title: Repurposing Resveratrol and Fluconazole To Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism.
abstract: Cytochrome P450 (P450) enzymes metabolize arachidonic acid (AA) to several biologically active epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). Repurposing clinically-approved drugs could provide safe and readily available means to control EETs and HETEs levels in humans. Our aim was to determine how to significantly and selectively modulate P450-AA metabolism in humans by clinically-approved drugs. Liquid chromatography-mass spectrometry was used to determine the formation of 15 AA metabolites by human recombinant P450 enzymes, as well as human liver and kidney microsomes. CYP2C19 showed the highest EET-forming activity, while CYP1B1 and CYP2C8 showed the highest midchain HETE-forming activities. CYP1A1 and CYP4 showed the highest subterminal- and 20-HETE-forming activity, respectively. Resveratrol and fluconazole produced the most selective and significant modulation of hepatic P450-AA metabolism, comparable to investigational agents. Monte Carlo simulations showed that 90% of human population would experience a decrease by 6-22%, 16-39%, and 16-35% in 16-, 18-, and 20-HETE formation, respectively, after 2.5 g daily of resveratrol, and by 22-31% and 14-23% in 8,9- and 14,15-EET formation after 50 mg of fluconazole. In conclusion, clinically-approved drugs can provide selective and effective means to modulate P450-AA metabolism, comparable to investigational drugs. Resveratrol and fluconazole are good candidates to be repurposed as new P450-based treatments.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: El-Sherbeni
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D016718:Arachidonic Acid / Q000737:chemistry* / Q000378:metabolism*; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D058492:Drug Repositioning / Q000379:methods; D015725:Fluconazole / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D000077185:Resveratrol; D021241:Spectrometry, Mass, Electrospray Ionization; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D013267:Stilbenes; D016718:Arachidonic Acid; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D000077185:Resveratrol
keywords: Monte Carlo simulation; arachidonic acid; epoxyeicosatrienoic acids; human cytochrome P450; hydroxyeicosatetraenoic acids