title: 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).
abstract: 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.
authors.affiliation: Advanced Technology Platform Research Laboratory, Fujisawa Pharmaceutical Co., Ltd.,Tsukuba, Ibaraki, Japan. kojo@biomarker.co.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kojo
authors.forename: Masao
authors.initials: M
authors.lastname: Fukagawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tajima
authors.forename: Akiko
authors.initials: A
authors.lastname: Suzuki
authors.forename: Takao
authors.initials: T
authors.lastname: Fujimura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aramori
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D021122:Protein Subunits / Q000819:agonists / Q000145:classification / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000145:classification / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists* / Q000145:classification / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors