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PubMed1991

Cholecalciferol metabolites attenuate cAMP production in rat thyroid cells (FRTL-5).

A rat thyroid cell line (FRTL-5) was used to study the effect of cholecalciferols on cAMP production. The active cholecalciferol metabolite, calcitriol, caused a reduction in basal and thyrotropin (TSH)-stimulated cAMP production. The inhibitory effects were demonstrated after 1 and 2 days, respectively. The maximum effect on both basal and TSH-stimulated cAMP production was observed after 3-4 days of treatment. The effect was detectable at 10(-10) and maximal at 10(-8) mol/l. Calcitriol was about 300 times more potent than calcidiol in attenuating cAMP production, whereas (24R)-hydroxycalcidiol in concentrations up to 3 x 10(-8) mol/l had no effect. After removal of added calcitriol the cAMP response to TSH returned to normal within 8 days. Calcitriol (10(-8) mol/l) also inhibited cell growth. Our results show that calcitriol at physiological concentrations inhibits both basal and TSH-stimulated cAMP production in rat thyroid cells. This indicates that calcitriol may modulate the effect of TSH on thyroid function and growth.

Adenylyl Cyclases↗

PubMed1978

Kinetics of liver microsomal cholecalciferol 25-hydroxylase in vitamin D-depleted and -repleated rats.

Kinetics of vitamin D-depleted and -repleted rat liver microsomal cholecalciferol 25-hydroxylase were studied. Anaerobiosis, CO, omission of a NADPH-generating system and addition of detergents all decreased the activities, showing that the hydroxylase behaves like a cytochrome P-450-dependent enzyme. An apparent Km of 0.18 micrometer and Vmax. of 32pmol/min per g of tissue were found for vitamin D-deficient animals. Although both apparent Km and Vmax. were significantly altered in vitamin D-repleted animals no inhibition of the enzyme was elicited. These latter results show that at normal vitamin D intake, rat liver cholecalciferol 25-hydroxylase is not feedback-inhibited.

Anaerobiosis↗

PubMed1986

Interrelationships in rats of tissue pools of cholecalciferol and 25-hydroxycholecalciferol formed in u.v. light.

Vitamin D-deficient rats were irradiated with u.v. light three times weekly for 30 min for several weeks. D3 (cholecalciferol) and 25(OH)D3 (25-hydroxycholecalciferol) concentrations in skin, plasma, muscle and adipose tissue were measured. In other experiments, isolated skin or the whole animal was irradiated once and the cholecalciferol response monitored. Only a small fraction of the 7-dehydrocholesterol in skin is converted into D3 (less than 2%), and the presence of fur decreases the proportion converted into 20% of that occurring in shaved rat skin. D3 formed in the skin disappears relatively slowly, so that about 90% has gone after 7 days. In normal rats 10 micrograms of D3 formed over 2 h irradiation only caused a small rise in plasma D3 concentration over the following week, indicative of a high rate of clearance from this tissue. Irradiation of vitamin D-deficient rats for a prolonged period raised plasma D3 and 25(OH)D3 concentrations to a constant value. D3, but not 25(OH)D3, could be found in adipose tissue and muscle. Prolonged irradiation of normal rats showed these tissues and plasma could hold very large amounts of D3. Pharmacokinetic analysis of the changes in D3 concentration in rats showed that the disposition kinetics of D3 was explained by a two-compartment model with half-lives of 13.8 and 7.7 days. The volume of distribution of the more-slowly-turning-over compartment was 500 ml, which presumably reflects the large amounts of D3 that can accumulate in adipose tissue. Rat skin can synthesize about 0.85 ng of D3/mJ of u.v. light energy, but it seems that not all this is available to the rat. Adipose-tissue D3 is available for use by the rat, the t1/2 being 12.0 days.

Adipose Tissue↗

PubMed1975

The effects of a diphosphonate and dietary calcium on the metabolism of vitamin D3 (cholecalciferol) in the chick.

1. Vitamin D-deficient chicks, maintained on a diet adequate in calcium and treated with ethane-1-hydroxy-1,1-diphosphonate for 2 days before a single oral dose of cholecalciferol (vitamin D3), converted the vitamin into 24,25-dihydroxycholecalciferol instead of into the normal metabolite 1,25-dihydroxycholecalciferol. 2. This inhibition of the renal 1-hydroxylase disappeared on withdrawal of the diphosphonate. 3. Kidneys from chicks given diphosphonate for 12 days converted 25-hydroxycholecalciferol into 24,25-dihydroxycholecalciferol on incubation in vitro. 4. The inhibition of the 1-hydroxylase was markedly accelerated by treating the birds with cholecalciferol. 5. No inhibition of renal 1-hydroxylation was observed in birds maintained on a diet low in calcium. 6. A possible mechanism producing this effect is discussed.

Animals↗

PubMed1980

The metabolism of a physiological dose of radioactive cholecalciferol (vitamin D3) to its hydroxylated metabolites in man.

1. The metabolism of an intravenous pulse-dose of 65 nmol (25 microgram) of double-isotope-labelled cholecalciferol has been studied in 28 individuals. The subjects comprised 19 with serum concentrations of 25-hydroxycalciferol (25-(OH)D) less than or equal to 25 nmol/l, of whom 12 had clinical osteomalacia, and nine with serum 25-(OH)D > 25 nmol/l (30-125 nmol/l). 2. The concentrations in serum of radioactive cholecalciferol, 25-hydroxycholecalciferol (25-(OH)D3) and the three dihydroxylated metabolites: 1,25-, 24,25- and 25,26-dihydroxycholecalciferol (1,25-(OH)2D3, 24,25-(OH)2D3 and 25,26-(OH)2D3) were measured for up to 10 days after the injection. 3. The temporal relationships between the formation of individual radioactive metabolites and factors apparently influencing their production are described and their molar concentrations in serum calculated. 4. Formation of radioactive 1,25-(OH)2D3 was detectable only in vitamin D-deficient subjects. Between individuals, its maximum serum concentration was correlated significantly and inversely with serum calcium but with not other measured variable. In the individual, concentrations of radioactive serum 1,25-(OH)2D3 varied directly with radioactive serum 25-(OH)D3. 5. The failure to detect formation of radioactive 1,25-(OH)2D3 in vitamin D-replete subjects suggests that current estimates of the daily turnover of the hormone in the normal individual may be severalfold too high. 6. Radioactive 25,26-(OH)2D3 was produced rapidly by all subjects and in greater amounts by vitamin D-deficient individuals. Between subjects and in the individual its concentration in serum correlated only with the radioactive serum 25-(OH)D3. Production of this metabolite appeared to be unregulated and dependent solely on the concentration of its precursor. 7. In vitamin D-replete subjects, production of 24,25-(OH)2D3 was also apparently determined by precursor concentration. In vitamin D-depleted subjects, production of radioactive 24,25-(OH)2D3 was variably delayed for up to or more than 10 days. 8. There appeared to be a constraint on the quantitative hepatic production of 25-(OH)D which is not explained by simple feed-back inhibition. 9. If sterols other than 1,25-(OH)2D3 are required to initiate the mineralization of osteomalacic bone, after correction of vitamin D deficiency in man, 25-(OH)D3 and 25,26-(OH)2D3 are produced sufficiently rapidly to meet this hypothetical requirement, but not 24,25-(OH)2D3.

Cholecalciferol↗

PubMed1996

Changes in vitamin-D metabolites and parathyroid hormone in plasma following cholecalciferol administration to pre- and postmenopausal women in the Netherlands in early spring and to postmenopausal women in Curaçao.

To study the effect on plasma 25-hydroxycholecalciferol (25(OH)D), 1,25-dihydroxycholecalciferol (1,25(OH)2D) and parathyroid hormone (PTH) we supplemented premenopausal (aged 30 (SD 7) years) and postmenopausal (aged 61 (SD 2) years) white women living in The Netherlands in late winter/early spring, and elderly black and white women (aged 75 (SD 6) years) living in Curaçao (Dutch Antilles) with either 10 or 20 micrograms cholecalciferol/d for 4, 5 and 9 weeks respectively. Baseline plasma 25(OH)D concentration of Dutch women was lower than that of Curaçao women. Postmenopausal Dutch women had a higher PTH concentration in plasma than premenopausal Dutch and postmenopausal Curaçao women. There were no differences in plasma 1,25(OH)2D. Cholecalciferol administration increased 25(OH)D in all groups, 1,25(OH)2D in postmenopausal Curaçao women and PTH in postmenopausal Curaçao women and premenopausal Dutch women. Serum and urinary Ca and phosphate concentrations did not change. There were no response differences between 10 and 20 microgram doses. Oral cholecalciferol administration (either 10 or 20 micrograms/d) to women living at northern latitudes in late winter/early spring increased 25(OH)D levels to the baseline levels of elderly people living in the tropics.

Administration, Oral↗

PubMed1976

Effects of ergosterol on bone mineralisation in chicks given cholecalciferol or ergocalciferol.

Groups of chicks were given diets containing cholecalciferol or ergocalciferol supplemented with 0, 0-1, 1 or 10 g ergosterol/kg. 2. Ergosterol had no significant effect on growth, on the plasma concentration of calcium or on the content of bone-ash, indicating that it did not impair the absorption of either form of vitamin D. 3. An explanation is given for the apparent disagreement in the published findings on the relative anti-rachitic potencies of ergocalciferol and cholecalciferol in the chick.

Animals↗

PubMed1977

Chick brain calcium binding protein: response to cholecalciferol and some developmental aspects.

Following oral administration of 3H-cholecalciferol to rachitic chicks, the radioactive metabolites found in brain tissues were separated by Sephadex LH-20 chromatography. The parent vitamins and two biologically important metabolites, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol were detected in the brain, although at relatively low levels. A comparison with other tissues suggested the brain was much less permeable to the vitamin D steroids than were other tissues. However, chronic cholecalciferol administration for 4 weeks to severely vitamin D deficient chicks elicited a significant increase in the cerebellar content of a calcium-binding protein (CaBP). The lowest level administered, 2 IU/day (130 pmole), increased the CaBP content by more than 50%, while 16 IU/day (1.04 nmole) doubled the CaBP content. Chick brain CaBP has the same physical characteristics and is immunologically identical to the vitamin D-induced CaBP present in chick intestine, it differs in that single acute doses of vitamin D do not increase the content of brain CaBP while intestinal CaBP synthesis is stimulated significantly. The time course of appearance and content of brain CaBP in embryonic chicks was monitored. It was first detectable in the brain at day 15 of incubation and increased to a near post-hatch level by day 20. It differed in its initial time of appearance from both kidney CaBP which first appears at day 10 and intestinal CaBP which is not detectable until hatch day.

Animals↗

PubMed1990

Influence of dietary calcium and cholecalciferol on composition of plasma lipids in young pigs.

Young growing pigs were fed diets containing either 1 or 3 times the daily requirement of calcium and 1, 5 or 25 times the daily requirement of vitamin D (as cholecalciferol) in a completely randomized design with treatments in a 2 X 3 factorial arrangement. Excess dietary calcium increased the phospholipid concentration in the plasma, but not its partitioning among plasma lipoproteins. The level of dietary calcium had no effect on cholesterol, triacylglycerol or protein concentrations in plasma or their partitioning among plasma lipoproteins. Excess dietary calcium decreased body weight gains of pigs. The level of dietary cholecalciferol had no effect on body weight gain or on the concentrations of cholesterol, phospholipid, triacylglycerol or protein in plasma, or on their partitioning among plasma lipoproteins. Increased vitamin D intake resulted in increased plasma 25-hydroxycholecalciferol, whereas high dietary calcium decreased concentrations of 1,25-dihydroxy-vitamin D. Increased dietary calcium also increased plasma calcium concentrations of only plasma phospholipids and decreased growth rate, whereas excess dietary vitamin D had no effect on growth or lipid composition of plasma in growing pigs.

Animals↗

PubMed1998

Effects of different levels of vitamins A and E on the utilization of cholecalciferol by broiler chickens.

Three experiments were conducted to determine the effects of high dietary levels of vitamins A and E on the utilization of cholecalciferol by broiler chicks. In Experiment 1, chicks were fed six levels of vitamin A (5,000, 10,000, 20,000, 40,000, 80,000, and 160,000 IU/kg). Cholecalciferol (vitamin D3) was not added to the basal diet but all birds were exposed to ultraviolet (UV) fluorescent light. Body weight was decreased only at levels of vitamin A of 80,000 IU/kg or above. In Experiment 2, birds were exposed to UV fluorescent light or no UV light, two levels of dietary vitamin A (1,500 and 45,000 IU/kg) and three levels of dietary vitamin D3 (0, 500, and 2,500 IU/kg) in a 2 x 2 x 3 factorial arrangement. The high level of vitamin A reduced (P < 0.001) bone ash but only at a marginal level of vitamin D3 (500 IU/kg) and when the birds were not exposed to UV light. In Experiment 3, birds were exposed to UV fluorescent light or no UV light, two levels of dietary vitamin E (10 and 10,000 IU/kg) and three levels of dietary vitamin D3 (0; 500 and 2,500 IU/ kg) in a 2 x 2 x 3 factorial arrangement. The high level of vitamin E significantly (P < 0.05) reduced body weight, bone ash, plasma calcium, and increased rickets but only at 500 IU/kg of vitamin D3. Feeding 2,500 IU/kg of vitamin D3 overcame the effects of the high level of vitamin E, causing a significant (P < 0.05) interaction. Ultraviolet light also prevented the detrimental effects of the high level of vitamin E. The results of these studies indicate that high dietary levels of vitamins A and E negatively affected the utilization of vitamin D3 only when D3 was present at a marginal level (500 IU/kg) in the diet but not when it was synthesized in the bird by exposure to UV light or supplemented at 2,500 IU/kg in the diet.

Animals↗

PubMed1979

Metabolism of intravenously administered cholecalciferol in man.

Following intravenous injection of (3H) cholecalciferol into healthy subjects the disappearance of label from the plasma was followed by the reappearance ("rebound") of (3H) radioactivity associated exclusively with cholecalciferol. Lipoprotein fractionation of plasma revealed an increasing association of label with protein rather than lipoprotein during the rebound phase. We conclude that the rebound of plasma radioactivity reflects the transfer of label from lipoprotein to Vitamin D-binding globulin in the liver followed by its release into plasma.

Adolescent↗

PubMed1986

Nuclear uptake of 1,25-dihydroxy[3H]-cholecalciferol in peripheral blood monocytes.

The active vitamin D metabolite, 1,25-dihydroxycholecalciferol induces differentiation of monocytes into macrophages. The pharmacological induction of differentiation of primitive, rapidly proliferating cell lines into more mature cells with lower proliferative potential is a new dimension in the treatment of myeloproliferative disorders, which may prove to be an important alternative to more traditional regimens. Furthermore, the cell primarily engaged in bone resorption--the osteoclast--represents another differentiated form of mononuclear phagocytes, and 1,25-dihydroxycholecalciferol increases the number of osteoclasts. Since the cellular action of 1,25-dihydroxycholecalciferol is exerted mainly through its binding to nuclear receptors, a detailed knowledge of ligand-receptor interactions is mandatory for future work in this area. In order to investigate the interaction between 1,25-dihydroxycholecalciferol and its receptor in mononuclear cells, the nuclear uptake of the hormone was studied using a whole cell assay. The nuclear uptake of 1,25-dihydroxy[3H]cholecalciferol in human monocytes at physiological temperature and pH was saturable, specific, and fully reversible. When eight normal individuals were investigated, the maximal binding capacity (Bmax) was 0.4-8.4 fmol/10(6) cells and the dissociation constants (Kd) were 0.12-0.45 nmol/l. The characterization of the nuclear uptake of 1,25-dihydroxy[3H]cholecalciferol in intact human monocytes shows that it is mediated by binding of the ligand to a specific nuclear receptor. The binding to the nuclear receptor is the result of the passage of ligand across the cytoplasmic membrane and of the cytoplasmic transport of ligand. In contrast to conventional receptor assays in hypertonic cellular extracts, this system provides information on the role of the cytoplasmic membrane in relation to the nuclear uptake of 1,25-dihydroxycholecalciferol, which may be closer to in vivo cellular conditions.

Binding, Competitive↗

PubMed1976

The effect of parathyroidectomy and large doses of cholecalciferol on the ability of rats to adapt to changes in dietary intake of calcium.

1. Adaptation to different dietary levels of calcium was produced by feeding a low (0-2%) calcium diet or one of two high (1-6 or 0-8%) calcium diets for 4 or 6 weeks. Adaptive changes in true and apparent absorption of calcium, apparent absorption of phosphate and urinary excretion of calcium, were observed. 2. Parathyroidectomy performed prior to adaptation did not greatly impair the ability of rats to adapt to different levels of calcium in the diet. The response of the rats to parathyroidectomy was affected by their subsequent dietary history. 3. Six weeks after parathyroidectomy the plasma calcium was significantly higher than it had been immediately post-operatively. This rise in plasma calcium was seen in the rats adapted to the 1-6% calcium diet but not in those adapted to the 0-2% calcium diet. 4. Parathyroidectomy performed after adaptation had taken place did not abolish the adaptive changes. The response of rats to parathyroidectomy was affected by their previous dietary history. 5. Large doses of cholecalciferol given for 8 days after adaptation had taken place increased the absorption of calcium in rats adapted to the 0-8% calcium diet thereby abolishing or reducing the adaptive differences in absorption between these rats and rats adapted to the 0-2% calcium diet. The cholecalciferol increased urinary calcium excretion but did not abolish adaptive differences in urinary excretion of calcium between rats adapted to diets with different calcium levels. 6. It is concluded that parathyroid hormone does not play a major role in mediating adaptation to different dietary intakes of calcium. The possible role of 1-25 dihydroxycholecalciferol is discussed.

Adaptation, Physiological↗

PubMed1982

Studies of the effects of cholecalciferol upon the metabolism of rachitic chick growth cartilage.

When a physiological dose of cholecalciferol was given to rachitic chicks, an early response was increased amino acid incorporation into growth cartilage protein, including collagen, but no evidence was found for induction of specific protein synthesis as in the intestine. Increased release into the medium of 45Ca and of hydroxyproline was observed when growth cartilage tissue was incubated in medium containing 1,25-dihydroxycholecalciferol. These studies suggest that the metabolism of cartilage tissue from the zones of proliferation and maturation was more affected than tissue from the zones of hypertrophy and calcification. Cholecalciferol metabolites may therefore have a direct effect upon chondrocytes as well as on bone cells during endochondral bone formation.

Animals↗

PubMed1986

Stimulation of melanogenesis by cholecalciferol in cultured human melanocytes: a possible mechanism underlying pigmentation after ultraviolet irradiation.

An increase in the amount of tyrosinase was demonstrated in the cultured human melanocyte after 6-day culturing with cholecalciferol (vitamin D3) by increased intensity of the immunofluorescent staining using monoclonal antibody against tyrosinase. Furthermore, the melanocytes became more dendritic as noted in those in the skin after the irradiation of ultraviolet. However, 7-dehydrocholesterol (pro-vitamin D3) or 1 alpha, 25-dihydroxy-vitamin D3 (activated vitamin D3) did not induce any such effect on the cultured human melanocytes. Since cholecalciferol is known to be photo-chemically converted by the ultraviolet irradiation from pro-vitamin D3 produced in the skin, the so-far-unknown mechanism of human skin pigmentation after the ultraviolet irradiation may be partly explained by this stimulating effect of vitamin D3 on the melanocytes.

Cells, Cultured↗

PubMed2000

Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis in dogs.

OBJECTIVE: To determine whether pamidronate disodium can reduce cholecalciferol-induced toxicosis in a dose-related manner. ANIMALS: 20 clinically normal, 8- to 12-month-old male Beagles. PROCEDURE: All dogs were given 8 mg of cholecalciferol (CCF)/kg of body weight once orally, then were randomly assigned to 4 groups of 5 dogs each. Dogs were treated with IV administration of 0.9% NaCl solution (SC group), 0.65 mg of pamidronate/kg in 0.9% NaCl solution (LP group), 1.3 mg of pamidronate/kg in 0.9% NaCl solution (MP group), or 2.0 mg of pamidronate/kg in 0.9% NaCl solution (HP group) on days 1 and 4 after administration of CCF. Dogs were observed for 14 days, and serial blood samples were collected for serum biochemical, electrolyte, and 25-hydroxyvitamin D3 analyses. Urine samples were collected for determination of specific gravity. Glomerular filtration rate (GFR) was determined by plasma iohexol clearance. Histologic examination of renal tissue was performed. RESULTS: One dog in the SC group was euthanatized 3 days after administration of CCF because of severe clinical signs of toxicosis. Dogs in the HP group had significantly higher mean GFR (day 3), serum potassium concentrations (day 14), and urine specific gravity (days 7 and 14) and significantly lower mean serum creatinine concentrations and total calcium X phosphorus concentration product (days 4 and 7) than dogs in the SC group. Dogs in the HP group had no abnormal findings on histologic examination of renal tissue, dogs in the LP and MP groups had trace to mild mineralization of renal tissue, and dogs in the SC group had moderate mineralization and cellular necrosis of proximal renal tubules. CONCLUSIONS AND CLINICAL RELEVANCE: Pamidronate disodium is a potentially useful drug to reduce CCF-induced toxicosis and other causes of hypercalcemia associated with increased bone resorption in dogs.

Animals↗

PubMed1980

Fate of isotopically labeled cholecalciferol and 25-hydroxycholecalciferol in sheep.

The fate of tritiated 25-hydroxycholecalciferol administered intramuscularly is compared in two groups of sheep raised either in confinement or outdoors. The uptake of radioactivity was more rapid by the indoor than the outdoor sheep. The assessment of radioactivity in plasma and tissues of outdoor sheep dosed with either tritiated 25-hydroxycholecalciferol or with equivalent amounts of tritiated cholecalciferol revealed that plasma and tissue radioactivity were substantially higher in sheep dosed with tritiated 25-hydroxycholecalciferol than in sheep dosed with tritiated cholecaliferol. Three days after the administration of tritiated cholecalciferol virtually all plasma radioactivity was associated with 25-hydroxycholecalciferol.

Animals↗

PubMed1994

The relationship of egg cholesterol to serum cholesterol, serum calcium, feed consumption, and dietary cholecalciferol.

Hy-Line W36 hens, 20 wk of age, were randomly assigned to one of three dietary treatments consisting of cholecalciferol at (0, 550, or 2,750 IU/kg of finished feed). Serum calcium and cholesterol, yolk cholesterol, and egg specific gravity were measured. Feed consumption, egg production, and egg weight measurements were also recorded. Feed consumption, egg production, and egg weights were initially reduced when cholecalciferol was omitted from the diet. These effects disappeared by the beginning of the fourth 28-d period. Egg cholesterol concentrations among treatments followed no consistent pattern. A positive correlation was noted between serum calcium and serum cholesterol.

Animals↗