title: Regulation of CYP3A4 by pregnane X receptor: The role of nuclear receptors competing for response element binding.
abstract: 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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Monica A
authors.initials: MA
authors.lastname: Istrate
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nussler
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Oliver
authors.initials: O
authors.lastname: Burk
mesh_terms: D001667:Binding, Competitive; D051838:COUP Transcription Factor I / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000378:metabolism; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism
chemical_list: D051838:COUP Transcription Factor I; D051837:COUP Transcription Factor II; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human