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PubMed1981

Calcium lysosomes in rachitic and vitamin D3 replete chick duodenal absorptive cells.

Calcium-containing lysomes were described in a previous communication in this series (Davis et al., 1979). Their potential role in intestinal calcium uptake and transcellular transports was hypothesized. To further this notion, the effects of a rachitogenic diet and vitamin D3 repletion were investigated. Intestinal absorptive cells from chicks maintained on a vitamin D deficient diet were characterized by decreased numbers of supranuclear calcium lysosomes. In contrast, intestinal cells from chicks given vitamin D3 (cholecalciferol) subsequent to the rachitogenic diet showed numerous large compound supranuclear calcium lysosomes. Since other steroid hormones are known to effect lysosomes, it is tempting to speculate that vitamin D, itself a steroid hormone, may activate lysosomes which themselves might be involved in calcium homeostatic mechanisms.

Animals↗
PubMed1996

Combined differentiating therapy for myelodysplastic syndromes: a phase II study.

An in vitro synergism between different inducers of AML cell differentiation has been previously observed. Therefore, we treated 53 myelodysplastic (MDS) patients with a low dose combination of cis-retinoic acid (cRA, 20-40 mg/day) and 1,25 alpha (OH)2 cholecalciferol [(OH)2D3, 1-1.5 micrograms/day] +/- intermittent 6-thioguanine (30 mg/m2/day). The latter was reserved for patients with bone marrow (BM) blast excess (> or = 5%). The treatment was well tolerated, without major toxicity. Among 25 patients with BM blasts less than 5%, we observed one complete, eight partial and four minor responses (response rate 52%) with a median response duration of 8 months (2 +/- 24). Median survival, which did not correlate with response, is projected at 76 months. Thirty-one patients with BM blast excess (> or = 5%), including three of the previous group who progressed to refractory anemia with excess of blasts (RAEB), were treated with the three-drug protocol. One complete, 12 partial and six minor responses were obtained (response rate 61%) with a median response duration of 6 months (2-29+). A significant difference in survival (P < 0.005) was observed between the 19 responders (median 25 months) and the 12 non-responders (median 9 months). A reduction in the transfusion need was observed in 41% of the transfusion-dependent patients with blast excess and in 53% of those without blast excess. Therefore, combined differentiating therapy seems more effective than previously reported single agent treatments and should be considered for a larger randomized study to assess its actual impact on survival of MDS patients.

Aged↗
PubMed1991

Hormonal effects on the sulfhydryl groups associated with intestinal brush border membrane proteins.

Previous studies demonstrated that the administration of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) to cholecalciferol-deficient chicks rapidly increases the reactivity and amount of the sulfhydryl (HS-) groups in intestinal brush border membranes (BBM). In the present study, the tissue and hormonal specificity of this effect was investigated. The HS- groups of intestinal and renal BBM were enhanced by vitamin D-3 and/or 1,25(OH)2D3, but no change was noted in isolated intestinal mitochondria and purified intestinal basolateral membranes, cardiac sarcolemma and erythrocyte membranes. Other steroid hormones including estradiol, testosterone, aldosterone, cortisol, dexamethasone and progesterone, yielded a response similar to 1,25(OH)2D3 on BBM HS- groups. Triiodothyronine and retinoic acid also resulted in an increase in intestinal BBM HS- groups. In a kinetic approach, using a specific sulfhydryl fluorescent probe (N-7-dimethylamino-4-coumarin-3-yl-maleimide, DACM), the reactivity of the BBM HS- groups was increased by estrogen and testosterone, as was previously shown for 1,25(OH)2D3. Intestinal BBM proteins, labeled with DACM, were separated by gel electrophoresis. Fluorescence scans of the gel showed two heavily labeled bands, one of 110 kDa, putatively brush border myosin I, and one of 43 kDa, putatively actin. Labeling of the 110 kDa protein was increased by 1,25(OH)2D3 and estradiol. Further studies are required to elucidate the physiological meaning of these hormone-mediated increases in reactivity and amount of the BBM sulfhydryl groups, as well as the nature of the intermediate biochemical reactions involved in this response.

Animals↗
PubMed1994

Microsomal 25-hydroxylation of vitamin D2 and vitamin D3 in pig liver.

A microsomal cytochrome P-450 catalysing 25-hydroxylation of vitamin D2 was purified from both male and female pigs to apparent homogeneity and a specific cytochrome P-450 content of 13 and 15.4 nmol x mg of protein-1, respectively. The enzyme also catalysed 25-hydroxylation of vitamin D3. The ratio between the 25-hydroxylase activities towards vitamin D2 and D3 was essentially the same in the different purification steps as well as in the apparently homogeneous enzyme preparation. The two enzyme activities showed the same pH optimum and decreased in parallel upon partial denaturation of the enzyme. Cholecalciferol competitively inhibited 25-hydroxylation of vitamin D2 and vice versa. The non-steroidal cytochrome P-450 inhibitor ketoconazole inhibited both enzyme activities and the Ki values were the same. The cytochrome P-450 showed the same apparent M(r), substrate specificity and N-terminal amino acid sequence as the previously purified vitamin D3 25-hydroxylase from pig liver microsomes. A monoclonal antibody raised against the vitamin D3 25-hydroxylase also recognized the vitamin D2 25-hydroxylase. The antibody immunoprecipitated the 25-hydroxylase activity towards both vitamin D2 and D3 in the purified enzyme. Taken together, the results show that the 25-hydroxylation of vitamin D2 and D3 is catalysed by the same microsomal cytochrome P-450 in pig liver microsomes. The properties of this 25-hydroxylase are discussed in relation to present knowledge concerning previously well-characterized vitamin D3 25-hydroxylases that are not able to catalyse 25-hydroxylation of vitamin D2.

Amino Acid Sequence↗
PubMed2005

Growth of embryonic renal parenchyme at the interphase of a polyester artificial interstitium.

The construction of an artificial kidney module by tissue engineering or the application of cell-based therapies for the treatment of renal failure requires exact information regarding the cellbiological mechanisms of parenchyme development in combination with different kinds of biomaterials. To learn more about these processes tissue cultures are frequently used experimental tools. However, apart from experiments with early kidney anlagen there is a lack of suitable in-vitro models regarding the generation and long-term maintenance of renal tubules. In the present paper we like to demonstrate an advanced culture technique, which allows to generate tubular elements derived from renal stem cells. For the growth of tubules it is essential to fine-tune the interface between the embryonic tissue and the dead fluid space within a perfusion culture container by offering a polyester artificial interstitium. Culture was performed in IMDM supplemented with hormones and growth factors but using serum-free conditions over 14 days. Formation of tissue was then analysed by immunohistochemistry and two-dimensional (2D) electrophoresis. Culture in pure IMDM leads to a complete loss of tissue formation. In contrast, application of aldosterone (A) induces the development of numerous polarised tubules. Surprisingly, addition of epidermal growth factor (EGF), a cocktail of insulin, transferrin and selenium (ITS), retinoic acid (RA), cholecalciferol (VitD3) or bovine pituitary extract (BPT) does not further improve development of tubules, but leads to intensive cell clustering and a decrease of tubule formation. 2D Western blots of developing tissue probed with soybean agglutinin (SBA) reveal a unique pattern of newly detected proteins. It is found that growth factors do not support but abolish protein spots upregulated by aldosterone. It remains to be investigated, which cellbiological effect stimulates the embryonic cells to develop tubules in competition to cell clusters at the interphase of an artificial interstitium.

Aldosterone↗
PubMed2004

Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults.

The physiologic range for circulating 25-hydroxyvitamin D3 [25(OH)D; the measure of Vitamin D nutrient status] concentration in humans and other primates extends to beyond 200 nmol/L (>80 ng/mL). This biologic "normal" value is greater than current population norms for 25(OH)D. Concentrations of 25(OH)D that correlate with desirable effects extend to at least 70 nmol/L, with no obvious threshold. Randomized clinical trials using 20 mcg (800 IU) per day of Vitamin D show that this suppresses parathyroid hormone, preserves bone mineral density, prevents fractures, lowers blood pressure and improves balance. Calcium absorption from diet correlates with 25(OH)D in the normal range. Health effects of Vitamin D beyond osteoporosis are mostly supported by the circumstantial evidence of epidemiologic studies and laboratory research. These include prevention of cancer and the autoimmune diseases, insulin-dependent diabetes and multiple sclerosis. One mcg per day of Vitamin D(3) (cholecalciferol) increases circulating 25(OH)D by about 1 nmol/L (0.4 ng/mL). A recommended dietary allowance (RDA) is the long-term daily intake level that meets the total requirements for the nutrient by nearly all healthy individuals (it would presume no sunshine). If 70 nmol/L is regarded as a minimum desirable target 25(OH)D concentration, then current recommendations of 15 mcg per day do not meet the criterion of an RDA.

Adult↗
PubMed2006

Regio and stereoselective oxidations of unsaturated steroidal compounds with H2O2 mediated by CH3ReO3.

We have investigated the oxidative behavior of sterols such as cholesteryl acetate (1), 7-dehydrocholesteryl acetate (2), ergosteryl acetate (3), cholecalciferol acetate (Vitamin D(3) acetate) (4) and ergocalciferol acetate (Vitamin D(2) acetate) (5) with the oxidant system methyltrioxorhenium/H(2)O(2)/pyridine in order to check potential parameters controlling the selectivity. The reactions, performed in CH(2)Cl(2)/H(2)O at 25 degrees C, have shown good regio- and stereoselectivity. All oxidation products were isolated by high-performance liquid chromatography (HPLC) and characterized by MS(EI) or FAB, (1)H NMR, (13)C NMR, APT, COSY, HSQC, HMBC, ROESY and NOEDS measurements. Seven new oxygenated compounds were also obtained. Under the experimental conditions adopted in this work, only the diene steroids, i.e. 7-dehydrocholesteryl acetate and ergosteryl acetate, undergo hydrolytic oxirane ring opening, whereas Vitamin D(2) and D(3) acetates, containing the triene system and cholesteryl acetate yield only epoxides. The selectivity seems to be controlled by the nucleophilicity of double bonds and by stereoelectronic and steric effects.

Cholecalciferol↗
PubMed1990

Effect of dietary calcium and lead status on intestinal calcium absorption.

Dietary lead intake was demonstrated to result in two very different effects on intestinal calcium absorption and associated parameters, depending on dietary calcium status. Normal growing 14-day-old chicks were fed diets either low (0.05%) or adequate (1.2%) in calcium and containing varying levels of lead (0%-0.8%) for an additional 10 days. In chicks fed the low calcium diet, ingested lead inhibited intestinal 47Ca absorption, and intestinal calbindin D and alkaline phosphatase synthesis in a dose-dependent fashion. Even at the highest levels of lead, however, this inhibition was limited to the stimulation of these parameters by low dietary calcium. In chicks fed the normal calcium diet, lead exposure did not diminish intestinal 47Ca absorption, or calbindin D or alkaline phosphatase synthesis, but actually elevated the values of these parameters at the higher lead exposure levels. The results indicate that the primary effect of lead, in both cases, occurs at or prior to intestinal protein synthesis and most likely involves the cholecalciferol endocrine system rather than any direct interactions between lead and calcium at the intestinal level.

Alkaline Phosphatase↗
PubMed1995

Pathophysiology of calcium metabolism in children with vitamin D-deficiency rickets.

OBJECTIVE: To improve understanding of the biochemical events in vitamin D-deficiency rickets (VDR). METHODS: We investigated 51 untreated patients, 2 to 36 months of age, during three stages of VDR. Nineteen of these patients were also studied during therapy with 5000 to 10,000 U vitamin D3 (cholecalciferol) and 0.5 to 1 gm calcium. Together with calcium and inorganic phosphate in serum and urine, we measured (1) parathyroid hormone (PTH) secretion (intact serum PTH) and action on the kidney (urinary adenosine 3',5'-cyclic monophosphate (cAMP)/creatinine ratio; (2) serum alkaline phosphatase level; (3) urinary hydroxyproline/creatinine ratio; and (4) serum 1,25-dihydroxyvitamin D (1,25(OH)2D) level. RESULTS: The untreated patients had secondary hyperparathyroidism (high serum PTH and urinary cAMP/creatinine ratio), low calcium and phosphate concentrations in serum, and increased bone turnover (elevated serum alkaline phosphatase and OHP/creatinine ratio), whereas serum 1,25(OH)2D was low, normal, or even slightly elevated. Serum calcium level was positively correlated to serum 1,25(OH)2D and to OHP/creatinine ratio, indicating that normocalcemia in untreated rickets (stage 2) is at least partially maintained by 1,25(OH)2D-induced calcium mobilization from bone. There was no correlation between serum calcium and serum PTH, or between serum PTH and urinary cAMP/creatinine ratio or serum phosphate, indicating disturbed regulation and action of PTH. During vitamin D treatment, serum 1,25(OH)2D values increased to supranormal concentrations in association with the restoration of the physiologic relationship of PTH to serum calcium and phosphate concentrations and urinary cAMP/creatinine ratio. CONCLUSION: Circulating 1,25(OH)2D has an important role in the pathophysiology of VDR before and during treatment, mainly by influencing the bone and kidney response to endogenous PTH.

Alkaline Phosphatase↗
PubMed2002

Rodenticides.

Rodenticides are second only to insecticides in the prevalence of pesticide exposure. Hundreds of rodenticide products currently exist, yet only a handful of them are involved in most toxicoses of companion animals. The most commonly reported toxicoses in the United States are those caused by anticoagulant rodenticides, bromethalin, cholecalciferol, strychnine, and zinc phosphide. The pathophysiologic findings, diagnosis, and treatment of each of these five rodenticides are discussed.

Aniline Compounds↗
PubMed2003

Calcium-vitamin D3 supplementation is cost-effective in hip fractures prevention.

OBJECTIVE: To assess the cost implications for a preventive treatment strategy for institutionalised elderly women with a combined 1200 mg/day calcium and 800 IU/day vitamin D(3) supplementation in seven European countries. DESIGN: Retrospective cost effectiveness analysis based on a prospective placebo-controlled randomised clinical trial. DATA SOURCES: Recently published cost studies in seven European countries. Clinical results from Decalyos, a 3-year placebo-controlled study in elderly institutionalised women. TRIALS: Decalyos study, with 36 months follow-up of 3270 mobile elderly women living in 180 nursing homes, allocated to two groups. One group received 1200 mg/day elemental calcium in the form of tricalcium phosphate together with 800 IU/day (20 microg) of cholecalciferol (vitamin D(3)), the other placebo. RESULTS: In the 36 months analysis of the Decalyos study, 138 hip fractures occurred in the group of 1176 women, receiving supplementation and 184 hip fractures in the placebo group of 1127 women. The mean duration of treatment was 625.4 days. Adjusted to 1000 women, 46 hip fractures were avoided by the calcium and vitamin D(3) supplementation. For all countries, the total costs in the placebo group were higher than in the group receiving supplementation, resulting in a net benefit of 79000-711000 per 1000 women. CONCLUSION: This analysis suggests that the supplementation strategy is cost saving. The results may underestimate the net benefits, as this treatment has also shown to be effective in decreasing the incidence of other non-vertebral fractures in elderly institutionalised women.

Aged↗
PubMed2001

Regulation of aromatase by nuclear receptors.

We investigated the effects of a nuclear receptor system constituted by retinoid X receptor (RXR) and its heterodimer partner on the aromatase activity in a cultured MCF-7 human breast cancer cell line and also in human ovarian granulosa cells, using each selective ligand for retinoic acid receptor, RAR (TTNPB), retinoid X receptor, RXR (LG100268), PPARgamma (troglitazone), and vitamin D3 receptor (cholecalciferol). In MCF-7 cells, the combined treatment with TTNPB and LG100268 caused a dramatic stimulation of the aromatase activity. The combined treatment with other ligand and LG100268 had little or no effect on the aromatase activity. The increase in the aromatase activity by TTNPB plus LG100268 was accompanied by an increase in the P450arom mRNA levels, which was also found to be related to the specific usage of promoter 1a of the CYP19 gene. These results suggest that a nuclear receptor system constituted by a RAR:RXR heterodimer is involved in the regulation of aromatase activity in MCF-7 breast cancer cells. In cultured human ovarian granulosa cells obtained from patients who underwent in vitro fertilization, troglitazone or LG100268 alone decreased the aromatase activity, while the combined treatment caused an even greater reduction in this activity. Little effect of other specific ligands for RXR heterodimer partners may support the notion that the effects of troglitazone and/or LG100268 in human granulosa cells may be mediated through the specific activation of PPARgamma:RXR heterodimer system. Since similar manners of effects of several PPARgamma ligands and/or LG100268 on the aromatase activity were observed in a newly established human ovarian granulosa cancer cell line, KGN, we performed the detailed analysis of the mechanisms of these effects using this cell line. As a result, the inhibitory effect of aromatase activity by troglitazone plus LG100268 was accompanied by the decrease of P450arom mRNA level. Furthermore, the loss of P450arom expression was considered to be due to both the decreased transcription and rapid degradation of its RNA based on the studies of nuclear run-on assay and RNA stability assay. In conclusion, RAR:RXR and PPARgamma:RXR heterodimer nuclear receptor systems may be other important modulators of estrogen production in human breast cancer cells and ovarian granulosa cells, respectively.

Aromatase↗
PubMed2000

Synthesis and evaluation of vitamin D-based cationic lipids for gene delivery in vitro.

A new panel of steroidal cationic lipids has been synthesized for gene delivery. Using commercially available vitamin D2 (calciferol) or vitamin D3 (cholecalciferol) as hydrophobic motifs and a variety of cationic head groups as binding sites for negatively charged phosphate groups in DNA, we demonstrated that the transfection activity of the synthetic vitamin D-based cationic lipids 1d, 2d formulated with dioleoylphosphatidylethanolamine (DOPE) as a co-lipid is comparable to that of 3-(-[N-N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol). These synthetic lipids are effective in transfecting a variety of cell lines. These results suggest that vitamin D-based cationic lipids are useful transfection reagents for in vitro gene transfer studies.

3T3 Cells↗
PubMed1998

Secretion of magnesium and calcium in the total saliva of sheep and its relevance to hypomagnesaemia.

The rate of total secretion of saliva was measured over a 3-h period, under steady state conditions, in conscious sheep. The rates of secretion of magnesium and calcium in saliva represented 25-30% of the magnesium and calcium in the extracellular fluid. Since the large stores of intracellular magnesium are not readily mobilizable, the only readily available reserve of magnesium to maintain magnesium homeostasis is a little in bone. Thus, if magnesium ions from food and saliva are not adequately reabsorbed in the fore-stomachs, their loss could contribute significantly to the failure of homeostasis noted in acute ruminant hypomagnesaemia. Studies of the salivary clearance of 28 Mg showed a delay of 5-13 h in the time course of the salivary specific activity of 28 Mg, relative to that in plasma. This delay is indicative of transcellular interchange between magnesium ions in the central compartment, represented by the extracellular fluid, and an outer compartment which includes the salivary epithelial cells. Prolonged hypercalcaemia, caused by injections of 1 alpha (OH) cholecalciferol, was accompanied by a significant increase in the secretion rate of calcium in saliva but the secretion rate of magnesium was unchanged.

Animals↗
PubMed2003

Rapid HPLC method for measurement of vitamin D3 and 25(OH)D3 in blood plasma.

The present work describes a novel, simplified high-performance liquid chromatography (HPLC) method for evaluation of vitamin D3 and its 25-hydroxy metabolite in blood plasma. The retrieval of the analytes from the blood plasma matrix is based on a single-step extraction using acetonitrile. The method is specific, sensitive, and ensures good reproducibility. The recovery of the analytes, precision, and reproducibility obtained using the present approach gave results comparable to or better than more complex, laborious, and time-consuming procedures. This method is suitable for evaluation of the host's vitamin D physiological status, as well as for rapid analysis of blood plasma samples in suspected cholecalciferol toxicity. With a significantly shortened time of analysis (10 minutes), the present method allows the possibility for processing of a large number of samples rapidly, efficiently, and at a low cost.

Calcifediol↗
PubMed2000

27-Oxygenation of C27-sterols and 25-hydroxylation of vitamin D3 in kidney: cloning, structure and expression of pig kidney CYP27A.

This paper describes the molecular cloning of a cytochrome P450 enzyme in pig kidney that catalyses the hydroxylations of vitamin D(3) (cholecalciferol) and C(27)-sterols. DNA sequence analysis of the cDNA revealed that the enzyme belongs to the CYP27 family. The first 36 amino acids have many hallmarks of a mitochondrial signal sequence. The mature pig kidney CYP27 protein contains 498 amino acids. The M(r) of the mature protein was calculated to be 56607. The structure of pig kidney CYP27, as deduced by DNA sequence analysis, shows 77-83% identity with CYP27A in rat, rabbit and human liver. Transfection of the renal CYP27A cDNA into simian COS cells resulted in the synthesis of an enzyme that catalysed the 25-hydroxylation of vitamin D(3) and the 27-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol, and the further oxidation of the product into the corresponding C(27)-acid 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid. As part of these studies, the enzymic activities of cultured human embryonic kidney cells were examined using vitamin D(3) and C(27)-sterols as substrates. The cells were found to express CYP27A mRNA and to convert the respective substrates into the same products as recombinantly expressed CYP27A, i.e. 25-hydroxyvitamin D(3) and 27-oxygenated C(27)-sterols. The results of the present study describing the structure and expression of CYP27A in kidney suggest that this enzyme is involved in the renal metabolism of vitamin D(3) and that the kidney plays a role in the metabolism of cholesterol and other C(27)-sterols.

Amino Acid Sequence↗
PubMed1968

Investigations on vitamin D esters synthesized rats. Detection and identification.

1. Vitamin D-deficient rachitic rats were given [1-(3)H]cholecalciferol by gastric intubation. After 24hr., diethyl ether extracts of liver and kidney contained 5-11% and 4.5-20% respectively of total vitamin D apparently esterified with long-chain fatty acids. 2. A two-dimensional thin-layer chromatographic technique was devised that completely separated seven synthetic vitamin D esters according to the chain length and number of double bonds in the fatty acid component. When the ;vitamin D ester' fraction from liver or kidney was co-chromatographed with the standard esters, radioactivity appeared mainly in vitamin D palmitate, stearate, oleate and linoleate regions. The proportion of radioactivity in the saturated fatty acid esters was higher in kidney than in liver. 3. The same percentage of tissue vitamin D in the esterified form was found at each of two dosages of vitamin D. 4. The possible specificity of a vitamin D esterification mechanism is discussed.

Animals↗
PubMed1968

Investigations on vitamin D esters synthesized in rats. Turnover and sites of synthesis.

1. The tissue contents of vitamin D alcohol and ester were estimated in rats 5, 10, 24, 48 and 72hr. after peroral administration of [1-(3)H]cholecalciferol. 2. The total vitamin D in liver decreased in an exponential fashion from 19% of the dose at 5hr. to 0.6% at 72hr., but the ester content remained at a relatively constant low value from 5hr., so that by 72hr. it represented 67% of the total vitamin D. Vitamin D ester in kidney increased slowly to 48hr., but by 72hr. it was only 10% of the total vitamin D. 3. The small intestine, unlike liver and kidney, contained a higher content of vitamin D ester 10hr. after administration than at later times, and it is postulated that some vitamin D was esterified during absorption from the alimentary tract. 4. Plasma contained vitamin D ester at all time intervals, and it is suggested that ester found in liver and kidney could have been transported to these sites in the blood. 5. Thoracic-duct lymph was found to transport 43% of a peroral dose of vitamin D in 12hr., of which 1.4% was esterified. The fatty acid components of the lymph vitamin D ester, determined by two-dimensional thinlayer chromatography, were mainly palmitate (31%), stearate (25%), oleate (16%) and linoleate (16%). This pattern was similar to that previously found in liver.

Animals↗