TY  - JOUR
A1  - Göbel, Tamara
A1  - Diehl, Olaf
A1  - Heering, Jan Peter
A1  - Merk, Daniel
A1  - Angioni, Carlo Federico
A1  - Wittmann, Sandra Kerstin
A1  - Buscató Arsequell, Estel·la
A1  - Kottke, Ramona
A1  - Weizel, Lilia
A1  - Schader, Tim
A1  - Maier, Thorsten Jürgen
A1  - Geisslinger, Gerd
A1  - Schubert-Zsilavecz, Manfred
A1  - Steinhilber, Dieter
A1  - Proschak, Ewgenij
A1  - Kahnt, Astrid Stefanie
T1  - Zafirlukast is a dual modulator of human soluble epoxide hydrolase and peroxisome proliferator-activated receptor γ
T2  - Frontiers in pharmacology
N2  - 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.
KW  - PPARγ
KW  - soluble epoxide hydrolase
KW  - zafirlukast
KW  - montelukast
KW  - pranlukast
KW  - metabolic syndrome
KW  - polypharmacology
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50161
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-501619
SN  - 1663-9812
N1  - 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.
VL  - 10
IS  - Art. 263
SP  - 1
EP  - 15
PB  - Frontiers Media
CY  - Lausanne
ER  -