Retinoids activate RXR/CAR-mediated pathway and induce CYP3A.
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.
Chen
Shiyong
S
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.
Wang
Kun
K
Wan
Yu-Jui Yvonne
YJ
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*
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
Nature. 2000 Oct 19;407(6806):920-3
11057673
Mutat Res. 1997 Nov 27;394(1-3):29-35
9434840
Mol Endocrinol. 2005 Jun;19(6):1646-53
15831521
Mol Cell Biol. 2000 May;20(9):2951-8
10757780
Toxicol Sci. 2006 Jul;92(1):51-60
16632523
Mol Cell Biol. 1994 Mar;14(3):1544-52
8114692
Cancer Res. 2004 Oct 15;64(20):7197-200
15492232
Mol Cell Biol. 2003 Nov;23(21):7678-88
14560013
Oncologist. 2000;5(5):361-8
11040271
Mol Pharmacol. 2002 Aug;62(2):359-65
12130689
Genes Dev. 2000 Dec 1;14(23):3014-23
11114890
Biochem Biophys Res Commun. 2000 Oct 14;277(1):66-71
11027641
Methods Cell Biol. 1976;13:29-83
177845
Drug Metab Dispos. 2000 Mar;28(3):292-7
10681373
Biochem Pharmacol. 2000 Aug 15;60(4):517-26
10874126
Mol Cell Biol. 1998 Oct;18(10):5652-8
9742082
Genes Dev. 1998 Oct 15;12(20):3195-205
9784494
Biochemistry. 2007 Jan 23;46(3):862-70
17223708
J Biol Chem. 2000 May 19;275(20):15122-7
10748001
Pharmacogenomics J. 2002;2(2):117-26
12049174
Hepatology. 1999 May;29(5):1347-51
10216114
Drug Metab Dispos. 2002 Feb;30(2):208-11
11792692
J Biol Chem. 2005 Feb 4;280(5):3458-66
15563456
Nature. 2000 Jul 27;406(6794):435-9
10935643
Gene Expr Patterns. 2003 Oct;3(5):621-7
12971996
J Biol Chem. 2003 Apr 18;278(16):14146-52
12571232
J Ocul Pharmacol Ther. 2004 Feb;20(1):65-74
15006160
J Biol Chem. 2002 Jul 12;277(28):25125-32
11991950
J Biol Chem. 1997 Jul 25;272(30):18702-8
9228041
Bioorg Med Chem. 2006 Jul 1;14(13):4323-40
16530416
Curr Drug Metab. 2003 Feb;4(1):1-10
12570742
Mol Pharmacol. 2001 Sep;60(3):427-31
11502872
Biochem Pharmacol. 2008 Jun 1;75(11):2204-13
18400206
Pharmacotherapy. 1998 Jan-Feb;18(1):84-112
9469685
J Pharmacol Exp Ther. 2006 Jun;317(3):1200-9
16513849
Mol Pharmacol. 2001 Dec;60(6):1399-406
11723248
Nucl Recept. 2003 Jun 6;1(1):2
12904257
Toxicol Appl Pharmacol. 1998 May;150(1):158-65
9630465
Mol Cell Biol. 2002 Aug;22(15):5270-80
12101224