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PubMed1974

Intranuclear localization and receptor proteins for 1,25-dihydroxycholecalciferol in chick intestine.

1. The intranuclear distribution of cholecalciferol and its metabolites was studied in the intestine of rachitic chicks. 2. At high doses of cholecalciferol the nuclei contain the vitamin and its 25-hydroxy metabolite, but over 80% of this is localized on the nuclear membranes. The hormone, 1,25-dihydroxycholecalciferol, is found within the cell nuclei irrespective of the intake of cholecalciferol, but significant amounts could not be found with chromatin isolated free of nuclear membranes. 3. 1,25-Dihydroxycholecalciferol is associated in the nucleus with an acidic protein. Since one of the actions of 1,25-dihydroxycholecalciferol is to control the synthesis of mRNA for calcium-binding protein it was to be expected that the hormone would be bound to chromatin, as with the other steroid hormones. It is suggested that the hormone-receptor complex exists as part of an equilibrium mixture of the complex bound to the DNA and in a free form. 4. A protein extract of nuclei was obtained, which when incubated at 4 degrees C for 1h took up the 1,25-dihydroxycholecalciferol. The nature of this binding was studied. 5. There appear to be two nuclear proteins able to bind the hormone one of which is the intestinal nuclear receptor. The binding sites on this protein are saturable with the hormone, have an association constant of 2x10(9)m(-1) and show a high chemical specificity for the 1,25-dihydroxycholecalciferol. The number of nuclear binding sites for the hormone provided by this receptor is similar to the maximum intestinal hormone concentration so far observed. Its sedimentation coefficient is 3.5S, and is very close to that observed for the nuclear protein to which is attached the 1,25-dihydroxycholecalciferol formed in vivo from vitamin D. 6. The cytoplasmic protein has an association constant of 1x10(9)m(-1)and a sedimentation coefficient of 3.0S, but its relation with the nuclear receptor is not yet clear.

Animals↗
PubMed1975

Vitamin D metabolism and parathyroid function in man.

1. The metabolism of an intravenous pulse dose of double-isotope-labelled cholecalciferol has been studied in control subjects with widely differing states of vitamin D nutrition and in patients with primary disorders of parathyroid function. 2. The formation of labelled 1,25-dihydroxy-cholecalciferol [1,25-(OH)2D3] and labelled 24,25-dihydroxycholecalciferol [24,25-(OH)2D3] has been related to the prevailing concentrations in serum of 25-hydroxycholecalciferol [25-(OH)D3], immunoreactive parathyroid hormonel, calcium and orthophosphate (Pi). 3. In control subjects with relative vitamin D deficiency [serum 25-(OH)2D3 was related inversely to the serum 25-(OH)D3 and serum calcium, and directly to serum immunoreactive parathyroid hormone. No formation of 1,25-(OH)2D3 was detectable to form labelled 24,25(OH)2D3 preferentially. 4. No control subject produced significant amounts of both labelled 1,25-(OH)2D3 and labelled 24,25-(OH)2D3 simultaneously. 5. All subjects with primary hyperparathyroidism produced significant amounts of labelled 1,25-(OH)2D3 and labelled 24,25-(OH)2D3 simultaneously; the renal turnover of 25-(OH)D3 was apparently greater than in nutritionally matched controls. Serum labelled 1,25-(OH)2D3 in this disease was not correlated with serum 25-(OH)D3, immunoreactive parathyroid hormone, calcium or Pi. Production of labelled 24,25-(OH)2D3 was inappropriately high for the prevailing nutritional state. 6. The indirectly estimated their concentration of 1,25-(OH)2D3 showed only a fourfold variation in control subjects (45-180 pmol/l), compatible with its having a regulated hormonal function. 7. The data suggest that the production of 1,25-(OH)2D3 from a pulse dose of cholecalciferol is normally regulated, directly or indirectly, by the parathyroid hormone.

Adult↗
PubMed1973

Biological activity of 1alpha-hydroxycholecalciferol, a synthetic analog of the hormonal form of vitamin D3.

1,25-Dihydroxycholecalciferol, the apparent active hormonal form of cholecalciferol (vitamin D(2)), is formed from cholecalciferol by specific and sequential hydroxylations of the sterol at carbons 25 and 1. Recently, 1alpha-hydroxycholecalciferol was synthesized and we report on its biological activity in rachitic chicks. 1alpha-Hydroxycholecalciferol is identical in potency to 1,25-dihydroxycholecalciferol in stimulation of intestinal calcium absorption; either sterol elicits a near maximal effect at a dose of 0.3-0.6 nmol. The time-course of action of 1alpha-hydroxycholecalciferol also parallels that of the active metabolite 1,25-dihydroxycholecalciferol with a maximal increase in calcium transport occurring 5-10 hr after administration of sterol to vitamin D-deficient chicks. 6.5 nmol of 1alpha-hydroxycholecalciferol causes a doubling in calcium absorption in only 2-3 hr, which is the most rapid physiologic response yet detected for a vitamin D-sterol. 1alpha-Hydroxycholecalciferol is active also in enhancing bone calcium resorption and, like 1,25-dihydroxycholecalciferol, is at least 10 times as active as cholecalciferol in mobilizing bone calcium and raising plasma calcium concentration. It is concluded that 1alpha-hydroxycholecalciferol represents a synthetic analog of 1,25-dihydroxycholecalciferol that can be used both to study the mechanism of action of this hormone and as a therapeutic agent in the treatment of patients with certain metabolic bone diseases.

Animals↗
PubMed1997

Effect of vitamin D deficiency on lipid composition and calcium transport in basolateral membrane vesicles from chick intestine.

Vitamin D deficiency affects the lipid composition and Ca2+ uptake of intestinal basolateral membranes from chick intestine. The increased cholesterol content causes an increase in the molar ratio cholesterol/phospholipid. Phospholipid classes remain unchanged, but the percentages of arachidonic acid from the from the major phospholipid fractions are increased. After 24 hours of oral administration of 2,000 IU of cholecalciferol to vitamin D-deficient chicks, the cholesterol values do not change, but the amount of arachidonic acid returns to normal values. Ca2+ uptake driven by ATP is diminished in vesicles from intestinal basolateral membranes of vitamin D-deficient chicks. Cholecalciferol treatment returns these values to the controls which might be due mainly to the increased number of Ca2+ pump units. In conclusion, changes in lipid composition and in Ca2+ pump caused by vitamin D deficiency seems to play a role in the decrease of vesicular Ca2+ transport. A single dose of cholecalciferol restores only partially the lipid-protein changes produced by vitamin D deficiency.

Adenosine Triphosphate↗
PubMed1976

Regulation of intestinal calcium absorption in the laying quail: independent of kidney vitamin D hydroxylation.

Two experiments were carried out with laying quail (Coturnix coturnix japonica) fed either cholecalciferol (40 mug/kg) or 1 alpha-hydroxycholecalciferol (8 mug/kg). Recovery following vitamin D depletion, as indicated by egg production and shell deposition, was faster in quail fed 1 alpha-hydroxycholecalciferol than in those fed cholecalciferol. Overall intestinal calcium absorption was higher in the 1 alpha-hydroxycholecalciferol-fed quail due to a higher absorption in the middle parts of the small intestine. This was associated with corresponding differences in the concentration of calcium binding protein. Intestinal calcium absorption was markedly higher during periods of shell formation than during periods of uterine inactivity in quail fed either cholecalciferol or 1 alpha-hydroxycholecalciferol. It is suggested, therefore, that the mechanism responsible for this difference is independent of vitamin D hydroxylation in the kidney.

Animals↗
PubMed1984

Effect of sow vitamin D status at parturition on the vitamin D status of neonatal piglets.

The plasma concentrations of calcium, phosphorus, vitamin D, and vitamin D metabolites were determined in cholecalciferol-treated sows and untreated sows at parturition and their piglets (at birth and at 10 days of age) to determine the relationship between sow vitamin D status and neonatal piglet vitamin D status. At birth, there was a high degree of correlation between sow and piglet plasma concentrations of 25-hydroxycholecalciferol (r = 0.944), 24,25-dihydroxycholecalciferol (r = 0.895), and 25,26-dihydroxycholecalciferol (r = 0.737). Neonatal piglet plasma 1,25-dihydroxyvitamin D was low (42.0 +/- 10.2 pg/ml) and was not correlated with maternal plasma 1,25-dihydroxyvitamin D (r = 0.022). Neonatal plasma calcium and phosphorus were significantly correlated (P less than 0.05) with maternal plasma 1,25-dihydroxyvitamin D (r = 0.515 and 0.581, respectively). Parenteral cholecalciferol treatment of sows before parturition proved an effective means of supplementing young piglets with cholecalciferol (via the sow's milk) and its more polar metabolites via placental transport. However, it had no significant effect on either the plasma mineral or 1,25-dihydroxyvitamin D status of the sow or young piglet.

Aging↗
PubMed1990

Efficacy of several vitamin D compounds in the prevention of tibial dyschondroplasia in broiler chickens.

Studies were conducted to evaluate several cholecalciferol (D3 metabolites: 1,25-dihydroxycholecalciferol [1,25-(OH)2D3], 1,24R,25-trihydroxycholecalciferol [1,24R,25-(OH)3D3], 1 alpha-hydroxy-cholecalciferol (1 alpha-OHD3), 24R,25-dihydroxycholecalciferol [24R,25-(OH)2D3], 1,25-dihydroxy-26,27 hexadeuterium cholecalciferol (1,25-(OH)2-26,27[2H]6D3) and 1,25-dihydroxy-24R-fluorocholecalciferol [1,25-(OH)2-24R-FD3] for their activity in preventing the development of tibial dyschondroplasia in broilers. The basal diet used is low in calcium, high in phosphorus and chlorine and is known to promote a high incidence of tibial dyschondroplasia. The chicks received ultraviolet radiation from fluorescent lights in addition to 1100 ICU/kg (27.5 micrograms/kg) of D3 in the basal diet. Supplementation of the diet with 10 micrograms/kg of all the metabolites except 24R,25-(OH)2D3 significantly lowered the incidence and severity of tibial dyschondroplasia and increased bone ash when compared to birds receiving the basal diet. None of the active D3 metabolites was effective when fed at 0.1 or 1.0 micrograms/kg of diet. Two active compounds tested [1,25-(OH)2D3 and 1,24R,25-(OH)3D3] at 5 micrograms/kg of diet were effective in reducing either the incidence or severity of tibial dyschondroplasia.

24,25-Dihydroxyvitamin D 3↗
PubMed1971

1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine.

The major polar metabolite of cholecalciferol (vitamin D(3)) present in chick intestinal mucosa has been chemically characterized by mass spectrometric analysis to have a molecular formula of C(27)H(44)0(3) and a structure of 1,25-dihydroxycholecalciferol. This compound, which is produced in the kidney from 25-hydroxycholecalciferol, has been previously shown to be from 4 to 13 times as active as cholecalciferol in stimulating intestinal calcium transport. 1,25-Dihydroxycholecalciferol (previously designated metabolite 4B in this (laboratory) probably represents the biologically active form of cholecalciferol in the intestine.

Age Factors↗
PubMed1978

Abnormal vitamin D metabolism in cirrhosis.

Vitamin D metabolism was investigated in 10 patients with cirrhosis. Mean plasma 25 hydroxycholecalciferol (25 OHD) centration in alcoholic cirrhosis was lower than in controls but the difference was not significant. In three patients restudied after the summer, plasma 25 OHD had risen. In contrast to the finding in normal subjects, the half-life of intravenously administered 3H cholecalciferol was short in cirrhotics and showed no correlation with plasma 25 OHD. Furthermore, the appearance of 3H 25 OHD from 3H cholecalciferol was reduced compared to the control group four hours after injection. Increased rate of metabolism of cholecalciferol and deficient production of 25 ohd contribute to vitamin D deficiency in liver disease.

Adult↗
PubMed1972

Dihydrotachysterol: a calcium active steroid not dependent upon kidney metabolism.

The activity of dihydrotachysterol and cholecalciferol was determined in nephrectomized or sham-operated vitamin D-depleted rats using in vitro transport of calcium and phosphate by everted intestinal preparations as the index of physiologic response. The activity of dihydrotachysterol was not reduced by absence of the kidneys whereas that of cholecalciferol was markedly inhibited so that at least a 10-fold greater dose of the latter was necessary to produce an equivalent effect in the nephrectomized rat as in the control. Dihydrotachysterol is therefore equipotent with cholecalciferol in the anephric rat although much less active in the intact animal.

Animals↗
PubMed1977

Vitamin D binding factors in bovine blood.

Both 25 [25,26-hydrogen-3] hydroxycholecalciferol and [1alpha,2alpha-hydrogen-3] cholecalciferol were added to bovine plasma in vitro. Analysis by gel-filtration and ion exchange chromatography, electrophoresis, ultracentrifugation, competitive binding specificity studies, and plasma stripping showed that vitamin D circulated with a protein of alpha-globulin mobility. This globulin had a much higher affinity for 25-hydroxycholecalciferol while vitamin D3 appeared to be associated first with an alpha-lipoprotein and with time because associated with the alpha-globulin. This alpha-globulin had a molecular weight of approximately 70,000 as determined by gel-filtration. Cholecalciferol appeared to bind tightly to the alpha-lipoprotein and resisted being stripped from the plasma. Thus, alpha-globulin appears to be the major carrier of vitamin D in the blood while the alpha-lipoprotein may aid in the transfer of cholecalciferol from the gut to the liver via the lymph system.

Alpha-Globulins↗
PubMed1982

[Biochemical and ultrastructural research on the antagonism between vitamins A and D at the leve of the erythrocyte membrane].

The reason for the antagonistic action between retinol and cholecalciferol on cellular membranes was investigated "in vitro" on human erythrocytes, by testing their lipoperoxide production, the amount of membrane-bound retinol and the morphology of these cells by scanning electron microscope. Lipoperoxides were assayed by TBA-test; the membrane-bound retinol was tested by the Karr-Price method on lipids extracted from red blood cells by the Folch method and vitamin D-deprived by TCL chromatography; the morphological changes of these cells treated with vitamin A, or D, or A+D, were tested by scanning electron microscope. In our experimental system both retinol and cholecalciferol increase the lipoperoxide production from the erythrocytes; nevertheless no synergism of action can be demonstrated between the two vitamins. Cholecalciferol decreases the amount of membrane-bo und retinol as well as the changes produced by vitamin A in red blood cell surface. These results are in good agreement with our previous observations obtained by nuclear magnetic resonance, using the same experimental system.

Binding, Competitive↗
PubMed1983

[Vitamin D metabolism, regulation, function].

In a review of the literature metabolism, regulation and function of vitamin D and its active metabolites is discussed. Vitamin D is absorbed from the gut and produced in the skin. 25-hydroxylation takes place in the liver, producing 25-hydroxy-vitamin-D. This metabolite is transferred and hydroxylated in the kidney. The most potent cholecalciferol is 1,25-dihydroxy-vitamin-D. This hydroxylation process is regulated by the need of phosphorus and calcium and by calcicotropic hormones, e. g. parathyroid-hormone. The active cholecalciferols regulate intestinal, renal and osseous handling of calcium and phosphorus by binding to a specific receptor protein. Thus, the control of serum calcium and -phosphate homeostasis by cholecalciferols guarantees adequate supply of these substances for mineralisation. Accordingly, perinatal period and puberty is associated with a marked increase in active vitamin D metabolites.

Bone and Bones↗
PubMed1984

Inhibition by 1,25 dihydroxycholecalciferol of hormonal secretion of rat parathyroid gland in organ culture.

The effect of vitamin D metabolites on parathyroid hormone secretion was studied using rat parathyroid gland cultured in basal medium Eagle containing 5% serum obtained from thyroparathyroidectomized rat, 1 mM magnesium, and calcium concentration varying from 0.75-2.25 mM, and radioimmunoassay for rat parathyroid hormone (rPTH). 1.25 dihydroxycholecalciferol (1,25(OH)2D3), 5 X 10(-10)-2.5 X 10(-8) M, consistently decreased rPTH secretion in dose-related manner; the effect reached steady state after 24 h in vitro addition of 1,25(OH)2D3 and was also observed at different medium calcium concentrations (0.75, 1.25, 1.75 mM). Comparison of dose-responses for inhibitory activity of some vitamin D metabolites on rPTH secretion showed: 1,25(OH)2D3 = 1,24,25(OH)3D3 greater than 1 alpha OHD3 greater than 25 OHD3. Cholecalciferol (10(-5) M), 24,25-dihydroxy-cholecalciferol (10(-8)-10(-6) M) and 25,26-dihydroxy-cholecalciferol (5 X 10(-9)-5 X 10(-7) M) did not inhibit rPTH secretion. Analysis of structural activity relation of vitamin D metabolites studied indicated that 1 alpha or pseudo-1 alpha hydroxylated metabolites or analogs were active in inhibiting rPTH secretion, while, non-1 alpha hydroxylated metabolites were without or were weakly inhibitory only at very high concentrations. This study provides further evidence for a direct role of 1,25(OH)2D3 on a negative feedback loop for regulation of parathyroid gland function.

Animals↗
PubMed1975

The location of calcium during its transport by the small intestine of the chick.

During the in vivo absorption of Ca by chicks, cholecalciferol (vitamin D3) increased the translocation of Ca by the mucosal cells of the small intestine and this was accompanied by a greater "turnover" of Ca within these cells. The location of Ca within mucosal cells was studied by differential centrifugation after conventional homogenation of the cells in isotonic sucrose medium at 0 degrees. Most of the Ca was in mitochondria with less than 2% of Ca being in the soluble phase. However, this finding may be misleading since there may be a redistribution of Ca at 0 degrees, with the mitochondria taking up Ca which in vivo would be located in other parts of the cell. When cells were homogenized in the presence of inhibitors of Ca uptake by mitochondria or were homogenized at 22 degrees-28 degrees, 15-30% of the Ca was found in the soluble cytosol fraction. The uptake of Ca by mitochondria was compared in sucrose media and in this media containing dialysed cell cytosol. The non-dialysable substances in the cytosol influenced uptake and release of Ca by mitochondria so that more Ca would be in the soluble phase in the presence of cell cytosol. Dialysed cell cytosol from cholecalciferol-pretreated chicks had greater effect than cytosol from rachitic chicks and this may partially account for the increased translocation brought about by cholecalciferol.

Animals↗
PubMed1979

Salmon calcitonin-induced stimulation of 1 alpha,25-dihydroxycholecalciferol synthesis in rats involving a mechanism independent of adenosine 3':5'-cyclic monophosphate.

The effect of natural salmon calcitonin on accumulation in plasma of 1 alpha,25-dihydroxy-[3H]cholecalciferol from 25-hydroxy[3H]cholecalciferol in vivo was investigated in vitamin D-deficient thyroparathyroidectomized rats into which graded doses of the hormone were continuously infused by use of a balance study system. A dose-dependent increase in plasma concentrations of 1 alpha,25-dihydroxy[3H]cholecalciferol was observed with calcitonin infusion for 6--30h at a rate greater than 20 M.R.C. m-units/h. Infusion of parathyrin or cyclic AMP produced a similar stimulation [Horiuchi, Suda, Takahashi, Shimazawa & Ogata (1977) Endocrinoly 101, 969--974], but the maximal effect of calcitonin was additive to that of either parathyrin or cyclic AMP. Furthermore concurrent infusion of theophylline (0.5 mumol/h) did not potentiate the effect of submaximal doses (3 and 20 M.R.C. m-units/h) of calcitonin. Plasma concentrations of calcium showed a decrease with calcitonin infusion for 30h, but those of Pi remained unchanged. These results strongly suggest that the rat kidney is endowed with a calcitonin-sensitive 1 alpha-hydroxylase system that is separate from the parathyrin/cyclic AMP system and is independent of changes in plasma Pi.

Animals↗
PubMed1981

Ornithine decarboxylase activity in chick duodenum induced by 1 alpha, 25-dihydroxycholecalciferol.

The effect of cholecalciferol and its metabolites on ornithine decarboxylase activity was investigated in the duodenal mucosa of vitamin D-deficient chicks. The duodenal ornithine decarboxylase activity decreased in animals fed a vitamin D-deficient diet and its retarded activity was increased dose-dependently by a single injection of cholecalciferol. Among various metabolites of cholecalciferol tested, 1 alpha, 25-dihydroxycholecalciferol [ 1 alpha, 25 (OH)2D3] was the most potent stimulator. Stimulation of the enzyme activity was detected as early as 2h after intravenous administration of 1 alpha, 25 (OH)2D3 and a maximal value was attained at 6 h. The maximal value was 27 times higher than the control. In addition, treatment with 1 alpha 25 (OH)2D3 affected the duodenal content of polyamines. The content of putrescine increased to a value of three times that of the control 6 h after the hormone administration. The spermidine content did not change appreciably. The enhancement of duodenal ornithine decarboxylase activity by 1 alpha, 25 (OH)2D3 occurred in parallel with the enhancement of calcium absorption, which was first detected 3 h after the hormone administration. The enhancement appeared to be tissue-specific. It was observed in every intestinal segment, but was highest in the duodenum. Enzyme activity in other tissues was not influenced appreciably by 1 alpha, 25 (OH)2D3. These results clearly indicate that the duodenal biosynthesis of polyamines is regulated by 1 alpha, 25 (OH)2D3, suggesting the possibility that duodenal ornithine decarboxylase may be involved in the calcium absorption mechanism.

Animals↗
PubMed2000

Influence of vitamin D and retinoids on the induction of functional differentiation in vitro of canine osteosarcoma clonal cells.

The efficacy of 22-oxacalcitriol (OCT), calcitriol, cholecalciferol, all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) to differentiate in vitro four clonal cells of the canine osteosarcoma cell line POS into cells having properties of a functionally mature osteoblast bone cell were investigated. The induction of intracellular alkaline phosphatase (ALP) activity, osteocalcin (GLA-OC) and type I collagen (PIP) production after 72 h treatment were used as markers of differentiation. At a concentration of 10(-8)M, OCT and calcitriol significantly induced all markers, and ATRA only the ALP of osteoblast, chondroblast and undifferentiated clonal cells. At the same concentration, 9-cis RA and cholecalciferol induced ALP of chondroblast and osteoblast cells, respectively; ATRA, 9-cis RA and cholecalciferol induced PIP of chondroblast and undifferentiated cells. None of the drugs significantly differentiated fibroblast cells. The ability of these agents to differentiate osteosarcoma cells into cells that exhibit properties of functionally mature osteoblastic bone cells may promote normal osteogenesis and reverse the loss of control of their differentiation.

Alkaline Phosphatase↗