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 promp
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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Metadaten
Author:Tamara Göbel, Olaf Diehl, Jan Peter Heering, Daniel Merk, Carlo Federico Angioni, Sandra Kerstin Wittmann, Estel·la Buscató Arsequell, Ramona Kottke, Lilia Weizel, Tim Schader, Thorsten Jürgen Maier, Gerd Geisslinger, Manfred Schubert-Zsilavecz, Dieter Steinhilber, Ewgenij Proschak, Astrid Stefanie Kahnt
URN:urn:nbn:de:hebis:30:3-501619
DOI:http://dx.doi.org/10.3389/fphar.2019.00263
ISSN:1663-9812
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=30949053
Parent Title (English):Frontiers in pharmacology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):John D. Imig
Document Type:Article
Language:English
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
Volume:10
Issue:Art. 263
Pagenumber:15
First Page:1
Last Page:15
Note:
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.
HeBIS PPN:454034881
Institutes:Pharmazie
Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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