title: Retinoids activate RXR/CAR-mediated pathway and induce CYP3A.
abstract: Retinoids and carotenoids are frequently used as antioxidants to prevent cancer. In this study, a panel of retinoids and carotenoids was examined to determine their effects on activation of RXR/CAR-mediated pathway and regulation of CYP3A gene expression. Transient transfection assays of HepG2 cells revealed that five out of thirteen studied retinoids significantly induced RXRalpha/CAR-mediated activation of luciferase activity that is driven by the thymidine kinase promoter linked with a PXR binding site in the CYP3A4 gene [tk-(3A4)(3)-Luc reporter]. All-trans retinoic acid (RA) and 9-cis RA were more effective than CAR agonist TCBOPOP in induction of the tk-(3A4)(3)-Luc reporter. Addition of retinoid and TCBOPOP further enhanced the inducibility and the induction was preferentially mediated by RXRalpha/CAR and RXRgamma/CAR heterodimer. Chromatin immunoprecipitation assay showed that retinoids recruit RXRalpha and CAR to the proximal ER6 and distal XREM nuclear receptor response elements of the CYP3A4 gene promoter. The experimental data demonstrate that retinoids can effectively regulate CYP3A gene expression through the RXR/CAR-mediated pathway.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Biomedical Research Center Building/KLSIC, 2146 W 39th Avenue, Kansas City, KS 66160, USA.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Chen
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
mesh_terms: D000077556:Alitretinoin; D001483:Base Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers; D019281:Dimerization; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin; D051544:Cytochrome P-450 CYP3A; D013937:Thymidine Kinase
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