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2019
Journal Article
Titel
Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor g
Abstract
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 mM, respectively. In contrast, only montelukast and zafirlukast activated PPARg in the reporter gene assay with EC50 values of 1.17 mM (21.9% max. activation) and 2.49 mM (148% max. activation), respectively. PPARa and d were not affected by any of the compounds. The activation of PPARg was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARg phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARg target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARg cofactor CBP upon ligand binding suggesting that both compounds act as PPARg modulators. In addition, zafirlukast impaired the TNFa triggered phosphorylation of PPARg2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARg modulator representing an excellent starting point for the further development of this compound class.