title: 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.
abstract: 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 metabolizing 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 (hGR) 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 1) GR-responsive genes tyrosine aminotransferase and both PXR and CAR; 2) CAR and PXR target genes, including cytochromes P450 (P450) CYP2B6, CYP2C9, and CYP3A4; UDP-glucuronosyltransferase 1A1, glutathione S-transferases A1 and A2; and transporter proteins (phase III) solute carrier family 21 form A6 and multidrug resistance protein 2. In parallel experiments, ketoconazole affected neither the expression of GR, the expression of glyceraldehyde-3-phosphate dehydrogenase, nor the inducible expression of CYP1A1 and 1A2. Miconazole behaved like ketoconazole, whereas fluconazole had no effect. We conclude that, in addition to their well known inhibitory effect on P450 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 human.
authors.affiliation: INSERM U632, Hepatic Physiopathology, 1919 route de Mende, 34293 Montpellier, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Duret
authors.forename: Martine
authors.initials: M
authors.lastname: Daujat-Chavanieu
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Lydiane
authors.initials: L
authors.lastname: Pichard-Garcia
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Fabre
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Vilarem
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Sabine
authors.initials: S
authors.lastname: Gerbal-Chaloin
mesh_terms: D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008825:Miconazole / Q000494:pharmacology*; D008875:Middle Aged; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D007654:Ketoconazole; D008156:Luciferases; D008825:Miconazole; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099148:UGT1A1 Enzyme; C484555:GSTA1 protein, human