Molecular Mechanism of Basal CYP3A4 Regulation by Hepatocyte Nuclear Factor 4α: Evidence for Direct Regulation in the Intestine

Tegude, Heike; Schnabel, Anke; Zanger, Ulrich M.; Klein, Kathrin; Eichelbaum, Michel; Burk, Oliver

doi:10.1124/dmd.106.013565

Cited by 43 publications

(45 citation statements)

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“…In addition, we should consider involvement of tissue-enriched transcription factors such as liver-enriched transcription factors (LEFTs -HNF4α, HNF1α, C/EBPα and β etc.) in CYP3A4 transactivation [3,4,13].…”

Section: Discussionmentioning

confidence: 99%

“…an unknown RE 5 LCA prER6 DR3 = CLEM4 no effect of eNR3A4 DR3 prER6 + CLEM4 2 no effect of eNR3A4 1 the same pattern for LS174T, HCT-8 and HT-29 intestinal cell lines, CLEM4 has a modulatory effect together with pER6 and DR3 sites; for CACO-2 cells-DR3 prER6 CLEM4, no effect of eNR3A4 2 cooperation, minimal individual effects of the response elements 3 In HepG2, relative fold induction is not affected by any response element mutation due to the parallel decrease in basal activation. 4 for Mz-Hep-1 cells…”

Section: A4 -114skpnimentioning

confidence: 99%

“…The CYP3A4 5'-flanking region is 35.8 kb [2], but only 13 kb have been systematically analyzed for regulation in hepatocyte or intestinal cells [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Pávek

Pospěchová

Svecova

et al. 2010

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Abstract CYP3A4 is the most important drug-metabolizing enzyme that is involved in biotransformation of more than 50% of drugs. Pregnane X receptor (PXR) dominantly controls CYP3A4 inducibility in the liver, whereas vitamin D receptor (VDR) transactivates CYP3A4 in the intestine by secondary bile acids. Four major functional PXR-binding response elements of CYP3A4 have been discovered and their cooperation was found to be crucial for maximal up-regulation of the gene in hepatocytes. VDR and PXR recognize similar response element motifs and share DR3(XREM) and proximal ER6 (prER6) response elements of the CYP3A4 gene.In this work, we tested whether the recently discovered PXR response elements DR4(eNR3A4) in the XREM module and the distal ER6 element in the CLEM4 module We thus describe a specific ligand-induced VDR-mediated transactivation of the CYP3A4 gene in intestinal cells that differs PXR-mediated CYP3A4 regulation in hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Section: A4 -114skpnimentioning

confidence: 99%

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Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Pávek

Pospěchová

Svecova

et al. 2010

Biochemical Pharmacology

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“…In a previous study, Tirona et al (2003) suggested a critical role of HNF4␣ in the PXR-and CAR-mediated transcriptional activation of CYP3A4 in Caco-2 cells. Furthermore, Tegude et al (2007) underscored the role of HNF4␣ in directly regulating CYP3A4 in LS174T cells. Thus, it is likely that in addition to GR␣, reduced expression of other transcription factors, such as HNF4␣ observed in LS174T cells, and/or interaction with CAR may also contribute to the apparent lack of CYP3A4 induction by tamoxifen/4OHT in these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we observed that both compounds activated the human pregnane X receptor (PXR) in cellbased reporter assays (Desai et al, 2002). It is well established that in addition to PXR, several other tissue-specific factors and nuclear receptors impact the transcriptional regulation of CYP3A4 (Pascussi et al, 2003a,b;Tegude et al, 2007). As such, the expression of PXR and other receptors, such as glucocorticoid receptor (GR) ␣, and transcriptional factors, such as hepatic nuclear factor (HNF) 4␣, impact the regulation of PXR target genes (Pascussi et al, 2000;Li and Chiang, 2006).…”

mentioning

confidence: 91%

Role of Human Pregnane X Receptor in Tamoxifen- and 4-Hydroxytamoxifen-Mediated CYP3A4 Induction in Primary Human Hepatocytes and LS174T Cells

Sane

Buckley²,

Buckley³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Previously we observed that the antiestrogens tamoxifen and 4-hydroxytamoxifen (4OHT) induce CYP3A4 in primary human hepatocytes and activate human pregnane X receptor (PXR) in cell-based reporter assays. Given the complex cross-talk between nuclear receptors, tissue-specific expression of CYP3A4, and the potential for tamoxifen and 4OHT to interact with a myriad of receptors, this study was undertaken to gain mechanistic insights into the inductive effects of tamoxifen and 4OHT. First, we observed that transfection of the primary cultures of human hepatocytes with PXRspecific small interfering RNA reduced the PXR mRNA expression and the extent of CYP3A4 induction by tamoxifen and 4OHT by 50%. Second, in LS174T colon carcinoma cells, which were observed to have significantly lower PXR expression relative to human hepatocytes, neither tamoxifen nor 4OHT induced CYP3A4.Third, N-desmethyltamoxifen, which did not induce CYP3A4 in human hepatocytes, also did not activate PXR in LS174T cells. We then used cell-based reporter assay to evaluate the effects of other receptors such as glucocorticoid receptor GR␣ and estrogen receptor ER␣ on the transcriptional activation of PXR. The cotransfection of GR␣ in LS174T cells augmented PXR activation by tamoxifen and 4OHT. On the other hand, the presence of ER␣ inhibited PXR-mediated basal activation of CYP3A4 promoter, possibly via competing for common cofactors such as steroid receptor coactivator 1 and glucocorticoid receptor interacting protein 1. Collectively, our findings suggest that the CYP3A4 induction by tamoxifen and 4OHT is primarily mediated by PXR but the overall stoichiometry of other nuclear receptors and transcription cofactors also contributes to the extent of the inductive effect.Tamoxifen is a prototypical selective estrogen receptor modulator by virtue of its tissue-specific estrogen/antiestrogen properties. It is a clinically effective endocrine agent for the treatment and chemoprevention of breast cancer, and despite the advent of new antiestrogens, such as the aromatase inhibitors anastrazole and letrozole, it remains the drug of choice, especially in premenopausal women. Although tamoxifen is generally well tolerated, its clinical use is associated with several unresolved problems. These include interindividual variability in its pharmacokinetics and the resulting variability in its safety and efficacy profile and drug-drug interactions. Because the systemic elimination of tamoxifen primarily entails hepatic metabolism, intersubject variability in its metabolism is the principal cause of the overall variability in its pharmacokinetics. Tamoxifen is biotransformed to a larger number of metabolites, including N-desmethyltamoxifen (NDMT) and 4-hydroxytamoxifen (4OHT), which are further converted to 4-hydroxy-N-desmethyltamoxifen (endoxifen) (Borges et al., 2006). Whereas NDMT is a weak antiestrogen, 4OHT and endoxifen are considerably more potent antiestrogens than tamoxifen and may contribute to the overall therapeutic properties of the latter. A...

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Transcriptional Regulation of Human Drug‐Metabolizing Cytochrome P450 Enzymes

Dvořák

2012

Metabolism of Drugs and Other Xenobiotics

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Molecular Mechanism of Basal CYP3A4 Regulation by Hepatocyte Nuclear Factor 4α: Evidence for Direct Regulation in the Intestine

Cited by 43 publications

References 30 publications

Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Intestinal cell-specific vitamin D receptor (VDR)-mediated transcriptional regulation of CYP3A4 gene

Role of Human Pregnane X Receptor in Tamoxifen- and 4-Hydroxytamoxifen-Mediated CYP3A4 Induction in Primary Human Hepatocytes and LS174T Cells

Transcriptional Regulation of Human Drug‐Metabolizing Cytochrome P450 Enzymes

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