MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pascussi, J.-M.
Right arrow Articles by Vilarem, M.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pascussi, J.-M.
Right arrow Articles by Vilarem, M.-J.

Vol. 58, Issue 6, 1441-1450, December 2000

Dexamethasone Enhances Constitutive Androstane Receptor Expression in Human Hepatocytes: Consequences on Cytochrome P450 Gene Regulation

Jean-Marc Pascussi,1 Sabine Gerbal-Chaloin,1 Jean-Michel Fabre, Patrick Maurel, and Marie-José Vilarem

Institut National de la Santé et de la Recherche Médicale U128-IFR24, Centre National de la Recherche Scientifique, Montpellier, France (J.-M.P., S.G.-C., P.M., M.-J.V.) and Service de Chirurgie, Hopital Saint Eloi, Montpellier, France (J.-M.F.)

The barbiturate phenobarbital induces the transcription of cytochromes P450 (CYPs) 2B through the constitutive androstane receptor (CAR; NR1I3). CAR is a member of the nuclear receptor family (NR1) mostly expressed in the liver, which heterodimerizes with retinoid X receptor (RXR) and was shown to transactivate both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element. Because previous studies in rodent hepatocyte cultures have shown that the phenobarbital-mediated induction of CYP2B genes is potentiated by glucocorticoids, we examined the role of activated glucocorticoid receptor in this process. We show that submicromolar concentrations of dexamethasone enhance phenobarbital-mediated induction of CYP3A4, CYP2B6, and CYP2C8 mRNA in cultured human hepatocytes. In parallel, we observed that glucocorticoid agonists, such as dexamethasone, prednisolone, or hydrocortisone, specifically increase human car (hCAR) mRNA expression. Accumulation of hCAR mRNA parallels that of tyrosine aminotransferase: both mRNAs reach a maximum at a concentration of 100 nM dexamethasone and are down-regulated by concomitant treatment with the glucocorticoid antagonist RU486. Moreover, the effect of dexamethasone on hCAR mRNA accumulation appears to be of transcriptional origin because the addition of protein synthesis inhibitor cycloheximide has no effect, and dexamethasone does not affect the degradation of hCAR mRNA. Furthermore, dexamethasone increases both basal and phenobarbital-mediated nuclear translocation of CAR immunoreactive protein in human hepatocytes. The up-regulation of CAR mRNA and protein in response to dexamethasone explains the synergistic effect of this glucocorticoid on phenobarbital-mediated induction of CYP2B genes and the controversial role of the glucocorticoid receptor on phenobarbital-mediated CYP gene inductions.

1 These two authors have equally contributed to this work.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Jia, G. L. Guo, S. Surapureddi, J. Sarkar, C. Qi, D. Guo, J. Xia, P. Kashireddi, S. Yu, Y.-W. Cho, et al.
Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity
PNAS, August 30, 2005; 102(35): 12531 - 12536.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
F. Rencurel, A. Stenhouse, S. A. Hawley, T. Friedberg, D. G. Hardie, C. Sutherland, and C. R. Wolf
AMP-activated Protein Kinase Mediates Phenobarbital Induction of CYP2B Gene Expression in Hepatocytes and a Newly Derived Human Hepatoma Cell Line
J. Biol. Chem., February 11, 2005; 280(6): 4367 - 4373.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Wang, S. Faucette, R. Moore, T. Sueyoshi, M. Negishi, and E. LeCluyse
Human Constitutive Androstane Receptor Mediates Induction of CYP2B6 Gene Expression by Phenytoin
J. Biol. Chem., July 9, 2004; 279(28): 29295 - 29301.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
C.-S. Yuan, G. Wei, L. Dey, T. Karrison, L. Nahlik, S. Maleckar, K. Kasza, M. Ang-Lee, and J. Moss
Brief Communication: American Ginseng Reduces Warfarin's Effect in Healthy Patients: A Randomized, Controlled Trial
Ann Intern Med, July 6, 2004; 141(1): 23 - 27.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Wang, S. Faucette, T. Sueyoshi, R. Moore, S. Ferguson, M. Negishi, and E. L. LeCluyse
A Novel Distal Enhancer Module Regulated by Pregnane X Receptor/Constitutive Androstane Receptor Is Essential for the Maximal Induction of CYP2B6 Gene Expression
J. Biol. Chem., April 11, 2003; 278(16): 14146 - 14152.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
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]

Home page
 Mol. Endocrinol.Home page
J. M. Pascussi, M. Busson-Le Coniat, P. Maurel, and M.-J. Vilarem
Transcriptional Analysis of the Orphan Nuclear Receptor Constitutive Androstane Receptor (NR1I3) Gene Promoter: Identification of a Distal Glucocorticoid Response Element
Mol. Endocrinol., January 1, 2003; 17(1): 42 - 55.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. A. Kocarek, M. S. Dahn, H. Cai, S. C. Strom, and N. A. Mercer-Haines
Regulation of CYP2B6 and CYP3A Expression by Hydroxymethylglutaryl Coenzyme A Inhibitors in Primary Cultured Human Hepatocytes
Drug Metab. Dispos., December 1, 2002; 30(12): 1400 - 1405.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
T. THUM and J. BORLAK
Testosterone, cytochrome P450, and cardiac hypertrophy
FASEB J, October 1, 2002; 16(12): 1537 - 1549.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
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]

Home page
 Mol. Pharmacol.Home page
J. M. Maglich, C. M. Stoltz, B. Goodwin, D. Hawkins-Brown, J. T. Moore, and S. A. Kliewer
Nuclear Pregnane X Receptor and Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic Detoxification
Mol. Pharmacol., September 1, 2002; 62(3): 638 - 646.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. L. Raucy, L. Mueller, K. Duan, S. W. Allen, S. Strom, and J. M. Lasker
Expression and Induction of CYP2C P450 Enzymes in Primary Cultures of Human Hepatocytes
J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 475 - 482.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
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]

Home page
 Drug Metab. Dispos.Home page
C. Lindley, G. Hamilton, J. S. McCune, S. Faucette, S. S. Shord, R. L. Hawke, H. Wang, D. Gilbert, S. Jolley, B. Yan, et al.
The Effect of Cyclophosphamide with and without Dexamethasone on Cytochrome P450 3A4 and 2B6 in Human Hepatocytes
Drug Metab. Dispos., July 1, 2002; 30(7): 814 - 822.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Stankova, S. Turcotte, J. Harris, and M. Rola-Pleszczynski
Modulation of Leukotriene B4 Receptor-1 Expression by Dexamethasone: Potential Mechanism for Enhanced Neutrophil Survival
J. Immunol., April 1, 2002; 168(7): 3570 - 3576.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
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]

Home page
 J. Biol. Chem.Home page
K. Bodin, L. Bretillon, Y. Aden, L. Bertilsson, U. Broome, C. Einarsson, and U. Diczfalusy
Antiepileptic Drugs Increase Plasma Levels of 4beta -Hydroxycholesterolin Humans. EVIDENCE FOR INVOLVEMENT OF CYTOCHROME P450 3A4
J. Biol. Chem., October 12, 2001; 276(42): 38685 - 38689.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
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]

Home page
 Drug Metab. Dispos.Home page
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]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics