![[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}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication December 23, 2005.
Revised March 23, 2006.
Accepted for publication April 11, 2006.
The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) play a major part in the control of drug metabolism and transport. We have previously shown that PXR and CAR expression is controlled by the glucocorticoid receptor (GR) and proposed the existence of a signal transmission cascade GR-(PXR/CAR)-drug metabolising and transporter systems. In the current study we investigated the effect of ketoconazole and other azole-derived drugs, miconazole and fluconazole on the transcriptional activity of the human GR in HeLa and HepG2 cells, and in primary human hepatocytes. The data show that ketoconazole inhibits GR transcriptional activity and competes with dexamethasone for hGR binding. In primary human hepatocytes ketoconazole inhibits the expression of: i) GR-responsive genes tyrosine aminotransferase and both PXR and CAR, ii) CAR and PXR target genes including cytochrome P450 (CYP) CYP2B6, CYP2C9, CYP3A4, UDP-glucuronosyltransferase (UGT1A1), glutathion-S-transferases (GSTA1 and A2) and transporter proteins (phase III) SLC21A6 and multidrug resistance protein (MRP2). In parallel experiments, ketoconazole affected neither the expression of GR, nor the expression of glyceraldehyde phosphate dehydrogenase, nor the inducible expression of CYP1A1 and 1A2. Miconazole behaved like ketoconazole, while fluconazole had no effect. We conclude that, in addition to their well known inhibitory effect on CYP enzyme activities, ketoconazole and miconazole are antagonists of hGR. These results provide a novel molecular mechanism by which these compounds may exert adverse and toxic effects on drug metabolism and other functions in man.
Key words:
Glucorticoids/Mineralocorticoids, Regulation of gene expression, Cytochrome P450, Liver transporters, Phase II enzymes, Regulation - transcriptional, Regulation - xenobiotic
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. Goel, M. Cohen, S. N. Comezoglu, L. Perrin, F. Andre, D. Jayabalan, L. Iacono, A. Comprelli, V. T. Ly, D. Zhang, et al. The Effect of Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Ixabepilone: A First in Class Epothilone B Analogue in Late-Phase Clinical Development Clin. Cancer Res., May 1, 2008; 14(9): 2701 - 2709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Healan-Greenberg, J. F. Waring, D. J. Kempf, E. A. G. Blomme, R. G. Tirona, and R. B. Kim A Human Immunodeficiency Virus Protease Inhibitor Is a Novel Functional Inhibitor of Human Pregnane X Receptor Drug Metab. Dispos., March 1, 2008; 36(3): 500 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Svecova, R. Vrzal, L. Burysek, E. Anzenbacherova, L. Cerveny, J. Grim, F. Trejtnar, J. Kunes, M. Pour, F. Staud, et al. Azole Antimycotics Differentially Affect Rifampicin-Induced Pregnane X Receptor-Mediated CYP3A4 Gene Expression Drug Metab. Dispos., February 1, 2008; 36(2): 339 - 348. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
