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(S)-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 pathway. The effects of 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-lipoxygenase (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, the human embryonic kidney 293 (HEK293) cell line expressing 5-LO, and human polymorphonuclear leukocytes (PMNLs) we investigated the effects of these compounds on several inflammatory pathways, namely, 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 exerts potent inhibitory activity toward the platelet 12-LO pathway (IC50 = 1.53 μM) while having a lesser affinity toward 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 nontargeted effects on the platelet’s activation or overall cell’s oxygen consumption.
Footnotes
- Received July 9, 2018.
- Accepted October 31, 2018.
L.H.B. was supported by the Canadian Institutes of Health Research, the New Brunswick Innovation Foundation (NBIF), and the Université de Moncton. M.T. was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), the Canadian Foundation for Innovation, the NBIF, and the Université de Moncton. J.-L.J. was a recipient of a New Brunswick Health Research Foundation and Maritime SPOR Support Unit postdoctoral fellowship. The work of N.P. is supported by grants from the NSERC, NBIF, and Université de Moncton. M.E.S. was supported by the NBIF.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Blood was obtained from healthy consenting volunteers. This research project was approved by the Comité d’Éthique de la Recherche avec les Êtres Humains at the Université de Moncton.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics