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At least 1,441 records · Page 80Linked to original sources
PubMed1996

Peroxidase activity of liver microsomal vitamin D 25-hydroxylase and cytochrome P450 1A2 catalyzes 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome.

Purified liver microsomal vitamin D 25-hydroxylase, a cytochrome P450, catalyzes 25-hydroxylation of vitamin D3 in the absence of NADPH and NADPH-cytochrome P450 reductase by using t-butyl hydroperoxide as electron donors. The rate of 25-hydroxylation was approximately the same when NADPH/ NADPH-cytochrome P450 reductase or t-butyl hydroperoxide was used as electron donor. The Km value for vitamin D3 in the presence of t-butyl hydroperoxide was found to be 30 microM. The rates of 25-hydroxylation of 1 alpha-hydroxyvitamin D3 and 5 beta-cholestane-3 alpha, 7 alpha-diol catalyzed by 25-hydroxylase were significantly higher when the reaction proceeded in the presence of NADPH/NADPH-cytochrome P450 reductase than in the presence of t-butyl hydroperoxide. Other liver microsomal cytochrome P450 forms such as taurochenodeoxycholic acid 6 alpha-hydroxylase and cytochromes P450 1A2 and 2B4 did not catalyze 25-hydroxylation of vitamin D3 in the presence of NADPH/NADPH-cytochrome P450 reductase or t-butyl hydroperoxide. The peroxidase activity of the 25-hydroxylase also catalyzed oxidation of dopamine to aminochrome. A linear correlation between increase in aminochrome formation and increase in the amount of 25-hydroxylase was observed in the oxidation of dopamine. The Km values for dopamine and t-butyl hydroperoxide were 8.6 microM and 1 mM when 25-hydroxylase catalyzes the formation of aminochrome in the presence of t-butyl hydroperoxide. Oxidation of dopamine to aminochrome catalyzed by the peroxidase activity of cytochrome P-450 1A2 was observed in the presence of t-butyl hydroperoxide. A linear correlation between formation of aminochrome and the amount of cytochrome P450 1A2 was found.

Animals↗
PubMed2001

BAG-1 p50 isoform interacts with the vitamin D receptor and its cellular overexpression inhibits the vitamin D pathway.

Human BAG-1 is an anti-apoptotic protein with four protein isoforms (BAG-1 p50, p46, p33, and p29). BAG-1 p46 was originally isolated in a screen for proteins binding to the glucocorticoid receptor; it binds and modulates the action of several members of the nuclear steroid hormone receptor superfamily. The vitamin D receptor (VDR) is another member of this superfamily, and the vitamin D pathway is important for prevention and therapy of osteoporosis, renal failure, cancer, and psoriasis. Therefore, we investigated the effect of the recently isolated BAG-1 p50 on the vitamin D pathway. By use of Far Western blot analysis and glutathione S-transferase BAG-1 p50 binding assays, BAG-1 p50 was demonstrated to interact with the VDR, and the BAG-1 p50 N-terminus was required. In U87 cells that were stably transfected with BAG-1 p50, binding of the VDR to its response element in electrophoretic mobility shift assays was blocked, enhancement of transcriptional activation was inhibited, cell growth rate was enhanced, cell growth inhibition induced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was blocked, and 1,25(OH)2D3-mediated VDR induction was inhibited. These results suggest that BAG-1 p50 is a novel regulator of the vitamin D signaling pathway, and its overexpression may lead to cellular resistance to 1,25(OH)2D3 therapy.

Calcitriol↗
PubMed1999

Expression of vitamin D3 25-hydroxylase (CYP27) mRNA after induction by vitamin D3 or UVB radiation in keratinocytes of human skin equivalents--a preliminary study.

The presence of both 1alpha-hydroxylase activity and 25-hydroxylase activity is a biochemical prerequisite for the enzymatic generation of 1alpha,25(OH)2D3 from vitamin D3 in keratinocytes. In contrast to 1alpha-hydroxylase, however, activity of a 25-hydroxylase in keratinocytes has not previously been demonstrated. In this study, using RT-PCR we detected vitamin D3 25-hydroxylase mRNA in human keratinocytes. The expression of vitamin D3 25-hydroxylase mRNA in keratinocytes was identical to that of CYP27 expressed in mitochondria of human hepatoma HepG2 cells. CYP27 mRNA in keratinocytes is not constitutively expressed but is inducible both by vitamin D3 (780 nM) and by UVB radiation (300 nm, 30 mJ/cm2).

Carcinoma, Hepatocellular↗
PubMed1990

Up-regulation of the intestinal 1,25-dihydroxyvitamin D receptor during hypervitaminosis D: a comparison between vitamin D2 and vitamin D3.

Concentrations of intestinal 1,25-dihydroxyvitamin D receptor were measured in rats receiving pharmacological amounts (25,000 IU/rat daily for 6 days) of either vitamin D2 or vitamin D3. The data showed that both hypervitaminosis D2 and hypervitaminosis D3 resulted in significant up-regulation of intestinal 1,25-dihydroxyvitamin D receptor (fmol/mg protein) relative to controls (409 +/- 24, vitamin D2-treated; 525 +/- 41, vitamin D3-treated; and 249 +/- 19, control). The 1,25-dihydroxyvitamin D receptor enhancement also was accompanied by elevated plasma 25-hydroxyvitamin D and hypercalcemia. These data suggest that increased target-tissue 1,25-dihydroxyvitamin D receptor may play a role in enhancing target-tissue responsiveness and, thus, have a significant role in mediating the toxic effects of hypervitaminosis D.

Animals↗
PubMed1996

Vitamin D3 elicits calcium response and activates blood monocyte-derived macrophages from patients with vitamin D dependent rickets type II.

We studied the effects of vitamin D3 metabolites on intracellular free Ca2+ concentration ([Ca2+]i) and the respiratory burst of monocyte-derived macrophages (MDM) from patients with vitamin D dependent rickets type II. Treatment of MDM from the patients and healthy donors with 1 nM 1,25(OH)2D3 produced a rapid elevation of [Ca2+]i and similarly primed both types of cells for enhanced capacity for O2- release with phorbol diester. These results suggest that macrophages may have distinct non-genomic pathways of vitamin D3, which partly explain the absence of immunodeficiency and the disappearance of rickets after treatment with vitamin D3 in the patients.

24,25-Dihydroxyvitamin D 3↗
PubMed1990

Calcitriol treatment in vitamin D-dependent and vitamin D-resistant rickets.

Use of 1,25(OH)2D3 (calcitriol) can be of benefit in the treatment of two hereditary types of rickets and osteomalacia, vitamin D dependency type I (VDD1) and X-linked hypophosphatemic vitamin D-resistant rickets (HPDR). VDD1 is due to inadequate activation of 25(OH)D to 1,25(OH)2D, leading to very low circulating levels of 1,25(OH)2D in plasma; the basic abnormality appears to be an alteration in renal 1 alpha-hydroxylase activity. In VDD1, replacement therapy with calcitriol results in complete correction of the abnormal phenotype. By contrast, in HPDR, plasma levels of 25(OH)D and 1,25(OH)2D are in the normal range, although it has been demonstrated that the ability of patients to produce 1,25(OH)2D under conditions of stress is impaired. When started early in life, the use of phosphate salts in HPDR generally results in healing of rickets, normal growth, and correction of lower limb deformities. However, osteomalacia is not corrected by treatment with phosphate, either alone or in combination with vitamin D. By pharmacologically increasing the level of 1,25(OH)2D3 in these patients, there is often a dramatic improvement in the appearance of the trabecular surface, leading to correction of the osteomalacic component of HPDR; in addition, the secondary hyperparathyroidism observed in previous patients treated with phosphate and vitamin D is easier to control. Closed medical follow-up allows the prevention of renal damage that could result from long-term administration of calcitriol.

Calcitriol↗
PubMed1989

Immune dysfunction in hypophosphatemic vitamin D-resistant rickets: immunoregulatory reaction of 1 alpha(OH) vitamin D3.

We investigated immunologic function in six cases with hypophosphatemic vitamin D-resistant rickets (VDRR) before and after treatment with 1 alpha-hydroxycholecalciferol (1 alpha(OH) vitamin D3). All cases suffered frequent episodes of infection, which tended to be more severe in the older patients. OKT9-, OKT10-, and OKM1-positive cells and adenosine deaminase (ADA) were significantly increased, whereas numbers and activity of natural killer (NK) cells were lower than normal before treatment. After administration of 1 alpha(OH) vitamin D3, however, the susceptibility to infection apparently decreased, and NK cell number and activity increased in all patients. ADA was also significantly decreased and remained in the normal range after treatment. These results suggest that vitamin D plays a role in the impaired immunoregulatory functions of NK cells in VDRR. Furthermore, ADA may be one parameter reflecting this immunologic impairment.

Adenosine Deaminase↗
PubMed1995

Does vitamin D3 have negative effects on serum levels of lipids? A follow-up study with a sequential combination of estradiol valerate and cyproterone acetate and/or vitamin D3.

The effects of four different treatment schedules on serum lipid concentrations were studied for 1 year in 402 postmenopausal women in the Kuopio Osteoporosis Study. The women were randomized to four treatment groups: A, Sequential combination of estradiol valerate and cyproterone acetate (Climen); B, Vitamin D3, 300 IU/day; C, Climen+Vitamin D3, D, placebo. In group A, serum concentrations of total cholesterol (Chol) decreased by 4.8% in 6 months and by 6.2% in 12 months (P < 0.001), but in group C the decrease was only 2.9% in 6 months (P < 0.05) and 3.4% in 12 months (P < 0.01). The decline of total-Chol in group A was accounted for by the 6.8% to 7.5% decrease in LDL-Chol levels (P < 0.001). The decrease of LDL-Chol in group C was statistically non-significant. Use of vitamin D3 (group B), increased serum Chol by 2.7% (6 months), P < 0.05 and by 2.1% (12 months) and the increases were the result of the 6.0% to 6.2% increase in LDL-Chol levels in 6 and 12 months, respectively (P < 0.001). Serum concentrations of HDL-Chol and TG remained relatively stable in all groups. No correlations were found between LDL-Chol, 25-OH-D3 and 1,25(OH)2-D3 levels in group B. Our results confirm the beneficial effect of estradiol valerate and cyproterone acetate on the lipid profile. In contrast, vitamin D3 had a negative influence on this profile by increasing serum concentrations of LDL-Chol.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecalciferol↗
PubMed1995

Pretreatment with 1,25(OH)2 vitamin D or 24,25(OH)2 vitamin D increases synergistically responsiveness to sex steroids in skeletal-derived cells.

We demonstrated previously that vitamin D metabolites modulate the response of bone and cartilage cells to 17 beta-estradiol (E2) and dihydrotestosterone (DHT) both in cell cultures and in vivo. In the present study, we investigated to what extent pretreatment with 1,25(OH)2D3 or 24,25(OH)2D3 would reduce the minimal effective dose of E2, DHT or progesterone (P) required for stimulation of DNA synthesis and creatine kinase specific activity in cultured osteoblast-like ROS 17/2.8 cells and in rat embryo epiphyseal cartilage cells, and to what extent such pretreatment would increase the maximal response. We measured responses to sex steroids after pretreatment of the cells for 5 days with 0.02% ethanol vehicle or with the vitamin D metabolites 1,25(OH)2D3 (0.12 nM), or 24,25(OH)2D3 (1.2 nM) singly or in combination. Pretreatment of ROS 17/2.8 cells with 1,25(OH)2D3, but not 24,25(OH)2D3, increased synergistically their response to E2 but not to P, and did not affect their lack of response to DHT. Pretreatment of epiphyseal cartilage cells with either 1,25(OH)2D3 or 24,25(OH)2D3 increased synergistically their DNA synthetic response to all three steroids, but their CK response only to E2 or DHT. The minimal dose for causing a significant response to E2 in ROS 17/2.8 cells or to either E2 or DHT in epiphyseal cartilage cells was reduced 10-fold after pretreatment with vitamin D metabolites. After pretreatment, the maximal response was more than doubled in ROS 17/2.8 cells; epiphyseal cartilage cells showed a similar 10-fold decrease in the dose required for maximal response to E2 or DHT; the improvement in the response to P was significant only for DNA synthesis. We conclude that pretreatment with the appropriate vitamin D metabolite(s) both reduces by an order of magnitude, or more, the amount of sex steroids needed to stimulate skeletal derived cells and increases synergistically the maximal response of the cells.

24,25-Dihydroxyvitamin D 3↗
PubMed2006

Degradation of vitamin D3 in a stressed formulation: the identification of esters of vitamin D3 formed by a transesterification with triglycerides.

Four unknown degradants in the LC-UV profile of a stressed experimental tablet formulation that contains vitamin D3 have been identified by a combination of Ag+-cationization electrospray ionization (ESI) LC/MS and atmospheric pressure chemical ionization (APCI) LC/MS/MS. The peaks elute in the method chromatography in two pairs of two peaks. The first pair of peaks has m/z 511 while the second pair has m/z 539. The major, first peak of each set of peaks corresponds to the octanoate and decanoate ester of vitamin D3, respectively. These are formed by a transesterification with the two major fatty acid components (octanoate and decanoate) of the triglycerides present in the formulation. The formation of two degradation products with each fatty acid is due to the presence of both vitamin D3 (major component) and the isomeric pre-vitamin D3 (minor component) in the stressed formulation.

Chemistry, Pharmaceutical↗
PubMed2000

Synthesis of vitamin D(3) and calcitriol dimers as potential chemical inducers of vitamin D receptor dimerization.

The design and synthesis of vitamin D(3) dimers 2 and 3 and 1 alpha, 25-dihydroxyvitamin D(3) (calcitriol) dimers 4 and 5 are described. The dimers were designed with a view to doubly binding the vitamin D receptor (VDR) and inducing the receptor homodimerization. In the dimers the units are linked through the C-11 position in ring C by an alkyl side chain of six or 10 carbon atoms, far from the hydroxy groups responsible for the VDR binding. The linker is formed by olefin metathesis of an olefinic side chain at the C-11 position introduced by stereoselective cuprate addition. The synthesis, which is both short and convergent, uses the Wittig-Horner approach to construct the vitamin D triene system and allows the preparation of dimers with a linker of modulated length with the purpose of optimizing the vitamin D(3)-VDR interaction.

Calcitriol↗
PubMed2004

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1alpha,25(OH)2-vitamin D3 signaling.

Structural and molecular studies have shown that the vitamin D receptor (VDR) mediates 1alpha,25(OH)2-vitamin D3 gene transactivation. Recent evidence indicates that both VDR and the estrogen receptor are localized to plasma membrane caveolae and are required for initiation of nongenomic (NG) responses. Computer docking of the NG-specific 1alpha,25(OH)2-lumisterol to the VDR resulted in identification of an alternative ligand-binding pocket that partially overlaps the genomic pocket described in the experimentally determined x-ray structure. Data obtained from docking five different vitamin D sterols in the genomic and alternative pockets were used to generate a receptor conformational ensemble model, providing an explanation for how VDR and possibly the estrogen receptor can have genomic and NG functionality. The VDR model is compatible with the following: (i) NG chloride channel agonism and antagonism; (ii) variable ligand-stabilized trypsin digest banding patterns; and (iii) differential transcriptional activity, employing different VDR point mutants and 1alpha,25(OH)2-vitamin D3 analogs.

Binding Sites↗
PubMed1987

Vitamin B-6 metabolism in the pregnant rat: effect of progesterone on the (re)distribution in maternal vitamin B-6 stores.

Parameters of vitamin B-6 metabolism were studied in pregnant rats, nonpregnant control rats and progesterone-supplemented ovariectomized rats. Plasma pyridoxal 5'-phosphate (PLP) and pyridoxal concentrations in pregnant rats were 20 and 40% of those of nonpregnant rats, respectively. Excretion of 4-pyridoxic acid in the urine in pregnant rats was about 40% of that of nonpregnant rats. Liver PLP content was also lower during pregnancy, but liver pyridoxamine 5'-phosphate (PMP), kidney PLP and PMP and muscle PLP contents did not change significantly. Progesterone administration to ovariectomized rats resulted in slightly lower plasma, liver and kidney PLP levels than in intact untreated control rats. Liver and kidney pyridoxal kinase (PK) and pyridoxamine 5'-phosphate oxidase activities were similar in pregnant and nonpregnant rats. Progesterone treatment resulted in a significantly lower PK activity in the kidney of the treated rats than in untreated controls. It is concluded that the pregnancy-induced changes in vitamin B-6 metabolism were unlikely to be related directly to progesterone. However, progesterone may secondarily affect maternal vitamin B-6 stores during pregnancy, by temporary deposition and increased retention of vitamin B-6.

Animals↗
PubMed1992

Vitamin A abuse: development of cirrhosis despite cessation of vitamin A. A six-year clinical and histopathologic follow-up.

We report the case of a 35-year-old man who contracted vitamin A-induced liver cirrhosis. Five years before, he had been investigated for vitamin A-induced non-cirrhotic portal hypertension. In this case, the clinical and histopathologic evolution from non-cirrhotic portal hypertension to cirrhosis was documented. In spite of the cessation of pharmaceutical vitamin A intake, the disease progressed. Therapy with colchicine and phenobarbital apparently did not influence evolution to cirrhosis. This suggests that vitamin A can trigger largely unknown mechanisms of liver fibrosis which seem to be self-perpetuating.

Adult↗
PubMed1984

Plasma concentrations of vitamin D metabolites before and during treatment of vitamin D deficiency rickets in children.

Plasma concentrations of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25-(OH)2D), and 24,25-dihydroxyvitamin D (24,25-(OH)2D) were determined in 17 children with vitamin D deficiency rickets before therapy was started. Thirteen of them also had these tests repeated during treatment. The median 25-OHD concentration was at the lower limit of the reference range before, but increased distinctly within one week of treatment with 1 700-4 000 IU vitamin D per day (17 vs. 37 nmol/l, p less than 0.01). 24,25-(OH)2D was undetectable in twelve of the patients before therapy. Detectable concentrations were in the range of 1.7 to 3.5% of the corresponding 25-OHD levels throughout the study, and the two metabolites were closely correlated (r = 0.84, p less than 0.0005). The median 1,25-(OH)2D concentration was near the average of the reference range before, but increased to well above the upper limit of normal within one week of treatment (121 vs. 368 pmol/l, p less than 0.01). The levels were largely normal after 10 weeks of therapy, as were the plasma concentrations of calcium, phosphate, and alkaline phosphatase. Parathyroid activity, as judged by serum parathyroid hormone or urinary cyclic AMP concentrations, was stimulated in 11 of 12 children studied prior to treatment. It is concluded that there may be no clear-cut differences between normal nad rachitic values of the different vitamin D metabolites under practical clinical conditions. A low 25-OHD level combined with evidence of a stimulated parathyroid activity, and a rise of 1,25-(OH)2D levels to supernormal values following a few days of vitamin D therapy may be diagnostic clues.

24,25-Dihydroxyvitamin D 3↗
PubMed1994

Seasonal variation in serum 25-hydroxy vitamin D3 does not affect 1,25-dihydroxy vitamin D.

The seasonal variation of serum 25-hydroxy vitamin D3 and 1,25-dihydroxy-vitamin D has been investigated. Blood was taken from 27 healthy volunteers, aged 21-44 years old at 3 monthly intervals over a period of 1 year. A scrolling monthly programme with 12 quarterly (3 month) time periods was developed. A summer associated increase in 25-hydroxy vitamin D3 was significantly correlated with but lagged behind by 2 months, the increase in recorded sunlight hours. However, four individuals showed no seasonal rise but maintained constant concentrations throughout the year within the established reference range. Serum 1,25-dihydroxy vitamin D showed marked intra-individual variability with no seasonal pattern although the highest concentration (180 pmol/L) was observed in the winter and no concentration greater than 108 pmol/L in the summer.

Adult↗
PubMed1992

Seasonal and climatic variation in cholesterol and vitamin C: effect of vitamin C supplementation.

Vitamin C (ascorbic acid) is an important anti-oxidant which may help to reduce free radical damage and atheroma formation in blood vessels. In a study in which a group of healthy volunteer subjects were followed up for 12 months and a group of patients with vascular disease taking Vitamin C supplements were followed for 23 months, we confirmed previous findings of seasonal variations in ascorbic acid and cholesterol and have shown an inverse relationship between leucocyte ascorbic acid and serum cholesterol levels. In healthy control subjects the increase in ascorbate and fall in cholesterol during the summer months was reversed when the weather changed to a more winter pattern, presumably due to dietary alterations. We found that ascorbic acid levels were lower in patients with peripheral vascular disease and that although normal ascorbic acid levels were achieved with Vitamin C supplementation, when supplements were stopped at the height of a normal summer, there was a fall in ascorbic acid and a rise in serum cholesterol to winter levels. Given these findings we suggest that patients with vascular disease should have Vitamin C supplements throughout the year.

Adult↗
PubMed1997

[Novel pharmacological activity of a vitamin (novel pharmacological action of vitamin D)].

The endocrine system to maintain calcium homeostasis involves the active vitamin D, as well as parathyloid hormone (PTH). Based on this 'classical' calcium-regulatory function, 1,25-(OH)2D3 and 1 alpha OHD3 was developed as the drug for vitamin D resistant rickets, renal dystrophy, and osteoporosis. Psoriasis is a chronic skin disease which is characterized by hyperproliferation and abnormal differentiation of epidermis. As an anti-psoriatic drug, 1,24R-(OH)2D3 has been on clinical use. The efficacy for psoriasis is explainable by the differentiation-inducing activity of this compound. 1,25-(OH)2D3 was also reported to suppress proliferation and induce differentiation of tumor cells including breast cancer, colon cancer and so forth, suggesting the possible therapy of malignant tumors. In immune system, active vitamin D3 exerts various effects; 1,25-(OH)2D3 suppresses proliferation and cytokine production in T cells and antibody production in B cells. Animal models of autoimmune diseases and skin-graft suggest active vitamin D becomes a novel immuno suppressant. Since 1,25-(OH)2D3 induces the synthesis of nerve growth factor (NGF), it will be a new therapy for the treatment of neuronal degenerative diseases.

Animals↗