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
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
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DOI：
10.1124/mol.105.022046
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发表时间：
2006-07-01
影响因子：
3.6
通讯作者：
Gerbal-Chaloin, Sabine
中科院分区：
文献类型：
--
作者：
Duret, Cedric;Daujat-Chavanieu, Martine;Gerbal-Chaloin, Sabine
组成型雄甾受体（CAR）和孕X受体（PXR）在药物代谢和转运的控制中起重要作用。我们之前已经证明PXR和CAR的表达受糖皮质激素受体（GR）的控制，并提出存在GR-(PXR/CAR)-药物代谢和转运系统的信号传递级联。在本研究中，我们研究了酮康唑和其他唑类药物咪康唑和氟康唑对人GR （hGR）在HeLa和HepG2细胞以及人原代肝细胞中的转录活性的影响。数据显示酮康唑抑制GR转录活性，并与地塞米松竞争hGR结合。在人原代肝细胞中，酮康唑抑制1)GR应答基因酪氨酸转氨酶和PXR和CAR的表达；2) CAR和PXR靶基因，包括细胞色素P450 （P450）、CYP2B6、CYP2C9和CYP3A4；葡萄糖醛酸转移酶1A1、谷胱甘肽s转移酶A1、A2；转运蛋白（III期）溶质载体家族21形成A6和多药耐药蛋白2。在平行实验中，酮康唑既不影响GR的表达，也不影响甘油醛-3-磷酸脱氢酶的表达，也不影响CYP1A1和1A2的诱导表达。咪康唑的表现与酮康唑相似，而氟康唑没有效果。我们得出结论，除了已知的对P450酶活性的抑制作用外，酮康唑和咪康唑是hGR的拮抗剂。这些结果为这些化合物对人体药物代谢和其他功能产生不良和毒性作用提供了一种新的分子机制。
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.