Regulation of CYP3A4 by pregnane X receptor: The role of nuclear receptors competing for response element binding
Autor: | Monica A. Istrate, Andreas K. Nussler, Oliver Burk, Michel Eichelbaum |
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Rok vydání: | 2010 |
Předmět: |
Receptors
Steroid Response element Biophysics Electrophoretic Mobility Shift Assay Biology Response Elements Biochemistry Calcitriol receptor Binding Competitive COUP Transcription Factor II Cell Line Tumor Cytochrome P-450 CYP3A Humans Electrophoretic mobility shift assay Receptor Enhancer Molecular Biology Psychological repression Pregnane X receptor COUP Transcription Factor I Pregnane X Receptor Thyroid Hormone Receptors beta Cell Biology Molecular biology Nuclear receptor Thyroid Hormone Receptors alpha |
Zdroj: | Biochemical and biophysical research communications. 393(4) |
ISSN: | 1090-2104 |
Popis: | Induction of the major drug metabolizing enzyme CYP3A4 by xenobiotics contributes to the pronounced interindividual variability of its expression and often results in clinically relevant drug-drug interactions. It is mainly mediated by PXR, which regulates CYP3A4 expression by binding to several specific elements in the 5' upstream regulatory region of the gene. Induction itself shows a marked interindividual variability, whose underlying determinants are only partly understood. In this study, we investigated the role of nuclear receptor binding to PXR response elements in CYP3A4, as a potential non-genetic mechanism contributing to interindividual variability of induction. By in vitro DNA binding experiments, we showed that several nuclear receptors bind efficiently to the proximal promoter ER6 and distal xenobiotic-responsive enhancer module DR3 motifs. TRalpha1, TRbeta1, COUP-TFI, and COUP-TFII further demonstrated dose-dependent repression of PXR-mediated CYP3A4 enhancer/promoter reporter activity in transient transfection in the presence and absence of the PXR inducer rifampin, while VDR showed this effect only in the absence of treatment. By combining functional in vitro characterization with hepatic expression analysis, we predict that TRalpha1, TRbeta1, COUP-TFI, and COUP-TFII show a strong potential for the repression of PXR-mediated activation of CYP3A4 in vivo. In summary, our results demonstrate that nuclear receptor binding to PXR response elements interferes with PXR-mediated expression and induction of CYP3A4 and thereby contributes to the interindividual variability of induction. |
Databáze: | OpenAIRE |
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