Zafirlukast is a dual modulator of human soluble epoxide hydrolase and peroxisome proliferator-activated receptor γ

  • Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.

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Author:Tamara Göbel, Olaf Diehl, Jan Peter Heering, Daniel MerkORCiDGND, Carlo Federico Angioni, Sandra Kerstin Wittmann, Estel·la Buscató Arsequell, Ramona Kottke, Lilia Weizel, Tim Schader, Thorsten Jürgen Maier, Gerd GeisslingerORCiDGND, Manfred Schubert-ZsilaveczGND, Dieter SteinhilberORCiDGND, Ewgenij ProschakORCiDGND, Astrid Stefanie Kahnt
Pubmed Id:
Parent Title (English):Frontiers in pharmacology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):John D. Imig
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/03/20
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/04/18
Tag:PPARγ; metabolic syndrome; montelukast; polypharmacology; pranlukast; soluble epoxide hydrolase; zafirlukast
Issue:Art. 263
Page Number:15
First Page:1
Last Page:15
Copyright © 2019 Göbel, Diehl, Heering, Merk, Angioni, Wittmann, Buscato, Kottke, Weizel, Schader, Maier, Geisslinger, Schubert-Zsilavecz, Steinhilber, Proschak and Kahnt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0