![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 58, Issue 2, 361-372, August 2000
Expression in Human Hepatocytes: Synergistic Increase of
CYP3A4 Induction by Pregnane X Receptor Activators
Institut National de la Santé et de la Recherche
Médicale U128, Institut Federatif de Recherche 24, Centre
National de la Recherche Scientifique, Montpellier, France
In this report we show that submicromolar concentrations of
dexamethasone enhance pregnane X receptor (PXR)
activator-mediated CYP3A4 gene expression in cultured human
hepatocytes. Because this result is only observed after 24 h of
cotreatment and is inhibited by pretreatment with cycloheximide, we
further investigated which factor(s), induced by dexamethasone, might
be responsible for this effect. We report that dexamethasone increases
both retinoid X receptor-
(RXR) and PXR mRNA expression in
cultured human hepatocytes, whereas PXR activators such as rifampicin
and clotrimazole do not. Accumulation of RXR and PXR mRNA reaches a
maximum at a concentration of 100 nM dexamethasone after treatment for
6 to 12 h and is greatly diminished by RU486. A similar pattern of
expression is observed with tyrosine aminotransferase mRNA. Moreover,
the effect of dexamethasone on PXR mRNA accumulation seems to be
through direct action on the glucocorticoid receptor (GR) because the
addition of cycloheximide has no effect, and dexamethasone does not
affect the degradation of PXR mRNA. Furthermore, dexamethasone induces
the accumulation of a RXR-immunoreactive protein and increases the
nuclear level of RXR:PXR heterodimer as shown by gel shift assays
with a CYP3A4 ER6 PXRE probe. This accumulation of latent PXR
and RXR in the nucleus of hepatocytes explains the synergistic
effect observed with dexamethasone and PXR activators together on
CYP3A4 induction. These results reveal the existence of functional
cross talk between the GR and PXR, and may explain some controversial
aspects of the role of the GR in CYP3A4 induction.
This article has been cited by other articles:
|
|
 |
|
  V. S. Narang, C. Fraga, N. Kumar, J. Shen, S. Throm, C. F. Stewart, and C. M. Waters Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier Am J Physiol Cell Physiol, August 1, 2008; 295(2): C440 - C450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. W. Cooper, T. M. Cho, P. M. Thompson, and A. D. Wallace Phthalate Induction of CYP3A4 is Dependent on Glucocorticoid Regulation of PXR Expression Toxicol. Sci., June 1, 2008; 103(2): 268 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sakuma, W. Bhadhprasit, T. Hashita, and N. Nemoto Synergism of Glucocorticoid Hormone with Growth Hormone for Female-Specific Mouse Cyp3a44 Gene Expression Drug Metab. Dispos., May 1, 2008; 36(5): 878 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Sane, D. J. Buckley, A. R. Buckley, S. C. Nallani, and P. B. Desai Role of Human Pregnane X Receptor in Tamoxifen- and 4-Hydroxytamoxifen-Mediated CYP3A4 Induction in Primary Human Hepatocytes and LS174T Cells Drug Metab. Dispos., May 1, 2008; 36(5): 946 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Takagi, M. Nakajima, T. Mohri, and T. Yokoi Post-transcriptional Regulation of Human Pregnane X Receptor by Micro-RNA Affects the Expression of Cytochrome P450 3A4 J. Biol. Chem., April 11, 2008; 283(15): 9674 - 9680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Bielefeld, C. Lee, and D. S. Riddick Regulation of Aryl Hydrocarbon Receptor Expression and Function by Glucocorticoids in Mouse Hepatoma Cells Drug Metab. Dispos., March 1, 2008; 36(3): 543 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Druilhe, J.-M. Zahm, L. Benayoun, D. El Mehdi, M. Grandsaigne, M.-C. Dombret, I. Mosnier, B. Feger, J. Depondt, M. Aubier, et al. Epithelium Expression and Function of Retinoid Receptors in Asthma Am. J. Respir. Cell Mol. Biol., March 1, 2008; 38(3): 276 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Wang, X. Ma, K. W. Krausz, J. R. Idle, and F. J. Gonzalez Role of Pregnane X Receptor in Control of All-Trans Retinoic Acid (ATRA) Metabolism and Its Potential Contribution to ATRA Resistance J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 674 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Bhadhprasit, T. Sakuma, N. Hatakeyama, M. Fuwa, K. Kitajima, and N. Nemoto Involvement of Glucocorticoid Receptor and Pregnane X Receptor in the Regulation of Mouse CYP3A44 Female-Predominant Expression by Glucocorticoid Hormone Drug Metab. Dispos., October 1, 2007; 35(10): 1880 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cerveny, L. Svecova, E. Anzenbacherova, R. Vrzal, F. Staud, Z. Dvorak, J. Ulrichova, P. Anzenbacher, and P. Pavek Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways Drug Metab. Dispos., July 1, 2007; 35(7): 1032 - 1041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Urquhart, R. G. Tirona, and R. B. Kim Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs J. Clin. Pharmacol., May 1, 2007; 47(5): 566 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ishizuka, F. Okajima, T. Tanikawa, H. Min, K. D. Tanaka, K. Q. Sakamoto, and S. Fujita Elevated Warfarin Metabolism in Warfarin-Resistant Roof Rats (Rattus rattus) in Tokyo Drug Metab. Dispos., January 1, 2007; 35(1): 62 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Jung, D. J. Mangelsdorf, and U. A. Meyer Pregnane X Receptor Is a Target of Farnesoid X Receptor J. Biol. Chem., July 14, 2006; 281(28): 19081 - 19091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Duret, M. Daujat-Chavanieu, J.-M. Pascussi, L. Pichard-Garcia, P. Balaguer, J.-M. Fabre, M.-J. Vilarem, P. Maurel, and S. Gerbal-Chaloin Ketoconazole and Miconazole Are Antagonists of the Human Glucocorticoid Receptor: Consequences on the Expression and Function of the Constitutive Androstane Receptor and the Pregnane X Receptor Mol. Pharmacol., July 1, 2006; 70(1): 329 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lemaire, W. Mnif, J.-M. Pascussi, A. Pillon, F. Rabenoelina, H. Fenet, E. Gomez, C. Casellas, J.-C. Nicolas, V. Cavailles, et al. Identification of New Human Pregnane X Receptor Ligands among Pesticides Using a Stable Reporter Cell System Toxicol. Sci., June 1, 2006; 91(2): 501 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P A Sinclair, W J Gilmore, Z Lin, Y Lou, and E J Squires Molecular cloning and regulation of porcine SULT2A1: relationship between SULT2A1 expression and sulfoconjugation of androstenone. J. Mol. Endocrinol., April 1, 2006; 36(2): 301 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Aouabdi, G. Gibson, and N. Plant TRANSCRIPTIONAL REGULATION OF THE PXR GENE: IDENTIFICATION AND CHARACTERIZATION OF A FUNCTIONAL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {alpha} BINDING SITE WITHIN THE PROXIMAL PROMOTER OF PXR Drug Metab. Dispos., January 1, 2006; 34(1): 138 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wyde, S. E. Kirwan, F. Zhang, A. Laughter, H. B. Hoffman, E. Bartolucci-Page, K. W. Gaido, B. Yan, and L. You Di-n-Butyl Phthalate Activates Constitutive Androstane Receptor and Pregnane X Receptor and Enhances the Expression of Steroid-Metabolizing Enzymes in the Liver of Rat Fetuses Toxicol. Sci., August 1, 2005; 86(2): 281 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Noreault, V. E. Kostrubsky, S. G. Wood, R. C. Nichols, S. C. Strom, H. W. Trask, S. A. Wrighton, R. M. Evans, J. M. Jacobs, P. R. Sinclair, et al. ARSENITE DECREASES CYP3A4 AND RXR{alpha} IN PRIMARY HUMAN HEPATOCYTES Drug Metab. Dispos., July 1, 2005; 33(7): 993 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sugatani, S. Nishitani, K. Yamakawa, K. Yoshinari, T. Sueyoshi, M. Negishi, and M. Miwa Transcriptional Regulation of Human UGT1A1 Gene Expression: Activated Glucocorticoid Receptor Enhances constitutive Androstane Receptor/Pregnane X Receptor-Mediated UDP-Glucuronosyltransferase 1A1 Regulation with Glucocorticoid Receptor-Interacting Protein 1 Mol. Pharmacol., March 1, 2005; 67(3): 845 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Phillips, S. R. Hood, G. G. Gibson, and N. J. Plant IMPACT OF TRANSCRIPTION FACTOR PROFILE AND CHROMATIN CONFORMATION ON HUMAN HEPATOCYTE CYP3A GENE EXPRESSION Drug Metab. Dispos., February 1, 2005; 33(2): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Song, M. Xie, H. Zhang, Y. Li, K. Sachdeva, and B. Yan THE PREGNANE X RECEPTOR BINDS TO RESPONSE ELEMENTS IN A GENOMIC CONTEXT-DEPENDENT MANNER, AND PXR ACTIVATOR RIFAMPICIN SELECTIVELY ALTERS THE BINDING AMONG TARGET GENES Drug Metab. Dispos., January 1, 2004; 32(1): 35 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Handschin and U. A. Meyer Induction of Drug Metabolism: The Role of Nuclear Receptors Pharmacol. Rev., December 1, 2003; 55(4): 649 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, S. S. Ferguson, M. Negishi, and J. A. Goldstein Identification of Constitutive Androstane Receptor and Glucocorticoid Receptor Binding Sites in the CYP2C19 Promoter Mol. Pharmacol., August 1, 2003; 64(2): 316 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wyde, E. Bartolucci, A. Ueda, H. Zhang, B. Yan, M. Negishi, and L. You The Environmental Pollutant 1,1-Dichloro-2,2-bis (p-chlorophenyl)ethylene Induces Rat Hepatic Cytochrome P450 2B and 3A Expression through the Constitutive Androstane Receptor and Pregnane X Receptor Mol. Pharmacol., August 1, 2003; 64(2): 474 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Raucy Regulation of CYP3A4 Expression in Human Hepatocytes by Pharmaceuticals and Natural Products Drug Metab. Dispos., May 1, 2003; 31(5): 533 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, S. R. Faucette, D. Gilbert, S. L. Jolley, T. Sueyoshi, M. Negishi, and E. L. LeCluyse Glucocorticoid Receptor Enhancement of Pregnane X Receptor-Mediated CYP2B6 Regulation in Primary Human Hepatocytes Drug Metab. Dispos., May 1, 2003; 31(5): 620 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. H. Chang, S. M. Bandiera, and J. Chen Constitutive Androstane Receptor and Pregnane X Receptor Gene Expression in Human Liver: Interindividual Variability and Correlation with CYP2B6 mRNA Levels Drug Metab. Dispos., January 1, 2003; 31(1): 7 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Kliewer, B. Goodwin, and T. M. Willson The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic Metabolism Endocr. Rev., October 1, 2002; 23(5): 687 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Raucy, L. Warfe, M.-F. Yueh, and S. W. Allen A Cell-Based Reporter Gene Assay for Determining Induction of CYP3A4 in a High-Volume System J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 412 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. El-Sankary, V. Bombail, G. G. Gibson, and N. Plant Glucocorticoid-Mediated Induction of CYP3A4 is Decreased by Disruption of a Protein: DNA Interaction Distinct from the Pregnane X Receptor Response Element Drug Metab. Dispos., September 1, 2002; 30(9): 1029 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Drocourt, J.-C. Ourlin, J.-M. Pascussi, P. Maurel, and M.-J. Vilarem Expression of CYP3A4, CYP2B6, and CYP2C9 Is Regulated by the Vitamin D Receptor Pathway in Primary Human Hepatocytes J. Biol. Chem., July 5, 2002; 277(28): 25125 - 25132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D F. Lewis, M G Bird, and M N Jacobs Human carcinogens: an evaluation study via the COMPACT and HazardExpert procedures Human and Experimental Toxicology, March 1, 2002; 21(3): 115 - 122. [Abstract] [PDF]
|
|
|
|
|
|
S. Gerbal-Chaloin, M. Daujat, J.-M. Pascussi, L. Pichard-Garcia, M.-J. Vilarem, and P. Maurel Transcriptional Regulation of CYP2C9 Gene. ROLE OF GLUCOCORTICOID RECEPTOR AND CONSTITUTIVE ANDROSTANE RECEPTOR J. Biol. Chem., January 4, 2002; 277(1): 209 - 217. [Abstract] [Full Text]
|
|
|
|
|
|
W. El-Sankary, G. G. Gibson, A. Ayrton, and N. Plant Use of a Reporter Gene Assay to Predict and Rank the Potency and Efficacy of CYP3A4 Inducers Drug Metab. Dispos., November 1, 2001; 29(11): 1499 - 1504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Drocourt, J.-M. Pascussi, E. Assenat, J.-M. Fabre, P. Maurel, and M.-J. Vilarem Calcium Channel Modulators of the Dihydropyridine Family Are Human Pregnane X Receptor Activators and Inducers of CYP3A, CYP2B, and CYP2C in Human Hepatocytes Drug Metab. Dispos., October 1, 2001; 29(10): 1325 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Falkner, J. A. Pinaire, G.-H. Xiao, T. E. Geoghegan, and R. A. Prough Regulation of the Rat Glutathione S-Transferase A2 Gene by Glucocorticoids: Involvement of Both the Glucocorticoid and Pregnane X Receptors Mol. Pharmacol., September 1, 2001; 60(3): 611 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Quattrochi and P. S. Guzelian CYP3A Regulation: From Pharmacology to Nuclear Receptors Drug Metab. Dispos., April 13, 2001; 29(5): 615 - 622. [Abstract] [Full Text]
|
|
|
|
|
|
J.-M. Pascussi, S. Gerbal-Chaloin, J.-M. Fabre, P. Maurel, and M.-J. Vilarem Dexamethasone Enhances Constitutive Androstane Receptor Expression in Human Hepatocytes: Consequences on Cytochrome P450 Gene Regulation Mol. Pharmacol., April 13, 2001; 58(6): 1441 - 1450. [Abstract] [Full Text]
|
|
|
|
|
|
S. Gerbal-Chaloin, J.-M. Pascussi, L. Pichard-Garcia, M. Daujat, F. Waechter, J.-M. Fabre, N. Carrère, and P. Maurel Induction of CYP2C Genes in Human Hepatocytes in Primary Culture Drug Metab. Dispos., March 1, 2001; 29(3): 242 - 251. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
