Vitamin D receptor ontogenesis in rat liver

Segura, Carmen; Alonso, María Alonso; Fraga, C.; García‐Caballero, Tomás; Diéguez, Carlos; Pérez-Fernández, Román

doi:10.1007/s004180050403

Cited by 30 publications

(26 citation statements)

References 29 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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“…Therefore, in this work, cells were treated with a range of concentrations of 1␣,25-(OH) 2 D 3 (0.1-100 nM) reflecting the blood level in the normal adult (19 -190 nM). Although it was considered in the past that VDR could be absent or expressed at very low level in the liver, it was recently demonstrated that this receptor is present in fetal, neonatal, and adult rat liver by RT-PCR and immunohistochemistry (38). Control experiments using the inducible expression of fructose-1,6-bisphosphatase, previously shown to be controlled by VDR (31), have clearly shown that VDR was expressed and activated in our cultures after treatment with 1␣,25-(OH) 2 D 3 .…”

Section: Discussionmentioning

confidence: 99%

Expression of CYP3A4, CYP2B6, andCYP2C9 Is Regulated by the Vitamin D Receptor Pathway in Primary Human Hepatocytes

Drocourt¹,

Ourlin

Pascussi

et al. 2002

Journal of Biological Chemistry

333

227

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The fully active dihydroxylated metabolite of vitamin D 3 induces the expression of CYP3A4 and, to a lesser extent, CYP2B6 and CYP2C9 genes in normal differentiated primary human hepatocytes. Electrophoretic mobility shift assays and cotransfection in HepG2 cells using wild-type and mutated oligonucleotides revealed that the vitamin D receptor (VDR) binds and transactivates those xenobiotic-responsive elements (ER6, DR3, and DR4) previously identified in CYP3A4, CYP2B6, and CYP2C9 promoters and shown to be targeted by the pregnane X receptor (PXR) and/or the constitutive androstane receptor (CAR). Full VDR response of various CYP3A4 heterologous/homologous promoter-reporter constructs requires both the proximal ER6 and the distal DR3 motifs, as observed previously with rifampicinactivated PXR. Cotransfection of a CYP3A4 homologous promoter-reporter construct (including distal and proximal PXR-binding motifs) and of PXR or CAR expression vectors in HepG2 cells revealed the ability of these receptors to compete with VDR for transcriptional regulation of CYP3A4. In conclusion, this work suggests that VDR, PXR, and CAR control the basal and inducible expression of several CYP genes through competitive interaction with the same battery of responsive elements.Cytochrome P450 (CYP) 1 enzymes are mainly expressed in the liver and catalyze the metabolic conversion of xenobiotics, including environmental pollutants and drugs, to more polar and easily disposable derivatives (2, 3). CYP genes from the CYP2 and CYP3 families are inducible by many xenobiotics, notably including barbiturates and rifampicin. Two nuclear receptors, the pregnane X receptor (PXR; NR1I2) and the constitutive androstane receptor (CAR; NR1I3), have recently been shown to mediate CYP2 and CYP3 gene induction in animals and man (4 -6). Both PXR and CAR form heterodimers with the retinoid X receptor (RXR; NR2B1). PXR is activated by a wide spectrum of xenobiotics and steroids (4, 7, 8) and controls CYP3A4 and CYP3A7 induction by targeting two specific responsive elements present in the regulatory region of these genes (4, 7-12). The first of these is the proximal PXR-responsive element, located at -160. It consists of an everted repeat of the nuclear receptor half-site AGGTCA separated by 6 nucleotides (ER6); this element is necessary but not sufficient for full transactivation of the CYP3A4 promoter. Indeed, full PXRmediated induction requires the presence of a second distal xenobiotic-responsive element (dPXRE), located between -7800 and Ϫ7200 (9). This element is composite and consists of two direct repeats separated by 3 nucleotides (DR3), encompassing an ER6 motif. In contrast to PXR, CAR is sequestered in the cytoplasm and translocates into the nucleus upon activation, notably in response to phenobarbital (6, 13). Several groups have identified a complex phenobarbital-responsive element module that consists of two nuclear receptor-binding sites (termed NR1 and NR2) and one nuclear factor 1 binding site (12,14). Both NR1 and NR2 are imperfect DR4...

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“…In the classical vitamin D-responsive organs, including the intestine, bone, kidney, and parathyroid gland, vitamin D 3 -activated VDR plays a central role in the regulation of calcium and phosphate homeostasis, bone mineralization, inhibition of cell growth, and parathyroid hormone synthesis (3,7). VDR is also expressed in many other nonclassical vitamin Dresponsive organs, including the liver (8,9).…”

Section: Introductionmentioning

confidence: 99%