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PubMed2007

Differential role of two VDR coactivators, DRIP205 and SRC-3, in keratinocyte proliferation and differentiation.

Cell programs such as proliferation and differentiation involve the selective activation and repression of gene expression. The vitamin D receptor (VDR), through 1,25(OH)(2)D(3), controls the proliferation and differentiation of keratinocytes. Previously, we have identified two VDR binding coactivator complexes. In proliferating keratinocytes VDR bound preferentially to the DRIP complex, whereas in differentiated keratinocytes the SRC complex was preferred. We proposed that different coactivators are required for sequential gene regulation in the transition from proliferation to differentiation. Here we examined the roles of DRIP205 and SRC-3 in this transition. Silencing of DRIP205 and VDR caused hyperproliferation of keratinocytes, demonstrated by increased XTT and BrdU incorporation. SRC-3 silencing, on the other hand, did not have an effect on proliferation. In contrast, SRC-3 as well as DRIP205 and VDR silencing blocked keratinocyte differentiation as shown by decreased expression of keratin 1 and filaggrin. These results are consistent with the differential localization of DRIP205 and SRC-3 in skin. These results indicate that DRIP205 is required for keratinocyte proliferation. Both DRIP205 and SRC-3 are required for the keratinocyte differentiation. These results support the concept that the selective use of coactivators by VDR underlies the selective regulation of gene expression in keratinocyte proliferation and differentiation.

Cell Differentiation↗
PubMedDate not supplied

Central role of VDR conformations for understanding selective actions of vitamin D(3) analogues.

The vitamin D(3) receptor (VDR) acts primarily as a heterodimer with the retinoid X receptor (RXR) on different types of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) response elements (VDREs). Therefore, DNA-bound VDR-RXR heterodimers can be considered as the molecular switches of 1alpha,25(OH)(2)D(3) signalling. Functional conformations of the VDR within these molecular switches appear to be of central importance for describing the biologic actions of 1alpha,25(OH)(2)D(3) and its analogues. Moreover, VDR conformations provide a molecular basis for understanding the potential selective profile of VDR agonists, which is critical for a therapeutic application. This review discusses VDR conformations and their selective stabilization by 1alpha,25(OH)(2)D(3) and its analogues, such as EB1089 and Gemini, as a monomer in solution or as a heterodimer with RXR bound to different VDREs and complexed with coactivator or corepressor proteins.

Animals↗
PubMedDate not supplied

Analysis of vitamin D-receptor (VDR) and retinoid X-receptor alpha in breast cancer.

The expression of vitamin D-receptor (VDR) and retinoid X-receptor alpha (RXR-alpha) has been analysed immunohistochemically in benign (n = 62 and n = 5 respectively) and malignant (n = 228 and n = 15 respectively) breast tissue samples using a monoclonal antibody 9A7gamma against VDR and a polyclonal antibody against RXR-alpha. A recently developed immunoreactive scoring method (IRS) was employed. The expression of VDR was detected at the RNA-level using the reverse transcriptase-polymerase chain reaction. A statistically significant higher expression of VDR at the protein level was seen in breast cancer compared with benign breast tissue, whereas at the mRNA level no visible differences in the expression of VDR were found. A higher expression of RXR-alpha was seen in breast cancer compared with benign breast tissue. Our findings indicate that breast tissue may be a new target organ for therapeutically applied vitamin D and retinoid analogues. VDR and RXR-alpha are upregulated at the protein level in breast carcinomas as compared to normal breast tissue, indicating a possibly increased sensitivity to therapeutically applied vitamin D analogues. New vitamin D analogues exerting less calcemic side effects may be promising new drugs for the treatment or chemoprevention of breast carcinomas as well as of precancerous breast lesions. Combination therapies of vitamin D and retinoid analogues with fewer side effects seen promising for the treatment of breast cancer.

Antibodies↗
PubMed2005

Ligand-induced transrepression by VDR through association of WSTF with acetylated histones.

We have previously shown that the novel ATP-dependent chromatin-remodeling complex WINAC is required for the ligand-bound vitamin D receptor (VDR)-mediated transrepression of the 25(OH)D3 1alpha-hydroxylase (1alpha(OH)ase) gene. However, the molecular basis for VDR promoter association, which does not involve its binding to specific DNA sequences, remains unclear. To address this issue, we investigated the function of WSTF in terms of the association between WINAC and chromatin for ligand-induced transrepression by VDR. Results of in vitro experiments using chromatin templates showed that the association of unliganded VDR with the promoter required physical interactions between WSTF and both VDR and acetylated histones prior to VDR association with chromatin. The acetylated histone-interacting region of WSTF was mapped to the bromodomain, and a WSTF mutant lacking the bromodomain served as a dominant-negative mutant in terms of ligand-induced transrepression of the 1alpha(OH)ase gene. Thus, our findings indicate that WINAC associates with chromatin through a physical interaction between the WSTF bromodomain and acetylated his tones, which appears to be indispensable for VDR/promoter association for ligand-induced transrepression of 1alpha(OH)ase gene expression.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2005

Association between VDR ApaI polymorphism and hip bone mineral density can be modified by body mass index: a study on postmenopausal Chinese women.

Osteoporosis is a major public health problem for old people. Genetic factors are considered to be major contributors to the pathogenesis of postmenopausal osteoporosis. The vitamin D receptor (VDR) gene is a prominent candidate gene for the regulation of postmenopausal bone mass; however, despite extensive studies, controversy remains regarding its association with postmenopausal body mineral density (BMD) variation. In this study, a total of 260 healthy postmenopausal Chinese women were genotyped at the VDR ApaI locus using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Raw hip BMD was significantly associated with VDR ApaI polymorphism with and without adjusting for age (P=0.015 and 0.040, respectively). This genetic effect can explain 3.32% of hip BMD variation. However, the significant association vanished after correcting for both age and body mass index (BMI) (P=0.169). In addition, we observed a significant association between VDR ApaI polymorphism with unadjusted BMI (P=0.042) or BMI adjusted for age (P=0.049). The raw hip BMD was also found to be significantly correlated with BMI (r=0.517, P=0.0001), with BMI explaining 26.35% of the variation of hip BMD. All of these facts prompt us to conclude that the significant association between the VDR ApaI genotype and hip BMD may be modified by BMI in postmenopausal Chinese women. Our findings may partially explain the earlier inconsistent association results concerning the VDR gene and BMD, and highlight the importance of incorporating covariates such as BMI into osteoporosis association studies.

Aged↗
PubMed1998

Characteristics of vitamin D3 receptor (VDR) binding to the vitamin D response element (VDRE) in rat bone sialoprotein gene promoter.

Bone sialoprotein (BSP) is a mineralised tissue-specific protein that is highly expressed during the initial formation of bone and cementum. Expression of BSP is suppressed by the osteotropic hormone, 1,25-dihydroxyvitamin D3 (vitamin D3), which regulates bone remodelling. In previous studies, we have identified a vitamin D response element (VDRE) that is integrated with a novel inverted TATA box in the rat BSP promoter which mediates the suppression of BSP transcription (1). Although the nucleotide sequences of VDREs in different genes conform to a direct (hexamer) repeat, spaced by three nucleotides, the precise sequences are unique for each VDRE. To determine whether the nucleotide differences in the VDRE influence VDR binding, we have compared interactions of VDR proteins with various VDREs using gel mobility shift analysis. Both natural and recombinant VDRs bound to rat BSP and both mouse and porcine osteopontin (OPN) VDRE oligonucleotides in a concentration-dependent manner with a strong preference for dimer formation, whereas equal amounts of dimer and monomer were bound to the human osteocalcin VDRE. However, whereas a truncated VDR comprising the DNA binding domain alone bound the mouse osteopontin VDRE, it failed to interact with the porcine OPN and rat BSP VDREs. VDR binding to the BSP was sequence specific, as shown by mutagenesis analysis, and could be abolished by heat and VDR antibody. These studies demonstrate that subtle differences in the nucleotide sequence of VDREs affect VDR binding, which mediates the vitamin D3 response.

Animals↗
PubMed2001

Novel N-terminal variant of human VDR.

The importance of N-terminal regions of nuclear hormone receptors in transcriptional regulation is increasingly recognized. As variant VDR gene transcripts indicated possible N-terminally extended receptors, we investigated their natural occurrence, transactivation capacity, and subcellular localization. A novel 54-kDa VDRB1 protein, in addition to the previously recognized 48-kDa VDRA form, was detected in human kidney tissue as well as in osteoblastic (MG63), intestinal (Int-407, DLD-1, and COLO 206F), and kidney epithelial (786) human cell lines by Western blots using isoform-specific and nonselective anti-VDR antibodies. VDRB1 was present at approximately one-third the level of VDRA. Isoform-specific VDRB1 expression constructs produced lower ligand-dependent transactivation than VDRA when transiently transfected with a vitamin D-responsive promoter into cell lines with low endogenous VDR. Intracellular localization patterns of the green fluorescent protein-tagged VDR isoforms differed. VDRB1 appeared as discrete intranuclear foci in the absence of 1,25-dihydroxyvitamin D3, whereas VDRA produced diffuse nuclear fluorescence. After 1,25-dihydroxyvitamin D3 treatment, both VDR isoforms exhibited similar diffuse nuclear signal. In the absence of 1,25-dihydroxyvitamin D3, the VDRB1 foci partially colocalized with SC-35 speckles and a subset of promyelocytic leukemia nuclear bodies. These data provide the first evidence of VDRB1, a novel N-terminally variant human VDR that is expressed at a level comparable to VDRA in human tissue and cell lines. It is characterized by reduced transactivation activity and a ligand-responsive speckled intranuclear localization. The intranuclear compartmentalization and altered functional activity of VDRB1 may mediate a specialized physiological role for this receptor isoform.

Cell Line↗
PubMed2005

Expression of calbindin-D9k, VDR and Cdx-2 messenger RNA in the process by which fructooligosaccharides increase calcium absorption in rats.

We have previously shown, through evidence that the expression of calbindin-D9k protein shows a dose-dependent change in the intestine, that calbindin-D9k plays a role in the ability of a fructooligosaccharide (FOS) diet to increase calcium absorption. This study shows that the regulation of calbindin-D9k expression occurs at the transcriptional level in a segment-specific manner, decreasing in the proximal intestine and increasing in the colorectal segment. To determine the transcriptional regulation of the FOS diet on calbindin-D9k expression, two transcription factors, vitamin D receptor (VDR) and cdx-2, were analyzed during 10 d feeding of the FOS diet. The mRNA expression of VDR and cdx-2 was influenced by the FOS diet and showed a segment-specific change. In the proximal small intestine, there was a significant correlation between the changes in both mRNAs (r = 0.69, p < 0.01), while the expression of calbindin-D9k correlated neither with VDR nor with cdx-2. This means that the transcriptional change induced by the FOS diet was not regulated by VDR and cdx-2. In the colorectal segment, there were significant correlations between gene expressions of calbindin-D9k vs. VDR, r = 0.73, p < 0.01 and calbindin-D9k vs. cdx-2, r = 0.52, p < 0.05. These results suggested that both transcription factors, VDR and cdx-2, were involved in the regulation of calbindin-D9k gene expression in the colorectal segment during the process through which the FOS diet enhanced calcium absorption.

Animals↗
PubMed2006

[Relationship between the absorption of dietary calcium and the Fok I polymorphism of VDR gene in young women].

OBJECTIVE: To investigate the relationship between the absorption of dietary calcium and VDR (Vitamin D(3) receptor, VDR) gene RFLPs in Chinese young women with representative diets. METHODS: Forty subjects were selected from three hundred young female students aged 18 - 23 years old. After identifying the VDR gene Fok I RFLPs, the subjects were given the representative diets during the 3-day adaptation period and the 12-day metabolism period. The copy food and drinking for measurement of nutrients and also the complete feces each day were collected. The dietary calcium absorption of each subject was examined and calculated. RESULTS: As expected, the intake of dietary calcium in subjects is close to the results set by the of National Nutrition Investigation in 1992 (from young women at 17 year old) or the daily reference intake (DRI) for adult woman; the difference of the absorption of dietary calcium among VDR gene RFLPs in young women was observed: ff < Ff < FF, (28.7 +/- 10.5)%, (30.4 +/- 15.9)% and (40.6 +/- 11.0)% respectively; only significant difference between FF genotype and Ff genotype, P < 0.05. CONCLUSION: Our results were consistent with those gained from the previous studies on children about the relationship between the absorption of dietary calcium and VDR (Vitamin D(3) receptor, VDR) gene RFLPs, and now it might occur in young women. Further studies need to be taken by using stable isotope and increasing subjects in young women.

Absorption↗
PubMedDate not supplied

Epigenetic corruption of VDR signalling in malignancy.

BACKGROUND: The ligand-mediated switch from binding co-repressor to co-activator complexes is central to the transcriptional actions of the vitamin D receptor (VDR) and other nuclear receptors. The capacity of deregulated co-repressors to attenuate the responsiveness of VDR signalling in cancer models was examined. MATERIALS AND METHODS: Proliferation and gene regulation studies were undertaken in non-malignant and malignant cell line and primary models. RESULTS: Both primary tissue models and cancer cell lines displayed a spectrum of suppressed responsiveness towards 1alpha, 25 hydroxy vitamin D3 (1alpha25(OH)2D3) which correlated with elevated co-repressor content: specifically, elevated silencing mediator of retinoid and thyroid hormone receptors/nuclear co-repressor 2 (NCoR2/SMRT) in prostate cancer cell lines and primary tumour cultures, and elevated nuclear receptor co-repressor 1 (NCoR1) in breast cancer cell lines. Interestingly, whilst the cancer cell lines frequently also displayed reduced VDR content, the primary tumour material retained and/or elevated VDR mRNA, correlated with co-repressor content. Functional approaches towards NCoR2/SMRT (siRNA) in prostate cancer cells or NCoR1 (overexpression) in non-malignant breast epithelial cells confirmed a role in suppressing VDR transcriptional and cellular actions. Targeted co-treatments of 1alpha25(OH)2D3 plus HDAC inhibitors (TSA, NaB) resulted in re-expression of antiproliferative target genes (e.g., GADD45alpha, p21(waf1/cip1)) and synergistic inhibition of proliferation. CONCLUSION: These data suggest that VDR actions in solid tumours are retained, but were skewed by epigenetic mechanisms to suppress selectively antiproliferative target gene promoter responses. This molecular lesion provides a novel chemotherapy target for acceptable doses of 1alpha25(OH)2D3 plus HDAC inhibitors.

Animals↗
PubMedDate not supplied

Modulation of MAPK ERK1 and ERK2 in VDR-positive and -negative breast cancer cell lines.

1alpha-25-Dihydroxyvitamin D3 (calcitriol), the biologically active metabolite of vitamin D, is known to regulate calcium and phosphate levels in bone metabolism. It is also known to influence proliferation and differentiation in carcinoma cells mediated by the vitamin D receptor (VDR). The antiproliferative effects of calcitriol are believed to be mediated by the nuclear pathway via binding the activated receptor to vitamin D-responsive elements. This induces the vitamin D-responsive genes. Another possible pathway might be the MAPK-cascade or rapid response pathway. The interaction of calcitriol and the MAP-kinase-cascade was evaluated on VDR-positive MCF-7 cells and VDR-negative MDA-MB-231 breast cancer cells. The cells were incubated with calcitriol solution at 10(-7) M and 10(-9) M, or ethanol as controls, for up to 48 h. The effects of calcitriol were measured by semi-quantitative Western blotting. Calcitriol stimulated the MAP-kinases ERK1 and ERK2. A biphasic activation was found for calcitriol in VDR-positive cells after incubation for 5 to 20 min and from 2 to 24 h. However, early activation of ERK1 and ERK2 was also demonstrated in VDR-negative cells. In the controls, ethanol also induced the MAPK-cascade at 5 to 10 min. Calcitriol induction was demonstrated after incubation from 2 to 24 h. In conclusion, it seems that the early induction of the MAPK-cascade was independent of the VDR. A calcitriol-induced MAPK activation was shown after 4 h, which may have been caused by activation of the nuclear receptor pathway.

Breast Neoplasms↗
PubMed1998

1,25-Dihydroxyvitamin D3 regulates the expression of VDR and NGF gene in Schwann cells in vitro.

The vitamin D receptor (VDR) is a nuclear receptor that mediates the effect of the active metabolite of vitamin D3, the 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). To investigate the potential role of this hormone in the peripheral nervous system, we have studied the VDR expression in Schwann cells. The VDR mRNA was detected by Northern blot analysis in rat primary cultures of Schwann cells, and its levels were strongly increased in the presence of 1,25-(OH)2D3. Using the mouse Schwann cell line, MSC80, we showed that concentrations as low as 10(-10) M of hormone stimulated the expression of the VDR gene and strongly increased the amounts of activated VDR, capable of binding to the specific vitamin D responsive element (VDRE). We also found that 1,25-(OH)2D3 stimulated the expression of the nerve growth factor gene in MSC80. These data suggest a role for the hormone in the peripheral nervous system, possibly as a mediator active in trauma.

Animals↗
PubMed2000

Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women.

In view of the reported associations between osteoporosis and polymorphisms of the vitamin D receptor (VDR), collagen Ialpha1 (COLIA1) and estrogen receptor (ER) genes, an association study was performed between VDR, COLLIA1, and ER genotypes and bone mineral density, biochemical markers of bone turnover and hip fracture occurrence in Belgian older postmenopausal women. The gene polymorphisms were evaluated by restriction fragment length polymorphism analyses, using the restriction enzymes BsmI (VDR), AccB7I (COLIA1), and PvuII and XbaI (ER), respectively. As expected, bone mineral density and biochemical analyses demonstrated significant differences between hip fracture patients and elderly controls. However, no significant differences in genotype distributions or allele frequencies were observed between the cases (n = 135, age 78 +/- 9 years) and controls (n = 239, age 76 +/- 4 years) for any of the gene polymorphisms. Stratification of both study populations according to VDR, COLIA1 or ER genotype did not reveal any statistically significant difference in bone density or bone turnover between subgroups with different genotypes. In conclusion, despite its limited statistical power the outcome of this study does not support the hypothesis of a major contribution of the VDR, COLIA1 or ER polymorphisms to explain variations in bone mineral density or bone turnover, or to identify elderly women at risk of osteoporotic hip fracture.

Aged↗
PubMed2006

VDR polymorphisms influence the immune response in type 1 diabetic children from Santiago, Chile.

OBJECTIVE: To evaluate the influence of ApaI, BsmI and TaqI polymorphisms of the VDR gene and HLA-DQB1* alleles in type 1 diabetic children and to assess their possible relationship with circulating levels of 25-hydroxyvitamin D(3), auto-antibodies, and INFgamma/TGFbeta1 cytokines levels in Chilean cases and controls. METHODS: DNA and serum samples from 216 newly diagnosed type 1 diabetic and 203 unrelated control children were evaluated for IA-2 and GAD(65) auto-antibodies, 25-hydroxyvitamin D(3) levels, HLA-DQB1* alleles, and VDR gene polymorphisms. RESULTS: The frequency of the b allele and the bb genotype in type 1 diabetic patients was significantly lower compared with the control group (0.635 versus 0.749, p<0.01 and 0.370 versus 0.567, p<0.04). 25-Hydroxyvitamin D(3) levels showed no differences between type 1 diabetic and healthy children. In cases, 25-hydroxyvitamin D(3) levels were not associated with a special auto-antibodies profile according to the presence or absence of GAD(65)(+) or IA-2(+). The haplotype combination BAT was higher in cases (0.062 versus 0.019, p<0.0022) and bAT was more frequent in controls (0.266 versus 0.180, p<0.003). In cases, the aaBbTT genotype showed the most significant increase in TGFbeta1 level across the VDR categories. Finally, when considering the HLA class II risk genotype (DQB1*0302) and the VDR genotypes (AabbTT and aabbTT), higher levels of GAD(65), IA-2 and TGFbeta1 were observed among diabetic children. CONCLUSION: We found an association between a VDR polymorphism (BsmI) and type 1 diabetes. An association was found of AabbTT and aabbTT genotypes and the HLA-DQB1*0302 allele with high levels of GAD(65), IA-2 and TGFbeta1.

Autoantibodies↗
PubMed2007

Transgenic expression of the human Vitamin D receptor (hVDR) in the duodenum of VDR-null mice attenuates the age-dependent decline in calcium absorption.

1,25(OH)(2)D(3) regulates calcium homeostasis through its actions in the intestine, bone, and kidney. These actions are mediated through the VDR. To determine if VDR's actions in the proximal small intestine can sufficiently restore calcium homeostasis, we generated transgenic mice expressing hVDR exclusively in the duodenum of mVDR-null mice by using the adenosine deaminase enhancer (hVDR+/mVDR-null). Unlike wild-type mice, hVDR+/mVDR-null mice express hVDR and VDR target genes only in the proximal small intestine. Despite having functional hVDR in the proximal small intestine, hVDR+/mVDR-null mice were hypocalcaemic when fed a normal rodent diet at weaning, like mVDR-null mice fed the same diet. The hypocalcemia in these mice is prevented if they are given the rescue diet before weaning. However, when 90-day-old rachitic mice were fed a rescue diet, serum calcium improved in hVDR+/mVDR-null mice, but not in mVDR-null mice. In conclusion, transgenic hVDR in the proximal small intestine of hVDR+/mVDR-null mice was transcriptionally active and regulated calcium absorption, but VDR actions elsewhere in the intestine are probably necessary to support adequate calcium homeostasis. In addition, hVDR+/mVDR-null mice responded better to the late rescue diet suggesting that expression of VDR in the proximal small intestine protected the calcium absorbing machinery from age-dependent decline.

Aging↗
PubMed2001

Variants of the VDR gene and risk of colon cancer (United States).

OBJECTIVES: Genetic factors involved in regulating cell growth, such as the vitamin D receptor (VDR) gene, may contribute to the etiology of colon cancer. METHODS: Using data from a population-based case-control study of colon cancer and from a family-based study of cases with colon cancer and population-based controls, we evaluated the association between four variants of the VDR gene and risk of colon cancer. RESULTS: The polyA (short), BsmI (BB), and TaqI (tt) variants of the VDR gene were in linkage disequilibrium in this mostly Caucasian population. These variants were associated with reduced risk of colon cancer (OR 0.5, 95% CI 0.3-0.9). The FokI variant was not associated with colon cancer risk. Although estimates of association were imprecise, there were suggestions that associations were slightly stronger for women than men, for people diagnosed at a younger age, and for those with proximal tumors. Consistent associations were observed from sporadic cases of colon cancer from a population-based study as well as from colon cancer cases from a family-based study. There were no interactions observed by family history. CONCLUSIONS: These data suggest that molecular variants of the VDR gene may be related to the development of colon cancer. To further define the impact of the VDR gene on cancer etiology, studies to evaluate the association of these variants with diet and lifestyle factors are needed.

Adult↗
PubMed2006

Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b.

BACKGROUND: There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone) and the Parathyroid Hormone (PTH). Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b), which recruits monocytes to the site of inflammatory immune challenge. RESULTS: Telmisartan was predicted to strongly antagonize (Ki asymptotically equal to 0.04 nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki asymptotically equal to10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki asymptotically equal to 30 nmol) and Losartan (Ki asymptotically equal to 70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki asymptotically equal to 0.3 nmol), while Losartan (Ki asymptotically equal to 3 nmol), Irbesartan (Ki asymptotically equal to 6 nmol), Olmesartan and Valsartan (Ki asymptotically equal to 12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki asymptotically equal to 9 nmol) additionally act as antagonists of a theoretical model of CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the Angiotensin II Type1 receptor (AT2R1) has been presented. CONCLUSION: Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.

Amino Acid Sequence↗
PubMed2006

Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds.

The NR1I subfamily of nuclear hormone receptors includes the 1,25-(OH)(2)-vitamin D(3) receptor (VDR; NR1I1), pregnane X receptor (PXR; NR1I2), and constitutive androstane receptor (CAR; NR1I3). PXR and VDR are found in diverse vertebrates from fish to mammals while CAR is restricted to mammals. Current evidence suggests that the CAR gene arose from a duplication of an ancestral PXR gene, and that PXR and VDR arose from duplication of an ancestral gene, represented now by a single gene in the invertebrate Ciona intestinalis. Aside from the high-affinity effects of 1,25-(OH)(2)-vitamin D(3) on VDRs, the NR1I subfamily members are functionally united by the ability to bind potentially toxic endogenous compounds with low affinity and initiate changes in gene expression that lead to enhanced metabolism and elimination (e.g., induction of cytochrome P450 3A4 expression in humans). The detoxification role of VDR seems limited to sensing high concentrations of certain toxic bile salts, such as lithocholic acid, whereas PXR and CAR have the ability to recognize structurally diverse compounds. PXR and CAR show the highest degree of cross-species variation in the ligand-binding domain of the entire vertebrate nuclear hormone receptor superfamily, suggesting adaptation to species-specific ligands. This review examines the insights that phylogenetic and experimental studies provide into the function of VDR, PXR, and CAR, and how the functions of these receptors have expanded to evolutionary advantage in humans and other animals.

Animals↗