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

2006 ◽  
Vol 70 (1) ◽  
pp. 329-339 ◽  
Author(s):  
Cedric Duret ◽  
Martine Daujat-Chavanieu ◽  
Jean-Marc Pascussi ◽  
Lydiane Pichard-Garcia ◽  
Patrick Balaguer ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
And Function

scholarly journals The Nuclear Receptor PXR in Chronic Liver Disease

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 61
Author(s):  
Katia Sayaf ◽  
Ilaria Zanotto ◽  
Francesco Paolo Russo ◽  
Daniela Gabbia ◽  
Sara De Martin
Keyword(s):  
Nuclear Receptor ◽  
Liver Diseases ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Chronic Liver ◽  
Cytochrome P450 3A4 ◽  
Chronic Liver Diseases ◽  
Metabolizing Enzymes ◽  
P Glycoprotein ◽  
And Function

Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

scholarly journals Regulation of CYP3A genes by glucocorticoids in human lung cells

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 173
Author(s):  
Jessica K Roberts ◽  
Chad D Moore ◽  
Erin G Romero ◽  
Robert M Ward ◽  
Garold S Yost ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Constitutive Androstane Receptor ◽  
A549 Cells ◽  
Persistent Asthma ◽  
Pregnane X Receptor ◽  
Lung Cells ◽  
Metabolic Clearance ◽  
Mrna Induction ◽  
Human Lung Cells ◽  
Tracheal Epithelial

Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma.  However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung.  CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes.  However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined.  In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7.  There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.

scholarly journals Regulation of CYP3A genes by glucocorticoids in human lung cells

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 173 ◽  
Author(s):  
Jessica K Roberts ◽  
Chad D Moore ◽  
Erin G Romero ◽  
Robert M Ward ◽  
Garold S Yost ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Constitutive Androstane Receptor ◽  
A549 Cells ◽  
Persistent Asthma ◽  
Pregnane X Receptor ◽  
Lung Cells ◽  
Metabolic Clearance ◽  
Mrna Induction ◽  
Human Lung Cells ◽  
Tracheal Epithelial

Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma.  However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung.  CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes.  However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined.  In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7.  There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.

scholarly journals Alpha-Tocopherol Metabolites (The Vitamin E Metabolome) and Their Interindividual Variability during Supplementation

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 173
Author(s):  
Desirée Bartolini ◽  
Rita Marinelli ◽  
Danilo Giusepponi ◽  
Roberta Galarini ◽  
Carolina Barola ◽  
...  
Keyword(s):  
Vitamin E ◽  
Target Genes ◽  
Interindividual Variability ◽  
Pregnane X Receptor ◽  
Alpha Tocopherol ◽  
Therapeutic Interventions ◽  
Intrinsic Variability ◽  
Blood Leukocytes ◽  
Definition Of ◽  
And Function

The metabolism of α-tocopherol (α-TOH, vitamin E) shows marked interindividual variability, which may influence the response to nutritional and therapeutic interventions with this vitamin. Recently, new metabolomics protocols have fostered the possibility to explore such variability for the different metabolites of α-TOH so far identified in human blood, i.e., the “vitamin E metabolome”, some of which have been reported to promote important biological functions. Such advances prompt the definition of reference values and degree of interindividual variability for these metabolites at different levels of α-TOH intake. To this end, a one-week oral administration protocol with 800 U RRR-α-TOH/day was performed in 17 healthy volunteers, and α-TOH metabolites were measured in plasma before and at the end of the intervention utilizing a recently validated LC-MS/MS procedure; the expression of two target genes of α-TOH with possible a role in the metabolism and function of this vitamin, namely pregnane X receptor (PXR) and the isoform 4F2 of cytochrome P450 (CYP4F2) was assessed by immunoblot in peripheral blood leukocytes. The levels of enzymatic metabolites showed marked interindividual variability that characteristically increased upon supplementation. With the exception of α-CEHC (carboxy-ethyl-hydroxychroman) and the long-chain metabolites M1 and α-13′OH, such variability was found to interfere with the possibility to utilize them as sensitive indicators of α-TOH intake. On the contrary, the free radical-derived metabolite α-tocopheryl quinone significantly correlated with the post-supplementation levels of α-TOH. The supplementation stimulated PXR, but not CYP4F2, expression of leucocytes, and significant correlations were observed between the baseline levels of α-TOH and both the baseline and post-supplementation levels of PXR. These findings provide original analytical and molecular information regarding the human metabolism of α-TOH and its intrinsic variability, which is worth considering in future nutrigenomics and interventions studies.

Regulatory Cross-Talk between Drug Metabolism and Lipid Homeostasis: Constitutive Androstane Receptor and Pregnane X Receptor Increase Insig-1 Expression

2008 ◽  
Vol 73 (4) ◽  
pp. 1282-1289 ◽  
Author(s):  
Adrian Roth ◽  
Renate Looser ◽  
Michel Kaufmann ◽  
Sharon M. Blättler ◽  
Franck Rencurel ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Cross Talk ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Lipid Homeostasis

scholarly journals Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis

2019 ◽  
Vol 51 (2) ◽  
pp. 226-235 ◽  
Author(s):  
Daisuke Uehara ◽  
Hiroki Tojima ◽  
Satoru Kakizaki ◽  
Yuichi Yamazaki ◽  
Norio Horiguchi ◽  
...  
Keyword(s):  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor
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