The orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4

Tirona, Rommel G.; Lee, Wooin; Leake, Brenda F.; Lan, Lu‐Bin; Cline, Cynthia; Lamba, Vishal; Parviz, Fereshteh; Duncan, Stephen A.; Inoue, Yusuke; Gonzalez, Frank J.; Schuetz, Erin G.; Kim, Richard B.

doi:10.1038/nm815

Cited by 413 publications

(381 citation statements)

References 22 publications

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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%

“…CYP3A4 induction by xenobiotics and hormones is mediated by the pregnane X receptor (PXR, NR1I2) [5][6][7], constitutive androstane receptor (CAR, NR1I3) [8,9], vitamin D receptor (VDR, NR1I1) [10,11], glucocorticoid receptor- (GR, NR3C1) [12], hepatocyte nuclear factor-4 (HNF4, NR2A1) [13] and retinoid X receptor- (RXR, NR2B1) in the liver [3]. In addition, basal (constitutive) CYP3A4 expression in the absence of an inducing agent has been found to correlate with expression of CAR, PXR and HNF4 in the liver [12,14].…”

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: Introductionmentioning

confidence: 99%

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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“…Given the major role of HNF4α in regulating liver gene expression [2,6,41], HNF4α may act by inducing the expression of one or more factors that block JAK2 activation or stimulate JAK2 deactivation (dephosphorylation) in GH-stimulated cells. For example, HNF4α may induce the expression of one or more JAK2-inhibitory cytokine receptor signalling inhibitors, such as SOCS (suppressor of cytokine signalling) 1 and SOCS3 [42].…”

Section: Discussionmentioning

confidence: 99%

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4α (hepatocyte nuclear factor 4α), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4α strongly inhibited β-casein and ntcp (Na + /taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-γ -stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4α towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4α on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4α, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4α inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4α blocked GHstimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4α exhibit bidirectional cross-talk that may augment HNF4α-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4α on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

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“…Further work is also needed to investigate the interplay of cytokine signalling pathways with transcription factors known to be relevant to drug-metabolising and transporting genes such as hepatocyte nuclear factor-4a, signal transducer and activators of transcription 3, CCAAT enhancer binding proteins and the pregnane X receptor, in order to further understand the mechanism by which IL-6 regulates drug clearance in the presence of tumours (Roy-Chowdhury et al, 2003;Tirona et al, 2003).…”

Section: Downregulation Of Hepatic Metabolism In Malignancymentioning

confidence: 99%

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

et al. 2007

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There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.

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The orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4

Cited by 413 publications

References 22 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

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

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