title: Differential activation of pregnane X receptor by carnosic acid, carnosol, ursolic acid, and rosmarinic acid.
abstract: Pregnane X receptor (PXR) regulates the expression of many genes, including those involved in drug metabolism and transport, and has been linked to various diseases, including inflammatory bowel disease. In the present study, we determined whether carnosic acid and other chemicals in rosemary extract (carnosol, ursolic acid, and rosmarinic acid) are PXR activators. As assessed in dual-luciferase reporter gene assays, carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, activated human PXR (hPXR) and mouse PXR (mPXR), whereas carnosol and ursolic acid, but not carnosic acid or rosmarinic acid, activated rat PXR (rPXR). Dose-response experiments indicated that carnosic acid, carnosol, and ursolic acid activated hPXR with EC50values of 0.79, 2.22, and 10.77μM, respectively. Carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, transactivated the ligand-binding domain of hPXR and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to the ligand-binding domain of hPXR. Carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, increased hPXR target gene expression, as shown by an increase in CYP3A4, UGT1A3, and ABCB1 mRNA expression in LS180 human colon adenocarcinoma cells. Rosmarinic acid did not attenuate the extent of hPXR activation by rifampicin, suggesting it is not an antagonist of hPXR. Overall, carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, are hPXR agonists, and carnosic acid shows species-dependent activation of hPXR and mPXR, but not rPXR. The findings provide new mechanistic insight on the effects of carnosic acid, carnosol, and ursolic acid on PXR-mediated biological effects.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chun Ling
authors.initials: CL
authors.lastname: Seow
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: aikjiang.lau@nus.edu.sg.
authors.forename: Aik Jiang
authors.initials: AJ
authors.lastname: Lau
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D053630:Depsides / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D000077297:Pregnane X Receptor; D051381:Rats; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism; D027542:Rosmarinus / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000097123:Rosmarinic Acid; D000097245:Ursolic Acid
chemical_list: D045784:Abietanes; D002934:Cinnamates; D053630:Depsides; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014315:Triterpenes; D000097123:Rosmarinic Acid; D000097245:Ursolic Acid; C068623:carnosol; C018381:salvin
keywords: ABCB1; CYP3A4; Carnosic acid; Carnosic acid (PubChem CID: 65126); Carnosol; Carnosol (PubChem CID: 442009); Ketoconazole (PubChem CID: 456201); Pregnane X receptor; Pregnenolone 16α-carbonitrile (PubChem CID: 15032); Rifampicin (PubChem CID: 5381226); Rosmarinic acid (PubChem CID: 5281792); UGT1A3; Ursolic acid (PubChem CID: 64945)