Elevated serum 1,25-dihydroxyvitamin D concentrations in the hypercalcemia of sarcoidosis: correction by glucocorticoid therapy.
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Child↗
Biomedical subjects
H F DeLuca
Publications and source records attributed to H F DeLuca.
Measurement of mammalian 25-hydroxyvitamin D3 24R-and 1 alpha-hydroxylase.
An in vitro assay of mammalian 25-hydroxyvitamin D3 1 alpha- and 24R-hydroxylases in kidney has been developed. It had been suggested that 25-hydroxyvitamin D binding protein present in mammalian blood and tissues inhibits the enzyme activities in cell-free preparations by binding the substrate 25-hydroxyvitamin D3 more strongly than the hydroxylases bind it. This inhibitory effect is overcome by the addition of substantial amounts of unlabeled 25-hydroxyvitamin D3 to saturate the binding sites of this protein. The resulting metabolites produced in vitro by rat kidney homogenates were isolated and firmly identified by ultraviolet absorption spectrometry and mass spectrometry as 1,25-dihydroxyvitamin D3 and (24R)-24,25-dihydroxyvitamin D3. Maximal 1 alpha-hydroxylation of 25-hydroxyvitamin D3 could be demonstrated in kidney homogenates prepared from vitamin D-deficient rats. Thyroparathyroidectomy of these rats resulted in total suppression of the 1 alpha-hydroxylase. Homogenates of kidney from rats given vitamin D showed little or no 1 alpha-hydroxylase and substantial 24R-hydroxylase activity. Thyroparathyroidectomy of these rts markedly increased the 24R-hydroxylase activity.
24,25-Dihydroxyvitamin D 3↗
Preparation of tritium- or deuterium-labeled vitamin D analogs by a convenient general method.
The three-step conversion of vitamin D analogs to 6-oxo-3,5-cyclovitamin D derivatives followed by reduction with a tritide or deuteride reagent and subsequent cycloreversion gives 6-tritio(deutero)vitamin D derivatives and corresponding 5,6-trans-analogs. The method is general and affords the 6-labeled-vitamin D analogs in approximately 20% overall yield.
Cholecalciferol↗
23,25-Dihydroxyvitamin D3: a natural precursor in the biosynthesis of 25-hydroxyvitamin D3-26,23-lactone.
To elucidate the biosynthesis of 25-hydroxyvitamin D3-26,23-lactone, two known metabolites of 25-hydroxyvitamin D3--23,25-dihydroxyvitamin D3 and 25,26-dihydroxyvitamin D3--were incubated individually with kidney homogenate prepared from vitamin D-supplemented chickens, a preparation known to produce the lactone from 25-hydroxyvitamin D3. The 25-hydroxyvitamin D3-26,23-lactone produced in vitro was then separated, purified, identified, and quantitated by consecutive straight-phase and reverse-phase high-performance liquid chromatography. 23,25-Dihydroxyvitamin D3 is a far better substrate for production of 25-hydroxyvitamin D3-26,23-lactone than is 25,26-dihydroxyvitamin D3. Production of lactone is highly selective for the natural 23(S)-hydroxy-23,25-dihydroxyvitamin D3 while both epimers of 25,26-dihydroxyvitamin D3 resulted in small amounts of product comigrating with natural lactone. It appears that 23(S),25-dihydroxyvitamin D3, but not 25,26-dihydroxyvitamin D3, is a natural precursor in the synthesis of 25-hydroxyvitamin D3-26,23-lactone; this result also implies that the configuration of the lactone at C-23 is S.
24,25-Dihydroxyvitamin D 3↗
DNA labeling of rat epithelial tissues in vitamin A deficiency.
We examined the effect of vitamin A nutritional status on cell division in various epithelial tissues of the rat. Tissues were examined by histological methods, and DNA labeling was assessed by autoradiography. Mild vitamin A deficiency decreased the DNA labeling index in the trachea and the epidermis, while not altering the histological appearance of the tissue. In some tracheae, foci of hyperplasia were present. The histological appearance and the DNA labeling index of the cornea, jejunum and colon were not altered by mild vitamin A deficiency. We concluded that a diminished proliferation of epithelial cells is a manifestation of suboptimal vitamin A availability in that tissue.
Animals↗
Effect of lead ingestion on functions of vitamin D and its metabolites.
A study of the effect of ingestion of lead on the metabolism and function of vitamin D was carried out in rats fed diets varying in calcium and phosphorus content. The ingestion of 0.82% lead as lead acetate suppressed plasma levels of 1,25-dihydroxycholecalciferol in rats fed either a low phosphorus or a low calcium diet while it had no effect on this parameter in rats fet either a high calcium diet or a normal phosphorus diet. Most important, the ingestion of lead totally blocked the intestinal calcium transport response to cholecalciferol, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. On the other hand, the ingestion of lead acetate had no influence on the mobilization of calcium from bone, the elevation of serum inorganic phosphorus and in the mineralization of rachitic bone in the same animals. Thus by the feeding of 0.82% lead on the intestinal responses to vitamin D and its metabolites was greatest in animals fed a low calcium or a low phosphorus diet, it was present with all diets tested.
Animals↗
Recent advances in the metabolism of vitamin D.
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Animals↗
1,25-Dihydroxyvitamin D3 target cells in rat mammary gland.
In autoradiograms of mammary glands of rats on days 18 and 20 of pregnancy and day 6 of lactation after injection of 3H 1,25-(OH)2 vitamin D3, a nuclear concentration of radioactivity is observed in alveolar and ductal cells, as well as in cells of the epidermis of the nipple. Myoepithelial cells and connective tissue cells do not concentrate the hormone in their nuclei. The nuclear radioactivity appears specific, since 1,25-(OH)2 vitamin D3 but not 25-(OH)2 vitamin D3 prevents the uptake. The results suggest the existence of nuclear receptors for 1,25-(OH)2 vitamin D3 in mammary tissues and thus complements previous biochemical evidence showing the presence of cytoplasmic receptors for the hormone in mouse mammary glands; in addition, our results allow the identification of the cell types possessing the receptors.
Animals↗
The biochemical basis of renal osteodystrophy and post-menopausal osteoporosis: a view from the vitamin D system.
The vitamin D endocrine system is now known to play an essential role in the regulation of plasma calcium and phosphorus concentrations and in overall organismal calcium economy. These two basic functions of the vitamin D endocrine system have provided important new insight into several disease states. The two disease states discussed here are the genesis of renal osteodystrophy and of post-menopausal osteoporosis. It seems likely that defects of alternations in the vitamin D system play important roles in the development of these disease states. Successful treatment undoubtedly will involve the vitamin D system and most likely the active form of vitamin D, 1,25- (OH)2D3.
Calcium↗
An examination of the importance of 24-hydroxylation to the function of vitamin D during early development.
To investigate the biological importance of 24R-hydroxylation of 25-hydroxyvitamin D to the early development of rats, the potency of 24,24-difluoro-25-hydroxyvitamin D3 had been compared to that of 25-hydroxyvitamin D3 in young rat pups born to vitamin D-deficient mothers. 24,24-Difluoro-25-hydroxyvitamin D3 and 25-hydroxyvitamin D3 were equally active in stimulating active calcium transport in the intestine, maintaining normal concentrations of calcium and phosphorus in the plasma and promoting bone growth and mineralization. These results provide strong evidence that the presence of a hydroxyl group at the 24 position of vitamin D3 is not required for the maintenance of calcium-phosphate homeostasis during growth and in the development and mineralization of bone.
Animals↗
Absence of seasonal variation in serum concentrations of 1,25-dihydroxyvitamin D despite a rise in 25-hydroxyvitamin D in summer.
The serum concentrations of the vitamin D metabolites 25-hydroxyvitamin D2 (25OHD2), 25-hydroxyvitamin D3 (25OHD3), and 1,25-dihydroxyvitamin D (calcitriol) have been measured in normal subjects whose ages varied from 18 months to 35 yr. Samples were obtained in all months of the year in order to assess the effects of season on serum concentration. During the months of April to September, 25OHD3 levels are higher than in the winter months. No seasonal variation in the 25OHD2 or calcitriol serum concentration was observed. Age-related differences in 25OHD2 and D3 concentrations did not exist. The levels of calcitriol are higher in adolescence and increase from 35 +/- 19 pg/ml (SD) at 1.5-10 yr of age to 54 +/- 21 pg/ml at 10-20 yr of age. In young adults, the levels fall again to 28 +/- 16 pg/ml. Accordingly, despite a seasonal variation in the precursor of calcitriol, the levels of this most active metabolite of vitamin D do not change in relation to sunlight exposure. This lack of seasonal variation is further evidence of the tight feedback regulation of calcitriol.
25-Hydroxyvitamin D 2↗
Assessment of 25-hydroxyvitamin D 1 alpha-hydroxylase reserve in postmenopausal osteoporosis by administration of parathyroid extract.
Previous studies have shown that the mean serum concentration of 1,25-dihydroxyvitamin D [1,25-(OH)2D] is lower than normal in patients with postmenopausal osteoporosis. We studied the mechanism of this abnormality in 12 women with postmenopausal osteoporosis and 10 age-comparable normal women. Parathyroid extract (200 U, twice daily for 3 days) was administered to stimulate the enzymatic conversion of 25-hydroxyvitamin D (25OHD) to 1,25-(OH)2D. The serum concentration of 1,25-(OH)2D was lower (P less than 0.05) at a baseline determination in the osteoporotic subjects than in the normal women and increased significantly (P less than 0.001) above basal values after the administration of parathyroid extract in both groups; however, the degrees of increase in the control and osteoporotic subjects were similar. We conclude, at least under the conditions of our study, that 25OHD 1 alpha-hydroxylase is normally responsive to parathyroid hormone in postmenopausal osteoporosis. Thus, the apparently impaired metabolism of 25OHD to 1,25-(OH)2D appears to be secondary to a decrease in factors that abnormally stimulate 25OHD 1 alpha-hydroxylase activity rather than a primary defect in enzyme reserve capacity.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
Synthesis of (22R)- and (22S)-22,25-Dihydroxyvitamin D3 and determination of their biological activity.
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Animals↗
Concentration of calcium, phosphorus, and 1,25-dihydroxyvitamin D in plasma of dairy cows during the lactation cycle.
Concentrations of calcium, phosphorus, and 1,25-dihydroxyvitamin D in plasma of four young, four nonparetic aged, and four paretic aged cows were measured during the lactation cycle. Concentration of 1,25-dihydroxyvitamin D in plasma was elevated significantly in paretic aged cows as compared to nonparetic aged and young cows from the day of calving to 3 days postcalving. In paretic aged cows, severe hypocalcemia and hypophosphatemia developed on the day of calving, whereas hypocalcemia and hypophosphatemia were only transient in nonparetic aged and young cows at this time. Changes were only minor in concentration of 1,25-dihydroxyvitamin D in plasma from 7 days postcalving to 7 days precalving in all cows.
Aging↗
Effects of 1,24 dihydroxyvitamin D3 and calcitonin on fracture healing in adult rats.
Calcitonin and 1.25(OH)2D3 have opposite effects on the serum concentrations of Ca and P, as well as on bone resorption, and can be observed in the process of healing of standardized fracture in adult rats. The rats given 1.25(OH)2D3 had a stronger fracture callus and slightly less pronounced postfracture osteopenia. Calcitonin did not significantly influence the fracture healing but had a pronounced effect in preventing the osteopenia. The effects of 1.25(OH)2D3 are believed to be indirect, i.e., through the changes in the serum Ca X P product, whereas the osteopenia preventing action of calcitonin may come from direct effect on bone.
Animals↗
Mineral metabolism in chronic renal failure with special reference to serum concentrations of 1.25(OH)2D and 24.25(OH)2D.
This study examines the interrelationship between serum levels of substances important in mineral metabolism including the 3 vitamin D metabolites 25OHD, 24.25(OH)2D and 1.25(OH)2D and static and dynamic histomorphometric measurements of bone remodelling in iliac crest biopsies in 17 patients with chronic renal failure. No correlation was found between the serum values of any of the vitamin D metabolites and the histomorphometric values. However, significant inverse correlations were found between serum calcium and both the osteoid surface extent (P less than 0.05) and osteoid volume (P less than 0.05) in trabecular bone. Serum immunoreactive parathyroid hormone (iPTH) was positively related to trabecular osteoclastic bone resorption. The serum level of 1.25(OH)2D was inversely related to endogenous creatinine clearance (P less than 0.01). These results support the hypothesis that the serum calcium concentration is more important than the serum concentration of vitamin D metabolites for bone remodelling in chronic renal failure.
Bone and Bones↗
Bone resorptive activity of side-chain fluoro derivatives of 25-hydroxy- and 1 alpha,25-dihydroxyvitamin D3 in culture.
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Animals↗