![[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. 31, Issue 5, 620-630, May 2003
Division of Drug Delivery and Disposition, School of Pharmacy,
University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina (H.W., S.R.F., D.G., S.L.J., E.L.L.); and Laboratory of
Reproductive and Developmental Toxicology, National Institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, North Carolina (T.S., M.N.)
Although the glucocorticoid receptor (GR) facilitates the
xenobiotic-induced expression of CYP2B in rodents, its role in the regulation of human CYP2B6 is unclear. In this report, the role of
human GR in the regulation of CYP2B6 was evaluated using primary human
hepatocytes and transfection assays with Huh7 cells. CYP2B6 expression
was not induced in primary hepatocytes treated with dexamethasone (DEX)
concentrations (0.01-1 µM) known to activate GR. In contrast,
treatment with 0.1 µM DEX enhanced CYP2B6 induction by different
pregnane X receptor (PXR) activators, including rifampin, phenytoin, clotrimazole, and phenobarbital. In Huh7 cells,
cotransfection of human (h)GR and hPXR with
CYP2B6-phenobarbital-responsive enhancer module (PBREM) reporter
constructs revealed that all hPXR ligands induce CYP2B6 reporter gene
activity, and this ligand-dependent activation is greatly enhanced by
activated hGR. CYP2B6 reporter gene expression was not induced in the
presence of hPXR ligands when hGR alone was cotransfected with CYP2B6
reporter construct. In hGR and human constitutive androstane receptor
(hCAR) cotransfection assays, activated hGR increased the constitutive
activation of PBREM reporter constructs by hCAR in the absence of
inducers. In the presence of activated hGR and known inducers of
CYP2B6, only PB treatment caused a further 2-fold activation of hCAR
compared with control. These studies show that hGR is involved
synergistically in the xenobiotic-responsive regulation of human CYP2B6
by hPXR and hCAR. Moreover, the results suggest that the GR-enhanced
expression of CYP2B6 is mediated through an indirect mechanism that
does not require increased expression of nuclear receptor.
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]
|
|
|
|
 |
|
 S. A. Grossman, J. Olson, T. Batchelor, D. Peereboom, G. Lesser, S. Desideri, X. Ye, T. Hammour, J. G. Supko, and for the New Approaches to Brain Tumor Therapy CNS Effect of phenytoin on celecoxib pharmacokinetics in patients with glioblastoma Neuro-oncol, April 1, 2008; 10(2): 190 - 198. [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]
|
|
|
|
 |
|
 K. Wang, A. J. Mendy, G. Dai, H.-R. Luo, L. He, and Y.-J. Y. Wan Retinoids Activate the RXR/SXR-Mediated Pathway and Induce the Endogenous CYP3A4 Activity in Huh7 Human Hepatoma Cells Toxicol. Sci., July 1, 2006; 92(1): 51 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Roymans, P. Annaert, J. Van Houdt, A. Weygers, J. Noukens, C. Sensenhauser, J. Silva, C. Van Looveren, J. Hendrickx, G. Mannens, et al. EXPRESSION AND INDUCTION POTENTIAL OF CYTOCHROMES P450 IN HUMAN CRYOPRESERVED HEPATOCYTES Drug Metab. Dispos., July 1, 2005; 33(7): 1004 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hukkanen, P. Jacob III, and N. L. Benowitz Metabolism and Disposition Kinetics of Nicotine Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hempel, H. Wang, E. L. LeCluyse, M. E. McManus, and M. Negishi The Human Sulfotransferase SULT1A1 Gene Is Regulated in a Synergistic Manner by Sp1 and GA Binding Protein Mol. Pharmacol., December 1, 2004; 66(6): 1690 - 1701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
J. P. Jackson, S. S. Ferguson, R. Moore, M. Negishi, and J. A. Goldstein The Constitutive Active/Androstane Receptor Regulates Phenytoin Induction of Cyp2c29 Mol. Pharmacol., June 1, 2004; 65(6): 1397 - 1404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Faucette, H. Wang, G. A. Hamilton, S. L. Jolley, D. Gilbert, C. Lindley, B. Yan, M. Negishi, and E. L. LeCluyse REGULATION OF CYP2B6 IN PRIMARY HUMAN HEPATOCYTES BY PROTOTYPICAL INDUCERS Drug Metab. Dispos., March 1, 2004; 32(3): 348 - 358. [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]
|
|
 |
 |
 |
|
 |
 |
 |
