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Biomedical subjects

H F DeLuca

Publications and source records attributed to H F DeLuca.

At least 433 records · Page 24Linked to original sources
PubMed1980

Successful treatment of genetically hypophosphatemic mice by 1 alpha-hydroxyvitamin D3 but not 1,25-dihydroxyvitamin D3.

The X-linked hypophosphatemia (Hyp) mutation in the mouse, a model for X-linked familial hypophosphatemic rickets in man, is characterized by defective phosphate transport. The role of vitamin D3 in the defective phosphate transport was investigated in three experiments by treatment of mutant mice with the natural hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, or its potent synthetic analog, 1 alpha-hydroxyvitamin D3. The results showed that both compounds were able to increase urinary phosphate conservation and improve rachitic bone morphology. Only 1 alpha-hydroxyvitamin D3, however, repaired the critically important hypophosphatemia and significantly increased intestinal transport of phosphate. These results indicate that defective phosphate transport in genetic hypophosphatemia is amenable to effective treatment. We hypothesize that the intestinal phosphate transport system is not genetically deleted but, instead, is unable to respond to 1,25-dihydroxyvitamin D3. Elucidation of the mechanism whereby 1 alpha-hydroxyvitamin D3 is able to stimulate the defective phosphate transport may provide fresh insight into the metabolic basis of the disease.

Animals↗
PubMed1980

Skeletal changes during pregnancy and lactation: the role of vitamin D.

To establish the role of vitamin D in bone metabolism during the mammalian reproductive cycle, female rats were maintained on a vitamin D-deficient diet from weaning and mated with normal males. Changes in the femurs of the females during pregnancy and lactation and after weaning were monitored. The concentration of calcium in the plasma of mature vitamin D-deficient rats was 5.5-5.8 mg/100 ml. This was reduced to 3.8 and 4.4 mg/100 ml by day 14 of lactation and weaning, respectively. Total femur calcium and calcium per unit volume were approximately two thirds of that observed in age-matched vitamin D-replete rats. During pregnancy, little or no change was observed in femurs from vitamin D-replete females. Bone volume, total bone calcium, and bone calcium per unit volume in vitamin D-deficient females, however, tended to increase during pregnancy. After parturition, both vitamin D-replete and -deficient females lost bone mineral. When based on an initial value equivalent to that on day 20 of pregnancy, the losses were similar and amounted to 42-46 mg calcium or 23-38% of the total bone mineral. After weaning, there was a trend toward replacement of bone mineral in vitamin D-replete females. These results indicate that vitamin D is not required for bone calcium mobilization during lactation and suggest that other as yet unidentified factors may play a key role in bone metabolism during reproduction.

Animals↗
PubMed1980

Phosphorus excretion in tumoral calcinosis: response to parathyroid hormone and acetazolamide.

The cause of hyperphosphatemia in patients with tumoral calcinosis never been explained. We studied two related patients who had tumoral calcinosis and hyperphosphatemia and two normal controls to determine their renal tubular response to parathyroid hormone (PTH) and acetazolamide (ACZ). During baseline periods, the patients had abnormally low fractional excretion of phosphorus (FEP) despite their hyperphosphatemia. Values for patients were 0.114 and 0.128; for controls, values were 0.193 and 0.165. PTH caused an increase in FEP and urinary cAMP in both patients and controls. ACZ also increased FEP in both groups, and the effects of PTH and ACZ were additive, suggesting that patients with tumoral calcinosis have normal sensitivities to PTH and normal responses to ACZ. Levels of vitamin D metabolites in the patients were normal. We conclude that patients with tumoral calcinosis have a reduced ability to excrete phosphorus. This defect does not seem to be due to impaired PTH secretion, an abnormal phosphaturic response to this hormone, or a disturbance of vitamin D metabolism.

Acetazolamide↗
PubMed1980

Normal intrauterine development of the fetus of a woman receiving extraordinarily high doses of 1,25-dihydroxyvitamin D3.

We monitored the course of pregnancy in a 28-yr-old patient with hereditary insensitivity to 1,25-dihydroxyvitamin D (1,25-(OH)2D). During pregnancy, she received 1,24-(OH)2D3 in doses of 17--36 micrograms/day (usual dose for hypocalcemia, 0.25--1.0 microgram/day). We separately measured 25-hydroxyvitamin D3 (25OHD3), 25OHD2, 1,25-(OH)2D3, and 1,25-(OH)2D2 to assess contributions to total 1.25-(OH)2D from endogenous biosynthesis (1 alpha-hydroxylation of 25OHD2 or 25OHD3) vs. contributions from exogenously administered 1.25-(OH)2D3. Serum concentrations of 1,25-(OH)2D were extraordinarily high throughout gestation. The evaluations of total 1,25-(OH)2D in maternal plasma reflected large amounts from both 1 alpha-hydroxylation of 25OHD and oral intake of 1,25-(OH)2D3. At parturition, the calcium concentration was 9.6 mg/dl in maternal serum and 10.2 mg/dl in cord serum. The concentration of total 1,25-(OH)2D in cord serum was high (470 pg/ml; normal mean for placental venous serum, 19 pg/ml); most derived from transplacental passage of maternal 1,25-(OH)2D3 and not from fetoplacental biosynthesis. The child manifested mild hypercalcemia in the first 2 days of life, indicating that the 1,25-(OH)2D3 measured in cord serum was active in vivo. The child showed no somatic features of the syndrome of elfin facies and supravalvular aortic stenosis. We conclude that an extraordinarily high concentration of 1.25-(OH)2D in maternal serum throughout gestation was not apparently toxic to the fetoplacental unit, though the maternal metabolite entered the fetal circulation.

Adolescent↗
PubMed1980

Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis.

Osteoporotic women have decreased calcium absorption and decreased serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] and are usually in negative calcium balance. Estrogen therapy improves calcium balance in patients with postmenopausal osteoporosis. In birds, estrogen administration increases the conversion of 25-hydroxyvitamin D (25OHD) to 1,25-(OH)2D. To determine if estrogen therapy affects vitamin D metabolism in human subjects, we studied 21 osteoporotic women before and after 6 months of treatment. We compared groups treated with either placebo (9 patients) or conjugated equine estrogen (1.2-2.5 mg/day; 12 patients). Fractional calcium absorption (mean +/- SE) was unchanged after treatment with placebo (0.51 +/- 0.03 to 0.52 +/- 0.01) but increased after treatment with estrogen (0.53 +/- 0.02 to 0.65 +/- 0.04; P < 0.005). The increase after estrogen was similar to the increase observed in 10 additional osteoporotic women treated for 6 months with a small dose of 0.5 microgram/day 1,25-(OH)2D (0.54 +/- 0.03 to 0.68 +/- 0.04; P < 0.005). Serum 1,25-(OH)2D was unchanged after treatment with placebo (27.5 +/- 1.3 to 27.6 +/- 1.7 pg/ml) but increased after treatment with estrogen (23.6 +/- 2.7 to 33.2 +/- 3.7 pg/ml; P < 0.005). Serum immunoreactive parathyroid hormone (PTH) increased (23.0 +/- 4.2 to 32.7 +/- 4.6 microliter eq/ml; P < 0.05) after estrogen but not after placebo treatment. After treatment with estrogen, the increases in serum immunoreactive PTH and serum 1,25-(OH)2D were correlated (r = 0.68; P < 0.05), and the increases in serum 1,25-(OH)2D and calcium absorption were highly correlated (r = 0.89; P < 0.001). We conclude that estrogen treatment increases calcium absorption in postmenopausal osteoporosis by increasing serum 1,25(OH)2D. This effect appears to be mediated indirectly through stimulation of renal 1 alpha-hydroxylase by increased serum PTH.

Aged↗
PubMed1980

Vitamin D metabolite levels in oncogenic osteomalacia.

Measurements of 1,25 (OH)2D3 and other metabolites of vitamin D in a patient with oncogenic osteomalacia confirm the selective, reversible deficiency of 1,25 (OH)2D3 in this syndrome, and indicate the rapidity of normalization (within days) of the hormone level and associated hypophosphatemia after resection of the tumor. In this patient, the tumor was an intranasal hemangiopericytoma.

Adult↗
PubMed1979

Characteristics of the rat liver microsomal enzyme system converting cholecalciferol into 25-hydroxycholecalciferol. Evidence for the participation of cytochrome p-450.

Properties of the rat hepatic cholecalciferol 25-hydroxylase have been studied. An assay system has been developed in which 25-hydroxycholecalciferol production is linear for at least 2h in both homogenates and microsomal fraction. Furthermore, the initial reaction velocity is linearly related to the amount of liver tissue or microsomal fraction. This enzyme system also metabolizes an analogue of cholecalciferol, namely dihydrotachysterol 3, into 25-hydroxydihydrotachysterol 3. The 25-hydroxylase is in the microsomal fraction and not in mitochondria. It has a Km of 44 nM for cholecalciferol and 360 nM for dihydrotachysterol 3. Its activity is not altered by dietary concentrations of calcium and phosphorus. Vitamin D-deficient rats have higher activities of the hepatic 25-hydroxylase than those receiving 25 ng of cholecalciferol daily. The 25-hydroxylase is inhibited by metyrapone. An atmosphere of CO/O2 (9:1, v/v) inhibits the reaction by 87%. This inhibition is partially reversed by white light. Additionally, cholecalciferol and 25-hydroxycholecalciferol competitively inhibit aminopyrine demethylase. These results support the idea that the cholecalciferol 25-hydroxylase is a cytochrome P-450-dependent mono-oxygenase.

Animals↗
PubMed1979

Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid.

After mature rats that had been fed on a vitamin D3-deficient diet were injected with tritium-labeled 1,25-dihydroxyvitamin D3, radioactivity became concentrated in nuclei of luminal and cryptal epithelium of the duodenum, jejunum, ileum, and colon; in nuclei of the epithelium of kidney distal tubules including the macula densa, and in podocytes of glomeruli; in nuclei of the epidermis including outer hairshafts and sebaceous glands; and in nuclei of certain cells of the stomach, anterior and posterior pituitary, and parathyroid. These results reveal cell types that contain receptors for 1,25-dihydroxyvitamin D3 or metabolites of this compound both in known or hypothesized target tissues and in tissues that were previously unknown to participate in vitamin D3 metabolism.

Animals↗
PubMed1979

25-Hydroxyvitamin D3 26,23-lactone: a new in vivo metabolite of vitamin D.

A major vitamin D metabolite was isolated in pure form from the blood plasma of chicks either maintenance levels or large doses of vitamin D3. The isolation involved methanol-chloroform extraction and five column chromatographic procedures. The metabolite purification and elution position on these columns were followed by a competitive protein binding assay. The metabolite was identified, using high- and low-resolution mass spectrometry, 270-MHz proton nuclear magnetic resonance spectrometry, ultraviolet absorption spectrophotometry, Fourier transform infrared spectrophotometry, and specific chemical reactions, as 3 beta,-25-dihydroxy-9,10-seco-5,7,10(19)-cholestatrieno-26,23-lactone. The trivial names 25-hydroxyvitamin D3 26,23-lactone or calcidiol 26,23-lactone are suggested for this compound.

Animals↗
PubMed1979

Isolation and characterization of 1 alpha-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D3.

The in vivo side-chain oxidation of 1 alpha,25-dihydroxyvitamin D3 was investigated by using a double-label radiotracer technique. Rats dosed with 1 alpha,25-dihydroxy-[3 alpha-3H]vitamin D3 and 1 alpha,25-dihydroxy[26,27-14C]vitamin D3 produced compounds with a high 3H/14C ratio. These compounds were found in sizable quantities in intestine and liver within 3 h after dosing. The major side-chain oxidized metabolite migrated as an acid on DEAE-Sephadex chromatography and contained no 14C. Methyl esterification of this compound with diazomethane proceeded in good yield and rendered the compound more amenable to chromatographic purification. The metabolite was isolated in several steps from rats dosed with 1 microgram of 1 alpha,25-dihydroxy[3 alpha-3H]vitamin D3. The metabolite was obtained in pure form as the methyl ester and was positively identified as 1 alpha,3 beta-dihydroxy-24-nor-9,10-seco-5,7,10(19)cholatrien-23-oic acid. The trivial name calcitroic acid is proposed for this major side-chain oxidized metabolite of 1,25-dihydroxyvitamin D3.

Animals↗