Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ
Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ
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DOI：
10.3389/fphar.2019.00263
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发表时间：
2019-03-20
影响因子：
5.6
通讯作者：
Kahnt, Astrid S.
中科院分区：
文献类型：
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作者：
Goebel, Tamara;Diehl, Olaf;Kahnt, Astrid S.
半胱氨酰白三烯受体1拮抗剂（CysLT 1 RA）经常用作治疗哮喘的附加药物。最近，这些化合物已显示出对心血管疾病的保护作用。这促使我们研究它们对可溶性环氧化物水解酶（sEH）和过氧化物酶体增殖物激活受体（PPAR）活性的影响，这两个靶点已知在CVD和代谢综合征中起重要作用。孟鲁司特、普仑司特和扎鲁司特抑制人sEH，IC 50值分别为1.9、14.1和0.8 μ M。相比之下，在报告基因测定中，仅孟鲁司特和扎鲁司特激活了PPAR γ，EC 50值为1.17 μ M（最大21.9%）。活化）和2.49 μ M（148%max.激活）。PPAR α和δ不受任何化合物的影响。在3 T3-L1脂肪细胞中进一步研究了PPAR γ的活化。脂质积累、靶基因的mRNA和蛋白质表达以及PPAR γ磷酸化的分析显示，孟鲁司特不能诱导脂肪细胞分化。相比之下，与罗格列酮相比，扎鲁司特引发中度脂质蓄积，并上调PPAR γ靶基因。此外，我们发现孟鲁司特和扎鲁司特显示出与配体结合后PPAR γ辅因子CBP募集有关的拮抗活性，表明这两种化合物均充当PPAR γ调节剂。此外，扎鲁司特损害TNF α触发的丝氨酸273上的PPAR γ 2磷酸化。因此，扎鲁司特是一种新型的双重sEH/PPAR γ调节剂，代表了进一步开发这类化合物的良好起点。
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.