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  1. Article ; Online: Enzymatic activation in vitamin D signaling - Past, present and future.

    Norlin, Maria / Wikvall, Kjell

    Archives of biochemistry and biophysics

    2023  Volume 742, Page(s) 109639

    Abstract: Vitamin D signaling is important in regulating calcium homeostasis essential for bone health but also displays other functions in cells of several tissues. Disturbed vitamin D signaling is linked to a large number of diseases. The multiple cytochrome ... ...

    Abstract Vitamin D signaling is important in regulating calcium homeostasis essential for bone health but also displays other functions in cells of several tissues. Disturbed vitamin D signaling is linked to a large number of diseases. The multiple cytochrome P450 (CYP) enzymes catalyzing the different hydroxylations in bioactivation of vitamin D
    MeSH term(s) Vitamin D ; Vitamins ; Cytochrome P-450 Enzyme System/metabolism ; Substrate Specificity ; Hydroxylation
    Chemical Substances Vitamin D (1406-16-2) ; Vitamins ; Cytochrome P-450 Enzyme System (9035-51-2)
    Language English
    Publishing date 2023-05-18
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 523-x
    ISSN 1096-0384 ; 0003-9861
    ISSN (online) 1096-0384
    ISSN 0003-9861
    DOI 10.1016/j.abb.2023.109639
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  2. Book ; Thesis: Studies on reconstituted hydroxylase activities in biosynthesis and metabolism of bile acids

    Wikvall, Kjell

    1977  

    Keywords Bile Acids and Salts / biosynthesis ; Bile Acids and Salts / metabolism ; Hydroxylases
    Size 35 S.
    Publishing country Sweden
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Stockholm, Univ., Diss., 1977
    HBZ-ID HT002578505
    Database Catalogue ZB MED Medicine, Health

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  3. Article ; Online: Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells.

    Emanuelsson, Ida / Wikvall, Kjell / Friman, Tomas / Norlin, Maria

    Basic & clinical pharmacology & toxicology

    2018  Volume 123, Issue 2, Page(s) 130–136

    Abstract: The active form of vitamin D (1α,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in ... ...

    Abstract The active form of vitamin D (1α,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose-dependently, in concentrations between 1 nM and 10 μM. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound-healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle-treated cells. However, they had no effect on caspase-3 and -7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Calcitriol/analogs & derivatives ; Calcitriol/pharmacology ; Calcitriol/therapeutic use ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dihydroxycholecalciferols/pharmacology ; Dihydroxycholecalciferols/therapeutic use ; Drug Evaluation, Preclinical ; Glioblastoma/drug therapy ; Glioblastoma/pathology ; Humans ; Receptors, Calcitriol/metabolism
    Chemical Substances Antineoplastic Agents ; Dihydroxycholecalciferols ; Receptors, Calcitriol ; VDR protein, human ; calcipotriene (143NQ3779B) ; 1 alpha,24-dihydroxyvitamin D3 (60965-80-2) ; Calcitriol (FXC9231JVH)
    Language English
    Publishing date 2018-04-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 2134679-3
    ISSN 1742-7843 ; 1742-7835
    ISSN (online) 1742-7843
    ISSN 1742-7835
    DOI 10.1111/bcpt.13007
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  4. Article ; Online: Effects of Osteoporosis-Inducing Drugs on Vitamin D-Related Gene Transcription and Mineralization in MG-63 and Saos-2 Cells.

    Wegler, Christine / Wikvall, Kjell / Norlin, Maria

    Basic & clinical pharmacology & toxicology

    2016  Volume 119, Issue 5, Page(s) 436–442

    Abstract: ... Vitamin ... ...

    Abstract Vitamin D
    MeSH term(s) 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism ; Anti-Retroviral Agents/adverse effects ; Benzoxazines/adverse effects ; Bone Density/drug effects ; Calcitriol/metabolism ; Cell Line, Tumor ; Dexamethasone/adverse effects ; Glucocorticoids/adverse effects ; Humans ; Osteoblasts/metabolism ; Osteoporosis/chemically induced ; Ritonavir/adverse effects ; Transcription, Genetic/drug effects ; Up-Regulation ; Vitamin D3 24-Hydroxylase/metabolism ; Vitamins
    Chemical Substances Anti-Retroviral Agents ; Benzoxazines ; Glucocorticoids ; Vitamins ; Dexamethasone (7S5I7G3JQL) ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (EC 1.14.13.13) ; CYP24A1 protein, human (EC 1.14.15.16) ; Vitamin D3 24-Hydroxylase (EC 1.14.15.16) ; CYP27B1 protein, human (EC 1.14.15.18) ; Calcitriol (FXC9231JVH) ; efavirenz (JE6H2O27P8) ; Ritonavir (O3J8G9O825)
    Language English
    Publishing date 2016-05-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2134679-3
    ISSN 1742-7843 ; 1742-7835
    ISSN (online) 1742-7843
    ISSN 1742-7835
    DOI 10.1111/bcpt.12612
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  5. Article: Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (review).

    Wikvall, K

    International journal of molecular medicine

    2000  Volume 7, Issue 2, Page(s) 201–209

    Abstract: The formation of 1alpha,25-dihydroxyvitamin D3 requires a 25-hydroxylation followed by a 1alpha-hydroxylation catalyzed by cytochrome P450 (CYP) enzymes in liver and kidney. The aim of this review is to give a brief summary of our research on the ... ...

    Abstract The formation of 1alpha,25-dihydroxyvitamin D3 requires a 25-hydroxylation followed by a 1alpha-hydroxylation catalyzed by cytochrome P450 (CYP) enzymes in liver and kidney. The aim of this review is to give a brief summary of our research on the cytochrome P450 enzymes catalyzing the 25-hydroxylation and 1alpha-hydroxylation and to discuss the results in relation to other published literature on these enzymes. Two hepatic P450 enzymes catalyzing 25-hydroxylation of vitamin D3 exist in mammalian liver - one mitochondrial and one microsomal. The mitochondrial vitamin D3 25-hydroxylase is apparently identical with CYP27A, an obligatory enzyme in bile acid biosynthesis in liver. The microsomal 25-hydroxylase has been purified to apparent homogeneity from pig liver. The enzyme catalyzed 25-hydroxylation of vitamin D3, 1alpha-hydroxyvitamin D3, vitamin D2 and 1alpha-hydroxyvitamin D2. A cDNA encoding pig liver microsomal vitamin D3 25-hydroxylase has been isolated in this laboratory. The primary structure of vitamin D3 25-hydroxylase shows 70-80% identity with members of the CYP2D subfamily and has been designated CYP2D25. Three different 1alpha-hydroxylating cytochromes P450 in kidney, i.e. CYP27A, CYP27B and a microsomal 1alpha-hydroxylase, have been described. Mitochondrial cytochrome P450, catalyzing 1alpha-hydroxylation and 27-hydroxylation but not 24-hydroxylation of 25-hydroxyvitamin D3, was partially purified from pig kidney. Purification and inhibition experiments as well as experiments with a monoclonal antibody against CYP27A indicated that one single enzyme catalyzes both 1alpha- and 27-hydroxylation. Treatment of rats with a single i.v. dose of 1alpha,25-dihydroxyvitamin D3 resulted in a marked suppression of CYP27A mRNA levels in kidney. The results suggest a role for CYP27A as a renal mitochondrial 1alpha-hydroxylase. Subsequently, several research groups reported the isolation of cDNA encoding mouse, rat and human kidney 25-hydroxyvitamin D3 1alpha-hydroxylase. The amino acid sequences deduced from these cDNA clones were similar but differed from that of CYP27A. This 1alpha-hydroxylase constitutes a new CYP27 subfamily, CYP27B. The expression of CYP27B was found to be influenced by vitamin D status and parathyroid hormone. Mutations in the CYP27B gene have been identified in patients with pseudovitamin D-deficiency rickets. A microsomal P450 catalyzing 1alpha-hydroxylation of 25-hydroxyvitamin D3 has been purified to apparent homogeneity from pig kidney. This finding demonstrate the presence of a microsomal 1alpha-hydroxylase in addition to the mitochondrial 1alpha-hydroxylases in kidney. The relative importance and regulation of the different renal 1alpha-hydroxylases in the bioactivation of vitamin D3 under normal and pathological conditions will be subject for future studies.
    MeSH term(s) Animals ; Calcitriol/metabolism ; Cholestanetriol 26-Monooxygenase ; Cytochrome P-450 Enzyme System/physiology ; Humans ; Hydroxylation ; Steroid Hydroxylases/metabolism ; Vitamin D/metabolism
    Chemical Substances Vitamin D (1406-16-2) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Steroid Hydroxylases (EC 1.14.-) ; CYP27A1 protein, human (EC 1.14.15.15) ; Cholestanetriol 26-Monooxygenase (EC 1.14.15.15) ; Cyp27a1 protein, mouse (EC 1.14.15.15) ; Calcitriol (FXC9231JVH)
    Language English
    Publishing date 2000-10-26
    Publishing country Greece
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1444428-8
    ISSN 1107-3756
    ISSN 1107-3756
    DOI 10.3892/ijmm.7.2.201
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  6. Article ; Online: Effects of glucocorticoids on vitamin D

    Zayny, Ahmad / Almokhtar, Mokhtar / Wikvall, Kjell / Ljunggren, Östen / Ubhayasekera, Kumari / Bergquist, Jonas / Kibar, Pinar / Norlin, Maria

    Molecular and cellular endocrinology

    2019  Volume 496, Page(s) 110525

    Abstract: Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects ... ...

    Abstract Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D
    MeSH term(s) Cell Line, Tumor ; Cholecalciferol/metabolism ; Gene Expression Regulation, Enzymologic/drug effects ; Glucocorticoids/pharmacology ; Humans ; Osteoblasts/cytology ; Osteoblasts/enzymology ; Promoter Regions, Genetic ; Vitamin D3 24-Hydroxylase/biosynthesis ; Vitamin D3 24-Hydroxylase/genetics
    Chemical Substances Glucocorticoids ; Cholecalciferol (1C6V77QF41) ; CYP24A1 protein, human (EC 1.14.15.16) ; Vitamin D3 24-Hydroxylase (EC 1.14.15.16)
    Language English
    Publishing date 2019-07-25
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187438-x
    ISSN 1872-8057 ; 0303-7207
    ISSN (online) 1872-8057
    ISSN 0303-7207
    DOI 10.1016/j.mce.2019.110525
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  7. Article ; Online: Human cytochromes P450 in health and disease.

    Nebert, Daniel W / Wikvall, Kjell / Miller, Walter L

    Philosophical transactions of the Royal Society of London. Series B, Biological sciences

    2013  Volume 368, Issue 1612, Page(s) 20120431

    Abstract: There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in ... ...

    Abstract There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.
    MeSH term(s) Animals ; Cholesterol/biosynthesis ; Cholesterol/metabolism ; Cytochrome P-450 Enzyme System/classification ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Dehydroepiandrosterone/metabolism ; Eicosanoids/metabolism ; Enzyme Activation ; Evolution, Molecular ; Humans ; Hydroxylation ; Metabolic Diseases/enzymology ; Metabolic Diseases/genetics ; Metabolic Diseases/pathology ; Multigene Family ; Oxidation-Reduction ; Pregnenolone/metabolism ; Tretinoin/metabolism ; Vitamin D/biosynthesis ; Vitamin D/metabolism
    Chemical Substances Eicosanoids ; Vitamin D (1406-16-2) ; Dehydroepiandrosterone (459AG36T1B) ; Tretinoin (5688UTC01R) ; Pregnenolone (73R90F7MQ8) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2013-01-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 208382-6
    ISSN 1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
    ISSN (online) 1471-2970
    ISSN 0080-4622 ; 0264-3839 ; 0962-8436
    DOI 10.1098/rstb.2012.0431
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  8. Article: Species-specific and age-dependent bile acid composition: aspects on CYP8B and CYP4A subfamilies in bile acid biosynthesis.

    Lundell, Kerstin / Wikvall, Kjell

    Current drug metabolism

    2008  Volume 9, Issue 4, Page(s) 323–331

    Abstract: The present review aims to give an overview of the cytochrome P450 8B (CYP8B) and cytochrome P450 4A (CYP4A) subfamilies in relation to biosynthesis of bile acids, in particular trihydroxy bile acids. Trihydroxy bile acids are basically required in most ... ...

    Abstract The present review aims to give an overview of the cytochrome P450 8B (CYP8B) and cytochrome P450 4A (CYP4A) subfamilies in relation to biosynthesis of bile acids, in particular trihydroxy bile acids. Trihydroxy bile acids are basically required in most species and have an impact on cholesterol and lipid metabolism. The primary trihydroxy bile acid in most mammals is cholic acid. Some species produce other important trihydroxy bile acids, for example the adult pig which produce hyocholic acid instead of cholic acid. The position of the third hydroxyl group in cholic acid and hyocholic acid, 12alpha or 6alpha position, respectively, has a profound effect on the hydrophilic-hydrophobic property of the trihydroxy bile acids. The CYP8B subfamily is required for introduction of the 12alpha-hydroxyl group in cholic acid biosynthesis. The enzyme responsible for 6alpha-hydroxylation in hyocholic acid biosynthesis, however, varies among species. This review will discuss, in particular, porcine members of the CYP8B and CYP4A subfamilies because interesting findings regarding members of these subfamilies have recently been recognized in this species. CYP8B1 was for a long time believed to be absent in the pig but was recently found to be expressed in fetal pig liver. The enzyme catalyzing the 6alpha-hydroxylation in hyocholic acid biosynthesis in pig was found to be an atypical member of the CYP4A subfamily, denoted CYP4A21. The review presents bile acid biosynthesis in view of these findings and discusses physiochemical properties and developmental-dependent aspects related cholic acid and hyocholic acid biosynthesis.
    MeSH term(s) Aging/physiology ; Animals ; Bile/metabolism ; Bile Acids and Salts/biosynthesis ; Bile Acids and Salts/metabolism ; Chemical Phenomena ; Chemistry, Physical ; Cytochrome P-450 CYP4A/metabolism ; Humans ; Species Specificity ; Steroid Hydroxylases/metabolism ; Swine
    Chemical Substances Bile Acids and Salts ; Steroid Hydroxylases (EC 1.14.-) ; Cytochrome P-450 CYP4A (EC 1.14.15.3)
    Language English
    Publishing date 2008-04-28
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2064815-7
    ISSN 1875-5453 ; 1389-2002
    ISSN (online) 1875-5453
    ISSN 1389-2002
    DOI 10.2174/138920008784220574
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  9. Article: Vitamin D-mediated regulation of CYP21A2 transcription - a novel mechanism for vitamin D action.

    Lundqvist, Johan / Wikvall, Kjell / Norlin, Maria

    Biochimica et biophysica acta

    2012  Volume 1820, Issue 10, Page(s) 1553–1559

    Abstract: Background: 1α,25-Dihydroxyvitamin D(3) has recently been reported to decrease expression and activity of CYP21A2. In this paper, we have studied the mechanisms for the 1α,25-dihydroxyvitamin D(3)-mediated effect on CYP21A2 transcriptional rate.: ... ...

    Abstract Background: 1α,25-Dihydroxyvitamin D(3) has recently been reported to decrease expression and activity of CYP21A2. In this paper, we have studied the mechanisms for the 1α,25-dihydroxyvitamin D(3)-mediated effect on CYP21A2 transcriptional rate.
    Methods: We have studied the effects of 1α,25-dihydroxyvitamin D(3) using luciferase reporter constructs containing different lengths of the CYP21A2 promoter. These constructs were transfected into cell lines derived from human and mouse adrenal cortex. The mechanism for the effects of vitamin D on the CYP21A2 promoter was studied using chromatin immunoprecipitation assay, mutagenesis and gene silencing by siRNA.
    Results: 1α,25-Dihydroxyvitamin D(3) was found to alter the promoter activity via a VDR-mediated mechanism, including the comodulators VDR interacting repressor (VDIR) and Williams syndrome transcription factor (WSTF). The involvement of comodulator VDIR was confirmed by gene silencing. We identified a vitamin D response element in the CYP21A2 promoter. Interaction between this novel response element and VDR, WSTF and VDIR was shown by chromatin immunoprecipitation assay. When this sequence was deleted, the effect of 1α,25-dihydroxyvitamin D(3) was abolished, indicating that this sequence in the CYP21A2 promoter functions as a vitamin D response element. Interestingly, an altered balance between nuclear receptors and comodulators reversed the suppressing effect of vitamin D to a stimulatory effect.
    General significance: This paper reports data important for the understanding of the mechanisms for vitamin D-mediated suppression of gene expression as well as for the vitamin D-mediated effects on CYP21A2. We report a novel mechanism for effects of 1α,25-dihydroxyvitamin D(3).
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/physiology ; Cells, Cultured ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Mice ; Models, Biological ; Promoter Regions, Genetic/drug effects ; Receptors, Calcitriol/genetics ; Receptors, Calcitriol/physiology ; Retinoid X Receptors/genetics ; Retinoid X Receptors/physiology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Steroid 21-Hydroxylase/genetics ; Transcription Factors/genetics ; Transcription Factors/physiology ; Transcription, Genetic/drug effects ; Vitamin D/analogs & derivatives ; Vitamin D/pharmacology ; Vitamin D/physiology ; Vitamin D Response Element/drug effects ; Vitamin D Response Element/physiology
    Chemical Substances BAZ1B protein, human ; Basic Helix-Loop-Helix Transcription Factors ; Receptors, Calcitriol ; Retinoid X Receptors ; TCF3 protein, human ; Transcription Factors ; dihydroxy-vitamin D3 ; Vitamin D (1406-16-2) ; CYP21A2 protein, human (EC 1.14.14.16) ; Steroid 21-Hydroxylase (EC 1.14.14.16)
    Language English
    Publishing date 2012-10
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbagen.2012.04.017
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  10. Article ; Online: Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.

    Almokhtar, Mokhtar / Wikvall, Kjell / Ubhayasekera, S J Kumari A / Bergquist, Jonas / Norlin, Maria

    The Journal of steroid biochemistry and molecular biology

    2016  Volume 158, Page(s) 178–188

    Abstract: Vitamin D3 is a pro-hormone, which is sequentially activated by 25- and 1α-hydroxylation to form 25-hydroxyvitamin D3 [25(OH)D3] and 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], respectively. Subsequent inactivation is performed by 24-hydroxylation. These ... ...

    Abstract Vitamin D3 is a pro-hormone, which is sequentially activated by 25- and 1α-hydroxylation to form 25-hydroxyvitamin D3 [25(OH)D3] and 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], respectively. Subsequent inactivation is performed by 24-hydroxylation. These reactions are carried out by a series of CYP450 enzymes. The 25-hydroxylation involves mainly CYP2R1 and CYP27A1, whereas 1α-hydroxylation and 24-hydroxylation are catalyzed by CYP27B1 and CYP24A1, respectively, and are tightly regulated to maintain adequate levels of the active vitamin D hormone, 1α,25(OH)2D3. Altered circulating vitamin D levels, in particular 25(OH)D3, have been linked to several disorders of the nervous system, e.g., schizophrenia and Parkinson disease. However, little is known about the mechanisms of vitamin D actions in the neurons. In this study, we examined vitamin D metabolism and its regulation in a murine motor neuron-like hybrid cell line, NSC-34. We found that these cells express mRNAs for the four major CYP450 enzymes involved in vitamin D activation and inactivation, and vitamin D receptor (VDR) that mediates vitamin D actions. We also found high levels of CYP24A1-dependent 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] production, that was inhibited by the well-known CYP enzyme inhibitor ketoconazole and by several inhibitors that are more specific for CYP24A1. Furthermore, CYP24A1 mRNA levels in NSC-34 cells were up-regulated by 1α,25(OH)2D3 and its synthetic analogs, EB1089 and tacalcitol. Our results suggest that NSC-34 cells could be a novel model for the studies of neuronal vitamin D metabolism and its mechanism of actions.
    MeSH term(s) Animals ; Brain/metabolism ; Cell Line, Tumor ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Cytochrome P-450 Enzyme System/genetics ; Mice ; Motor Neurons/metabolism ; RNA, Messenger/metabolism ; Receptors, Calcitriol/genetics ; Vitamin D/metabolism
    Chemical Substances Cytochrome P-450 Enzyme Inhibitors ; RNA, Messenger ; Receptors, Calcitriol ; Vitamin D (1406-16-2) ; Cytochrome P-450 Enzyme System (9035-51-2)
    Language English
    Publishing date 2016-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1049188-0
    ISSN 1879-1220 ; 0960-0760
    ISSN (online) 1879-1220
    ISSN 0960-0760
    DOI 10.1016/j.jsbmb.2015.12.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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