title: Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation.
abstract: OBJECTIVE
  To investigate the effects of three natural product compounds, carapin, santonin and isokobusone, on the activity of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in induction of drug-metabolizing enzymes and inhibition of inflammation.
  
  
  METHODS
  The monkey kidney-derived fibroblast (CV-1) cells and human embryonic kidney HEK293 cells were used for transient transfection and luciferase reporter gene assays. Human primary hepatocytes and primary hepatocytes from wild type, PXR-/-, and hPXR transgenic mice were used to study the induction of drug-metabolizing enzymes and the implication of these compounds in inflammation.
  
  
  RESULTS
  Carapin, santonin and isokobusone activated both PXR and CAR in transient transfection and luciferase reporter gene assays. Mutagenesis studies showed that two amino acid residues, Phe305 of the rodent PXR and Leu308 of the human PXR, are critical for the recognition of these compounds by PXR. Importantly, the activation of PXR and CAR by these compounds induced the expression of drug-metabolizing enzymes in primary human and mouse hepatocytes. Furthermore, activation of PXR by these compounds inhibited the expression of inflammatory mediators in response to lipopolysaccharide (LPS). The effects of these natural compounds on drug metabolism and inflammation were abolished in PXR-/- hepatocytes.
  
  
  CONCLUSIONS
  Our results show that carapin, santonin and isokobusone activate PXR and CAR and induce drug-metabolizing enzymes. In addition, these compounds inhibited the expression of inflammatory mediators in response to LPS through the activation of PXR.
authors.affiliation: Department of Physiology Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Suticha
authors.initials: S
authors.lastname: Kittayaruksakul
authors.forename: Wenchen
authors.initials: W
authors.lastname: Zhao
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.forename: Songrong
authors.initials: S
authors.lastname: Ren
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Ju
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D034242:Cyclooctanes / Q000494:pharmacology*; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D000882:Haplorhini; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry; D011083:Polycyclic Compounds / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012500:Santonin / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D001688:Biological Products; D000090702:Constitutive Androstane Receptor; D034242:Cyclooctanes; D008070:Lipopolysaccharides; D004364:Pharmaceutical Preparations; D011083:Polycyclic Compounds; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C586975:carapin; C586976:isokobusone; D012500:Santonin; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C101679:Cyp2b10 protein, mouse; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2
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