using high-resolution respirometry and flow cytometry, we also evaluated some normal cell functions that could be modulated by our compounds. We identified a peracetylated quercetin (compound 6) that exert potent inhibitory activity towards the platelet 12-LO pathway (IC50 = 1.53 μM) while having a lesser affinity towards the COX pathway. This study characterizes the peracetylated quercetin (compound 6) as a more selective platelet-type 12-LO inhibitor than baicalein, with no measurable non-targeted effects on the platelet's activation or overall cell's oxygen consumption.
• Keywords: Anti-inflammatory drugs, Eicosanoids, Flavonoids, Inflammation, Leukotrienes, Platelets • Bioblast editor: Plangger M
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Human Tissue;cell: Platelet Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET Pathway: ROX HRR: Oxygraph-2k