Evaluation of human peroxisome proliferator-activated receptor (PPAR) subtype selectivity of a variety of anti-inflammatory drugs based on a novel assay for PPAR delta(beta).

The nuclear receptor PPAR (peroxisome proliferator-activated receptor) has three subtypes named alpha, delta(beta), and gamma that may act as receptors for a range of compounds including antihyperglycaemic drugs, insulin sensitizers, and non-steroidal anti-inflammatory drugs (NSAIDs). Although profiling of the subtype selectivity of the compounds for PPAR is indispensable to elucidate their pharmacological action, the absence of an appropriate transactivation assay for PPAR delta led us to develop a sensitive and reproducible method. We found that co-expression of PPAR delta, retinoid X receptor (RXR) alpha, and coactivators such as CBP and SRC-1 enhanced basal and agonist-dependent activation of PPAR responsive element (PPRE)-driven transcription by PPAR delta, rendering a PPRE-driven reporter assay reliable and sensitive. Utilizing this assay for PPAR delta, we re-evaluated the subtype selectivity of a variety of anti-inflammatory drugs for human PPAR. The PPAR agonists tested included two leukotriene (LT) D(4) antagonist, seven NSAIDs, and two anti-rheumatoid drugs. We found that a novel LTD(4) antagonist, FK011 ([2-(((2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl)oxy)methyl)phenyl]acetic acid), showed marked agonistic activity for PPAR gamma. NSAIDs were classified into the following three groups: those showing no activity for all subtypes, those that were selective for PPAR gamma such as indomethacin and diclofenac, and those showing agonistic activity for the delta and gamma subtypes such as ibuprofen. These results will be important to studies on the molecular mechanisms of pharmacological actions of LTD(4) antagonists and NSAIDs.