Immunocytochemical Detection of 1,25-Dihydroxyvitamin D Receptors in Normal Human Tissues*

Berger, U.; Wilson, Patricia D.; McClelland, Richard Andrew; Colston, K. W.; Haussler, Mark R.; Pike, J. Wesley; Coombes, R. Charles

doi:10.1210/jcem-67-3-607

Cited by 189 publications

(119 citation statements)

References 21 publications

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“…Although VDR levels in liver might be low, it has been revealed recently that VDR is present in human liver [9,33]; as well as fetal, neonatal, and adult rat liver [34]. Furthermore, the level of VDR is much higher (>20-fold) in mouse than in human or rat hepatocytes [35].…”

Section: Discussionmentioning

confidence: 99%

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

Wang

Chen

Xie

et al. 2008

Biochemical Pharmacology

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A panel of retinoids and carotenoids was screened as potential inducers of CYP3A4 through the RXR/VDR-mediated signaling pathway. Transient transfection assays revealed that 3 out of 12 retinoids screened transactivated RXRα/VDR and induced CYP3A4 reporter activity. These three retinoids are the active metabolites of retinoids, 9-cis-retinal, 9-cis-retinoic acid (9-cis-RA), and alltrans-retinoic acid (all-trans-RA). 9-cis-RA and all-trans-RA, preferentially transactivated the RXR/ VDR heterodimers and RXR homodimers. Retinoids and VDR agonist 1α, 25-dihydroxyvitamin D 3 , but not PXR or CAR activator, could induce Cyp3a11 mRNA level in hepatocytes derived from PXR/CAR double null mouse. Moreover, retinoids induced CYP3A4 enzyme activity in HepG2 human hepatoma and Caco-2 human colorectal adenocarcinoma cells. A direct role of retinoidmediated CYP3A4 induction through RXRα/VDR was proved by the results that 9-cis-retinal, 9-cis-RA, and all-trans-RA recruited RXRα and VDR to CYP3A4 regulatory region pER6 (proximal everted repeat with a 6-nucleotide spacer) and dXREM (distal xenobiotic-responsive enhancer module). Thus, using various approaches, we have unequivocally demonstrated that retinoids transactivate RXR/VDR heterodimers and RXR homodimers and induce CYP3A expression at mRNA as well as enzyme activity levels in both liver and intestinal cells. It is possible that retinoids might alter endobiotic metabolism through CYP3A4 induction in vivo.

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Section: Discussionmentioning

confidence: 99%

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

Wang

Chen

Xie

et al. 2008

Biochemical Pharmacology

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“…1A, Fig. 2) and both receptors are expressed in the intestine [31], we investigated, whether VDR competes with PXR in the CYP3A4 gene regulation in the intestinal cells. We 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 endogenous activities of VDR and PXR in LS174T cells [25,27].…”

Section: Vdr and Pxr Cooperatively Up-regulate Intestinal Cyp3a4 Tranmentioning

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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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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“…These include interaction of calcitriol with a membrane receptor, either a novel receptor or the known vitamin D receptor, thereby activating cell signalling pathways (Nemere and Campbell, 2000;Holick, 2003;Evans et al, 2004;Fleet, 2004;Mizwicki et al, 2004;Dusso et al, 2005;Hendy et al, 2006). There is growing direct evidence that the traditional vitamin D receptor may also have a unique, nontranscriptional role in plasma membrane initiated signalling (Fleet, 2004 (Berger et al, 1988;Sandgren et al, 1991;Rougui et al, 1998;Sheinin et al, 2000;Chatterjee, 2001;Holick, 2003;Lee et al, 2003). The exact roles of calcitriol at all these sites are not always completely understood.…”

mentioning

confidence: 99%

“…Vitamin D receptors are also more abundant deep in crypts than in villar cells (Clemens et al, 1988). Results are, however, controversial in some instances (Berger et al, 1988;Sandgren et al, 1991;Kinyamu et al, 1997;Wood et al, 1998;Colin et al, 1999;Sheinin et al, 2000;Leonard et al, 2001;Lee et al, 2003;Pazianas et al, 2003;Chen et al, 2006). …”

mentioning

confidence: 99%

Vitamin D receptor distribution in intestines of domesticated sheep Ovis ammon f. aries

Riner

Boos

Hässig

et al. 2007

Journal of Morphology

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The biologically active form of vitamin D, i.e., 1,25‐dihydroxycholecalciferol or calcitriol, plays an important role in bone metabolism and calcium homeostasis, which is often disturbed at the onset of lactation in high milk‐yielding domestic ruminants. Gene transcription is modulated via vitamin D receptors, but nongenomic effects of vitamin D via membrane receptors have also been described. In the intestines, vitamin D promotes calcium absorption via vitamin D receptors. Vitamin D receptors are of clinical relevance, but have not been systematically assessed within all segments of the intestine in any species. Thus, we present for the first time an immunohistochemical study of the distribution patterns of the vitamin D receptor protein in sheep, which may be the basis for present and future investigations on mineral homeostasis in domestic ruminants. Tissue probes of the intestines were collected from five lambs and five nonlactating and nonpregnant dams, fixed in formalin, embedded in paraffin, and used for the assessment of vitamin D receptor protein. Nuclear vitamin D receptor immunoreaction was scored semiquantitatively and exhibited a segment‐specific distribution pattern. Goblet cells always were devoid of any vitamin D receptor immunoreaction. Surface epithelial cells and enterocytes of the crypt openings generally demonstrated only a weak immunoreaction. Basally and/or intermediately located crypt epithelial cells exhibited stronger immunoreactions in duodenum, jejunum, and colon descendens. This basal/intermediate to superficial gradient was most pronounced in the duodenum and less evident in jejunum and colon descendens and not observed in ileum and cecum. There were no age‐dependent variations in vitamin D receptor protein expression. Results demonstrate that intestinal vitamin D receptor distribution patterns are segment‐specific and strongest immunoreactions correlate with highest intestinal calcium absorptive activities, as reported in literature. Strong expression of vitamin D receptors within the lower half of crypts also suggests a role for calcitriol in epithelial differentiation and cellular homeostasis. J. Morphol., 2008. © 2007 Wiley‐Liss, Inc.

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Immunocytochemical Detection of 1,25-Dihydroxyvitamin D Receptors in Normal Human Tissues*

Cited by 189 publications

References 21 publications

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway

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

Vitamin D receptor distribution in intestines of domesticated sheep Ovis ammon f. aries

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