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 mu M, respectively. In contrast, only montelukast and zafirlukast activated PPAR gamma in the reporter gene assay with EC50 values of 1.17 mu M (21.9% max. activation) and 2.49 mu M (148% max. activation), respectively. PPAR alpha and delta were not affected by any of the compounds. The activation of PPAR gamma was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPAR gamma phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPAR gamma target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPAR gamma cofactor CBP upon ligand binding suggesting that both compounds act as PPAR gamma modulators. In addition, zafirlukast impaired the TNF alpha triggered phosphorylation of PPAR gamma 2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPAR gamma modulator representing an excellent starting point for the further development of this compound class.