SCOPE: CYP3A4 is the most important drug-metabolizing enzyme regulated via the vitamin D receptor (VDR) in the intestine. However, less is known about VDR in the regulation of CYP3A4 and other drug-metabolizing enzymes in the liver. METHODS AND RESULTS: This study investigates whether 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3 ) regulates major cytochrome P450 enzymes, selected phase I and II enzymes, and transporters involved in xenobiotic and steroidal endobiotic metabolism in 2D and 3D cultures of human hepatocytes. The authors found that 1α,25(OH)2 D3 increases hepatic CYP3A4 expression and midazolam 1'-hydroxylation activity in 2D hepatocytes. The results are confirmed in 3D spheroids, where 1α,25(OH)2 D3 has comparable effect on CYP3A4 mRNA expression as 1α-hydroxyvitamin D3 , an active vitamin D metabolite. Other regulated genes such as CYP1A2, AKR1C4, SLC10A1, and SLCO4A1 display only mild changes in mRNA levels after 1α,25(OH)2 D3 treatment in 2D hepatocytes. Expression of other cytochrome P450, phase I and phase II enzyme, or transporter genes are not significantly influenced by 1α,25(OH)2 D3 . Additionally, the effect of VDR activation on CYP3A4 mRNA expression is abolished by natural dietary compound sulforaphane, a common suppressor of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). CONCLUSION: This study proposes that VDR or vitamin D supplementation is unlikely to significantly influence liver detoxification enzymes apart from CYP3A4.

• MeSH
• cytochrom P-450 CYP3A * genetika   MeSH
• hepatocyty MeSH
• lidé MeSH
• messenger RNA MeSH
• receptory kalcitriolu genetika   MeSH
• stanovení celkové genové exprese MeSH
• systém (enzymů) cytochromů P-450 genetika   MeSH
• vitamin D farmakologie   MeSH
• xenobiotika * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• alfa receptor estrogenů fyziologie   genetika   MeSH
• kolagen typu I, řetězec alfa 1 fyziologie   genetika   MeSH
• kolagen typu I fyziologie   genetika   MeSH
• kostní denzita * genetika   MeSH
• LDL receptor related protein 5 fyziologie   genetika   MeSH
• lidé MeSH
• ligand RANK fyziologie   genetika   MeSH
• osteoporóza * genetika   metabolismus   patofyziologie   MeSH
• osteoprotegerin fyziologie   genetika   MeSH
• polymorfismus genetický MeSH
• receptory kalcitriolu fyziologie   genetika   MeSH
• Check Tag
• lidé MeSH

PURPOSE: Turner syndrome (TS) patients display considerable immune misregulation, and it is hypothesized that Vitamin D (VTD) activity may fluctuate according to Vitamin D receptor (VDR) polymorphisms and/or expression profile. To uncover a possible relationship between VDR genotype and clinical conditions in TS patients, we investigated two functional VDR variants (Cdx-2 and FokI) for allele and genotype frequencies, as well as expression profile in TS individuals versus healthy controls (HC). METHODS: We performed a genetic association study including 100 TS patients and 116 HC. Genotyping for VDR Cdx-2 G > A (rs11568820) and FokI C > T (rs2228570) was performed using Taqman Genotyping Assays. VDR gene expression was also evaluated in 15 TS and 15 HC, using fluorogenic probes by qPCR. Statistical analyses were performed using nonparametric Mann-Whitney test, with a 5% significance level (p < 0.05) to uncover differences between groups. In addition, we investigated whether shifted VDR mRNA levels were associated with Cdx-2 and FokI variants in TS patients. RESULTS: We detected a significantly higher frequency of T allele (p = 0.006) as well as T/T genotype (p = 0.01) for FokI in TS patients when compared to HC. When assessing VDR expression, we identified a downregulation in TS woman (- 2.84 FC) versus HC (p < 0.001). Furthermore, C/T (11.24 FC; p = 0.01) and T/T (9.20 FC; p = 0.01) FokI genotypes were upregulated when compared to C/C reference genotype. CONCLUSION: TS patients show different distribution of FokI polymorphism. Downregulation of VDR gene expression may contribute to immunological imbalance in TS.

• MeSH
• alely MeSH
• autoimunita genetika   MeSH
• dítě MeSH
• dospělí MeSH
• down regulace MeSH
• frekvence genu * MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• receptory kalcitriolu genetika   MeSH
• studie případů a kontrol MeSH
• Turnerův syndrom genetika   imunologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Low vitamin D status has been frequently associated with impaired glucose metabolism. We examined associations between 25-hydroxyvitamin D (25-OH-D) and several parameters of glucose homeostasis in virtually healthy subjects, and explored possible interaction with vitamin D receptor (VDR) polymorphism. Nondiabetic subjects without chronic medication or any known significant manifest disease were selected from large general-population based population survey. Insulin sensitivity and β cell secretion were calculated by homeostasis model assessment (HOMA) and soluble isoform of receptor for advanced glycation end-products (sRAGE) using commercial ELISA. Subjects were also genotyped for rs2228570 polymorphism of VDR. After adjustment for potential confounders, we observed a significant relationship between 25-OH-D and fasting glycemia (β coefficient=-5.904; p=0.002) or insulin sensitivity (β=0.042; p=0.001), but not with β cell secretion or sRAGE. We found also an interaction with VDR polymorphism. Subjects with low 25-OH-D and AA genotype had significantly lower insulin sensitivity than those with GG genotype plus highest 25-OH-D concentrations (107.3% vs. 183.9%, p=0.021). In conclusion, low vitamin D status was in virtually healthy subjects associated with decreased insulin sensitivity, namely in those with GG genotype of rs2228570 VDR polymorphism.

• MeSH
• dospělí MeSH
• glukosa metabolismus   MeSH
• homeostáza * MeSH
• inzulinová rezistence genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• multivariační analýza MeSH
• průřezové studie MeSH
• receptory kalcitriolu genetika   MeSH
• rizikové faktory MeSH
• senioři MeSH
• vitamin D analogy a deriváty   krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We developed and characterized a novel human luciferase reporter cell line for the assessment of peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity, PAZ-PPARg. The luciferase activity induced by PPARγ endogenous agonist 15d-PGJ2 and prostaglandin PGD2 reached mean values of (87.9 ± 14.0)-fold and (89.6 ± 19.7)-fold after 24 h of exposure to 40 μM 15d-PGJ2 and 70 μM PGD2, respectively. A concentration-dependent inhibition of 15d-PGJ2- and PGD2-induced luciferase activity was observed after the application of T0070907, a selective antagonist of PPARγ, which confirms the specificity of response to both agonists. The PAZ-PPARg cell line, along with the reporter cell lines for the assessment of transcriptional activities of thyroid receptor (TR), vitamin D3 receptor (VDR), androgen receptor (AR), and glucocorticoid receptor (GR), were used for the screening of 27 commonly marketed flavored nonalcoholic beverages for their possible disrupting effects. Our findings indicate that some of the examined beverages have the potential to modulate the transcriptional activities of PPARγ, VDR, and AR.

• MeSH
• aktivace transkripce účinky léků   MeSH
• androgenní receptory genetika   metabolismus   MeSH
• buněčné linie MeSH
• chuťové esence škodlivé účinky   farmakologie   MeSH
• lidé MeSH
• nápoje škodlivé účinky   analýza   MeSH
• PPAR gama genetika   metabolismus   MeSH
• prostaglandin D2 farmakologie   MeSH
• receptory glukokortikoidů genetika   metabolismus   MeSH
• receptory kalcitriolu genetika   metabolismus   MeSH
• receptory thyreoidních hormonů genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, pa = 0.02; Taq, pg = 0.02, pa = 0.02; BsmI, pg = 0.02, pa = 0.04; ApaI, pg = 0.008, pa = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: pg = 0.01, pa = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT pcorr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women.

• MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• receptory kalcitriolu genetika   MeSH
• roztroušená skleróza genetika   patologie   MeSH
• senioři MeSH
• sexuální faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The role of vitamin D receptor (VDR) in immune responses has been broadly studied and it has been shown that activated VDR alters the levels of some interleukins (ILs). In this study, we studied the opposite, i.e. whether 13 selected pro-inflammatory and anti-inflammatory ILs influence the transcriptional activity of human VDR. The experimental models of choice were two human stably transfected gene reporter cell lines IZ-VDRE and IZ-CYP24, which were designed to evaluate the transcriptional activity of VDR. The gene reporter assays revealed inhibition of calcitriol-induced luciferase activity by IL-4 and IL-13, when 1 ng/mL of these two compounds decreased the effect of calcitriol down to 60% of the control value. Consistently, calcitriol-induced expression of CYP24A1 mRNA was also significantly decreased by IL-4 and IL-13. The expression of VDR and CYP27B1 mRNAs was not influenced by any of the 13 tested ILs. These data suggest possible cross-talk between the VDR signalling pathway and IL-4- and IL-13-mediated cell signalling.

• MeSH
• 1-alfa-hydroxylasa 25-hydroxyvitaminu D3 genetika   MeSH
• buněčné linie MeSH
• CYP24A1 genetika   MeSH
• genetická transkripce účinky léků   MeSH
• interleukiny farmakologie   MeSH
• lidé MeSH
• receptory kalcitriolu genetika   MeSH
• reportérové geny genetika   MeSH
• transfekce MeSH
• transgeny genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor.

• MeSH
• kalcitriol genetika   metabolismus   MeSH
• lidé MeSH
• mutace genetika   MeSH
• nedostatek vitaminu D farmakoterapie   genetika   metabolismus   MeSH
• receptory kalcitriolu genetika   metabolismus   MeSH
• vitamin D aplikace a dávkování   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Essential oils (EOs) of culinary herbs and spices are consumed on a daily basis. They are multicomponent mixtures of compounds with already demonstrated biological activities. Taking into account regular dietary intake and the chemical composition of EOs, they may be considered as candidates for endocrine-disrupting entities. Therefore, we examined the effects of 31 EOs of culinary herbs and spices on transcriptional activities of glucocorticoid receptor (GR), androgen receptor (AR) and vitamin D receptor (VDR). Using reporter gene assays in stably transfected cell lines, weak anti-androgen and anti-glucocorticoid activity was observed for EO of vanilla and nutmeg, respectively. Moderate augmentation of calcitriol-dependent VDR activity was caused by EOs of ginger, thyme, coriander and lemongrass. Mixed anti-glucocorticoid and VDR-stimulatory activities were displayed by EOs of turmeric, oregano, dill, caraway, verveine and spearmint. The remaining 19 EOs were inactive against all receptors under investigation. Analyses of GR, AR and VDR target genes by means of RT-PCR confirmed the VDR-stimulatory effects, but could not confirm the anti-glucocorticoid and anti-androgen effects of EOs. In conclusion, although we observed minor effects of several EOs on transcriptional activities of GR, AR and VDR, the toxicological significance of these effects is very low. Hence, 31 EOs of culinary herbs and spices may be considered safe, in terms of endocrine disruption involving receptors GR, AR and VDR.

• MeSH
• aktivace transkripce účinky léků   MeSH
• androgenní receptory chemie   metabolismus   MeSH
• androgeny škodlivé účinky   MeSH
• antagonisté androgenů škodlivé účinky   MeSH
• endokrinní disruptory škodlivé účinky   MeSH
• jedlé rostliny chemie   MeSH
• koření * MeSH
• léčivé rostliny chemie   MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• oleje prchavé škodlivé účinky   MeSH
• receptory glukokortikoidů agonisté   antagonisté a inhibitory   genetika   metabolismus   MeSH
• receptory kalcitriolu agonisté   antagonisté a inhibitory   genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• reportérové geny účinky léků   MeSH
• reprodukovatelnost výsledků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH

AIM: We analyzed the VDR TaqI (rs731236) gene polymorphism in children with and those without dental caries. METHODS: A total of 388 subjects, 153 caries-free (with decayed/missing/filled teeth [DMFT] = 0) and 235 children with dental caries (DMFT ≥1), were genotyped by the TaqMan method. RESULTS: Although no significant differences in VDR TaqI allele and genotype frequencies between caries-free and caries-affected children were detected, a significant association between this polymorphism and gingivitis was found (p < 0.05). CONCLUSIONS: In contrast to previous studies from China and Turkey, the VDR TaqI gene variant cannot be used as a marker for identification of Czech children with increased dental caries risk.

• MeSH
• alely MeSH
• DMF Index MeSH
• genetická predispozice k nemoci genetika   MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• gingivitida epidemiologie   genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• mladiství MeSH
• odds ratio MeSH
• receptory kalcitriolu genetika   MeSH
• restrikční endonukleasy typu II MeSH
• studie případů a kontrol MeSH
• zubní kaz epidemiologie   genetika   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH