Circulating vitamin D metabolites in nephropathic cystinosis.
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Calcifediol↗
Biomedical subjects
H F DeLuca
Publications and source records attributed to H F DeLuca.
A microassay for mammalian renal 25-hydroxyvitamin D3-1-hydroxylase applicable to man.
A micro determination of the renal 25-hydroxyvitamin D3-1-hydroxylase activity was developed that uses as little as 1 mg of rat kidney tissue. The method was applied to the remaining portions of needle kidney biopsy specimens taken for diagnostic purposes from children who had asymptomatic proteinuria and/or hematuria (more than 1-year duration) but were otherwise normal in calcium metabolism and renal function. The 25-hydroxyvitamin D3-1-hydroxylase levels of these children were found to be 66 1,25-dihydroxyvitamin D3 per milligram of tissue per 20 min for an 11-year-old male, 117 pg for a 9-year-old male, and 89 pg for a 10-year-old female.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
Studies of bone tissue in rats treated by prednisolone and 1,25-(OH)2D3.
Adult male rats were treated for six weeks by prednisolone and/or 1,25-(OH)2D3 and given a diet containing either 0.5% calcium or 0.01% Ca and 0.6% phosphorus. Both prednisolone administration and a low-Ca diet were associated with a lower bone mass than that observed in control rats given a 0.5% Ca diet. The percentage of osteoid surface was decreased in rats given prednisolone; these rats also had a lower osteoclast number. The results were consistent with a lower bone turnover during prednisolone treatment. Administration of 1,25-(OH)2D3, resulting in a slightly higher mean level of 1,25-(OH)2D3 in serum, had a positive effect on bone mass, which may be related to increased osteoblastic activity; no increase in the osteoclast number occurred.
Animals↗
Stimulation of specific 1,25-dihydroxyvitamin D3 binding protein in cultured postnatal rat intestine by hydrocortisone.
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Aging↗
24-hydroxylation of 25-hydroxyvitamin D3: is it required for embryonic development in chicks?
As shown previously, laying hens given 1,25-dihydroxyvitamin D3 as their sole source of vitamin D produce fertile eggs having normal shells, but only 35 to 55 percent of the embryos are normal. Giving these hens additional 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D3, or 24,24-difluoro-25-hydroxyvitamin D3 at 1.25 nanomoles per day resulted in 90 to 100 percent normal embryos, and hence, hatchability. Since 24,24-difluoro-25-hydroxyvitamin D3 cannot be 24-hydroxylated, 24-hydroxylation is not required for this function of 25-hydroxyvitamin D3.
24,25-Dihydroxyvitamin D 3↗
Metabolism of retinoic acid in vivo in the vitamin A-deficient rat.
Sample preparation and high-pressure liquid-chromatography separation methods useful for the study of retinoic acid metabolism are reported. The sample preparation procedure does not cause significant degradation of retinoic acid, and the gradient high-pressure liquid-chromatography separation method gives excellent separation of the major metabolites of retinoic acid. These methods were used to examine the metabolites of retinoic acid in blood, trachea and lung, testes, kidneys and small intestine of vitamin A-deficient rats dosed subcutaneously with 2 micrograms of [11,12-3H] retinoic acid. At 6h after dosing, a total of eight metabolites of retinoic acid produced in vivo were found in the tissues examined. Of these, four were found in most of the epithelial tissues examined, and therefore may be of interest as possible active metabolites in the epithelial functions of vitamin A.
Animals↗
Biliary metabolites of all-trans-retinoic acid in the rat: isolation and identification of a novel polar metabolite.
The biliary metabolites from normal rats dosed with either pharmacological or physiological doses of all-trans-[11,12-3H2]retinoic acid were investigated. Biliary metabolites excreted during the first 24 h account for approximately 60-65% of the radiolabeled dose. A major polar metabolite was purified to homogeneity by using Sephadex LH-20 chromatography and several high-performance liquid chromatographic procedures. This metabolite was negatively charged as revealed by high-performance liquid chromatography on ion-exchange columns and accounts for 10% of the total biliary radioactivity (6% of the dose). The polar compound was positively identified by using Fourier transform proton nuclear magnetic resonance spectroscopy, high- and low-resolution mass spectrometry, fast atom bombardment mass spectrometry, ultraviolet absorption spectrophotometry, Fourier transform infrared spectroscopy, amino acid analysis, and chemical derivatization as 2-[8-[6-(hydroxymethyl)-2,6-dimethyl-3-oxo-1-cyclohexen-1-yl]-2,6- dimethyl-5,7-octadienamido]ethanesulfonic acid. The metabolic transformations required for the generation of this metabolite from all-trans-retinoic acid are the following: (1) allylic oxidation at carbon 4 of the cyclohexene ring to produce a 4-keto group, (2) hydroxylation of one of the methyl groups at carbon 1 of the cyclohexene ring, (3) saturation of the two terminal double bonds in the side chain, (4) loss of the terminal carboxyl group of the side chain via decarboxylation, and (5) conjugation of the resulting retinoid with taurine. To our knowledge, this metabolite represents the first taurine conjugate of a fat-soluble vitamin to be identified.
Amino Acids↗
Retinoic acid 5,6-epoxidase. Properties and biological significance.
A retinoic acid epoxidase is present in rat kidney homogenates. It is found in the particulate fraction, and is dependent on ATP, NADPH, and oxygen. It is stimulated by Fe2+ and inhibited by Mn2+, Zn2+, Cu2+, EDTA, and N,N'-diphenyl-para-phenylenediamine. Its properties are closest to those of microsomal lipid peroxidases previously studied. Epoxidase activity is not affected by the rat's vitamin A status, nor is it inducible by retinoic acid. In N,N'-diphenyl-para-phenylenediamine-feeding experiments, it was shown that blocking epoxidation in vivo does not inhibit the function of retinoic acid. It is concluded that retinoic acid epoxidation is not required for retinoic acid function.
Animals↗
Metabolites of all-trans-retinoic acid in bile: identification of all-trans- and 13-cis-retinoyl glucuronides.
The metabolites of all-trans-[3H]retinoic acid were studied in the rat bile. In the bile duct cannulated rat 80 to 86% of the dose is excreted into the bile within 24 h after the intravenous administration of either a physiological or pharmacological dose of all-trans-[3H]retinoic acid. Polar metabolites of retinoic acid predominate (73 to 96% of bile 3H) in the bile at all times; some free retinoic acid (0.2 to 4.8% of bile 3H) is excreted into the bile during the initial 6-h period after dosing. Retinoyl glucuronides are excreted into the bile for 12 h after dosing; their excretion is highest during the first 2 h. More retinoyl glucuronide is excreted from the pharmacological dose (10% of the radiolabel dose) than the physiological dose (4.4% of the dose) of all-trans-retinoic acid. The retinoyl glucuronides were separated and were shown to consist of all-trans- and 13-cis-retinoyl glucuronides in a ratio of 1.5 to 1.0. Since the starting material was 99% all-trans-retinoic acid and the methods used do not cause isomerization, it is concluded that cis-trans isomerization of retinoic acid is a physiologically relevant reaction.
Animals↗
Metabolism in vivo of all-trans-retinoic acid. Biosynthesis of 13-cis-retinoic acid and all-trans- and 13-cis-retinoyl glucuronides in the intestinal mucosa of the rat.
The metabolites of all-trans-[3H]retinoic acid appearing in the intestines of bile duct-cannulated rats were compared to those of similarly treated intact rats. 2.4% of administered radioactivity was found in the small intestines of bile duct-cannulated rats 2 H after dose, while a much larger proportion of the dose (7.2%) was found in the intestines of the intact rats. All-trans- and 3-cis-retinoic acids predominate in the intestinal mucosa of bile duct-cannulated rats shortly after dosing. Retinoyl glucuronide was the major metabolite occurring as a mixture of the all-trans and 13-cis forms. Highly polar metabolites of retinoic acid appear in mucosa at all times in both intact and bile duct-cannulated rats demonstrating rapid metabolism of retinoic acid in intestine. The finding of a similar proportion of the 13-cis isomers in retinoic acids and retinoyl glucuronides suggests that injected all-trans-retinoic acid is isomerized in vivo probably prior to conjugated with glucuronic acid.
Animals↗
Brain target sites for 1,25-dihydroxyvitamin D3.
Autoradiographic studies with 3H-labeled 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] demonstrate, in certain neurons of rat forebrain, hindbrain, and spinal cord, a nuclear retention and concentration of radioactivity, which can be prevented by treatment with 1,25(OH)2D3, but not with 25-hydroxyvitamin D3. These results indicate the presence of brain receptors in addition to pituitary receptors for 1,25(OH)2D3 and suggest a central modulation of calcium homeostasis and other central effects for this hormone. The existence of a brain-pituitary axis for certain 1,25(OH)2D3-mediated endocrine-autonomic effects is postulated.
25-Hydroxyvitamin D 2↗
Role of vitamin D in maternal skeletal changes during pregnancy and lactation: a histomorphometric study.
The effect of vitamin D on bone changes during the reproductive cycle in female rats has been investigated. One group of female rats was maintained on a vitamin D-deficient diet and another group of a vitamin D-replete diet from weaning. Both groups were mated with normal males and changes in their bones were determined histomorphometrically during pregnancy, lactation, and after weaning. All vitamin D-deficient rats had bone changes typical of rickets. Pregnancy caused significant reductions in mineralized tissue of trabecular and cortical bone in the vitamin D-deficient rats. Lactation caused further significant reductions in mineralized tissues of cortical and trabecular bone in both the vitamin D-deficient and vitamin D-replete animals, with the greatest changes seen at weaning. Some restoration of mineralized tissues occurred following weaning. There was an increase in tetracycline-labeled bone surface in the vitamin D-replete animals during lactation, likely due to an increase in bone formation rates. In the vitamin D-deficient animals during lactation, there was a decrease in tetracycline-labeled bone surface, likely due to severely depressed bone mineralization. These results indicate that the mobilization of calcium from bone to maintain pregnancy and lactation occurs by a mechanism independent of vitamin D.
Animals↗
Effect of 1,25-dihydroxyvitamin D3 on osteopenia induced by prednisolone in adult rats.
Adult male rats were fed a diet containing 0.15% calcium, 0.3% phosphorus, an either 100, 50, or 20 mg of prednisolone per kg of diet. All these levels of prednisolone led to osteopenia, decreased intestinal absorption of calcium, slightly lower serum calcium and phosphorus, and a decreased level of serum 1,25-dihydroxyvitamin D3. Exogenous parenteral 1,25-dihydroxyvitamin D3 corrected steroid-induced changes in serum calcium and phosphorus, but could not completely correct the low intestinal calcium transport; nor did it prevent the development of osteopenia. The prednisolone-induced osteopenia seems at least in part to be caused by impaired intestinal calcium transport. The impaired calcium transport may be the result of low levels of 1,25-dihydroxyvitamin D3 and a direct effect of presnisolone on the intestine.
Animals↗
Role of parathyroid hormone and 1,25-dihydroxyvitamin D3 in the development of osteopenia in oophorectomized rats.
The effect of ovarian insufficiency on calcium metabolism has been thought to involve an increased bone resorptive effect of parathyroid hormone and possible impaired synthesis of 1,25-dihydroxyvitamin D3. In the present study a rat model allowing for controlled serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D3 was used. Oophorectomy in this species is associated with increased serum levels of 1,25-dihydroxyvitamin D3 and decreased bone mass. Although thyroparathyroidectomy increased bone mass, an increased sensitivity of bone to parathyroid hormone in oophorectomized rats was not observed. Thus the development of the osteopenia did not seem to be related to increased parathyroid hormone sensitivity or to reduced levels of 1,25-dihydroxyvitamin D3. Exogenous 1,25-dihydroxyvitamin D3 increased bone mass in oophorectomized as well as intact rats. Intestinal calcium transport was increased by moderate doses of 1,25-dihydroxyvitamin D3. Intestinal calcium transport was also reduced by thyroparathyroidectomy and increased by the administration of parathyroid extract. A tendency for increased accumulation of 1,25-dihydroxyvitamin D3 in blood in oophorectomized rats has been noted. It is suggested that the tendency to hypercalcemia in ovarian-insufficient females given 1-hydroxylated vitamin D compounds may be related to a diminished metabolism of 1,25-dihydroxyvitamin D3.
Animals↗
Primary isotope effect of tritium on the hydroxylations of 25-hydroxyvitamin D3.
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24,25-Dihydroxyvitamin D 3↗
Circulating vitamin D metabolite concentrations in childhood renal diseases.
Vitamin D metabolites were measured in children, untreated with glucocorticoids, who had renal disease. Two groups were defined in relation to endogenous creatinine clearance values: those with impaired clearance , 0 to 48 ml/min per 1.73 m2; and those with unimpaired clearance, 75 to 150 ml/min per 1.73 m2. Serum 1.25(OH)2D was 16 +/- (SD) 12 pg/ml in impaired patients (N=24) and 48 +/- 16 pg/ml in unimpaired patients (N=18). The latter level is not different from healthy childhood controls (43 +/- 12 pg/ml; N=194). Serum samples of 25(OH)D2 and D3 were comparable in each group and not different from control values of 33.2 +/- 10.3 ng/ml. Serum 24,25(OH)2D was 0.6 +/- (SD) 0.14 ng/ml in patients with a clearance of less than 13 ml/min per 1.73 m2, 1.39 +/- 0.54 ng/ml in those with a clearance of 18 to 48 ml/min per 1.73 m2, and 152 +/- 0.91 ng/ml in patients without an impairment of clearance. Only patients with the lowest clearance had values different from control values of 1.70 +/- 0.57 ng/ml. In our study we suggest that a significant reduction in 24,25(OH)2D and 1,25(OH)2D are found at low clearance values in children with tubulointerstitial disease. Our study further suggests that a reduction in renal tubular mass is important in accounting for these changes in vitamin D metabolite values.
24,25-Dihydroxyvitamin D 3↗
Metabolism and molecular mechanism of action of vitamin D: 1981.
Cholecalciferol must be regarded as a pro-hormone rather than a vitamin, since it is normally produced in skin under the influence of ultraviolet light. Cholecalciferol must be metabolized in liver to 25-hydroxycholecalciferol and subsequently to 1,25-dihydroxycholecalciferol before it can act on intestine, bone and kidney to provide calcium and phosphorus for bone mineralization and neuromuscular activity. 1,25-Dihydroxycholecalciferol is metabolized in liver and intestine to a C-23-carboxylic acid that is inactive, 25-Hydroxycholecalciferol is metabolized to a variety of metabolic products, including 23S,25-dihydroxycholecalciferol, 23S,25R-25-hydroxycholecalciferol-26,23-lactone, 24R,25-dihydroxycholecalciferol and 25,26-dihydroxycholecalciferol. These metabolites are not involved in the known actions of vitamin D. 1,25-Dihydroxycholecalciferol localizes in the nuclei of target organs through a receptor mechanism. It is believed to initiate transcription of DNA that codes for calcium and phosphorus transport proteins, the nature of which is undetermined. Production of 1,25-dihydroxycholecalciferol is stimulated by low plasma calcium through parathyrin and by low plasma phosphorus. During pregnancy and lactation, 1,25-dihydroxycholecalciferol levels are greatly increased to meet calcium demands. However, vitamin D is not absolutely essential for reproduction. It is likely that some other hormone, possibly prolactin, functions at these periods to mobilize calcium. The clinical application of the vitamin D hormone and its analogues to the treatment of bone disease is presented to illustrate the application of basic science to medical practice. Evidence for each of these points is presented.
Adult↗
Purification of chicken intestinal receptor for 1 alpha, 25-dihydroxyvitamin D3 to apparent homogeneity.
The chicken intestinal 1 alpha, 25-dihydroxyvitamin D3 receptor-like protein has been purified to apparent homogeneity as determined by sodium dodecyl sulfate gel electrophoresis. The techniques employed for the purification include selective precipitation of the receptor by Polymin P (polyethyleneimine) and (NH4)2SO4 and batch adsorption to and selective elution from hydroxylapatite, followed by gel exclusion and DEAE-cellulose chromatography. Finally, the labeled receptor was eluted at a pH of approximately 6.0 on a chromatofocusing column. The protein was purified 6100-fold and the receptor was obtained in 9% yield.
Animals↗