孕烷X受体
酮康唑
雄激素受体
CYP3A4型
糖皮质激素受体
药理学
CYP3A型
咪康唑
CYP2B6型
生物
药物代谢
细胞色素P450
化学
核受体
受体
生物化学
新陈代谢
基因
药品
转录因子
微生物学
抗真菌
作者
Cédric Duret,Martine Daujat-Chavanieu,Jean‐Marc Pascussi,Lydiane Pichard-Garcia,Patrick Balaguer,Jean‐Michel Fabre,Marie‐José Vilarem,Patrick Maurel,Sabine Gerbal‐Chaloin
出处
期刊:Molecular Pharmacology
[American Society for Pharmacology & Experimental Therapeutics]
日期:2006-04-11
卷期号:70 (1): 329-339
被引量:84
标识
DOI:10.1124/mol.105.022046
摘要
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.
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