Effect of 1,25-dihydroxyvitamin D deficiency on the metabolic clearance rate of 1,25-dihydroxyvitamin D3: studies using pigs with vitamin D-dependent rickets type 1

1985 ◽  
Vol 69 (5) ◽  
pp. 549-552
Author(s):  
John Fox ◽  
Anthony D. Care
Keyword(s):  
Vitamin D ◽  
Clearance Rate ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D3 ◽  
Steady State Levels

1. We have used pigs with inherited vitamin D-dependent rickets type 1 to study the effect of 1,25-dihydroxyvitamin D deficiency on the metabolic clearance rate of 3H-1,25-dihydroxyvitamin D3 infused to steady-state levels in plasma. 2. Plasma levels of 1,25-dihydroxyvitamin D were 24 ± 1 (sem) pmol/l in the hypocalcaemic, homozygous piglets and 196 ± 27 pmol/l in their normocalcaemic, heterozygous siblings. 3. The metabolic clearance rate of 1,25-dihydroxyvitamin D3 was the same in both normal heterozygous (0.90 ± 0.02) and hypocalcaemic, homozygous piglets (0.90±0.01 ml−1 min−1 kg−1 metabolic bodysize). 4. We conclude that a deficiency of circulating 1,25-dihydroxyvitamin D does not influence the clearance of 1,25-dihydroxyvitamin D3 from the circulation of pigs.

A primed-infusion technique for rapid estimation of the metabolic clearance rate of 1,25(OH)2D3

1987 ◽  
Vol 253 (3) ◽  
pp. E246-E250
Author(s):  
R. Eastell ◽  
B. L. Riggs ◽  
R. Kumar
Keyword(s):  
Production Rate ◽  
Clearance Rate ◽  
Human Subjects ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Study Interval ◽  
Normal Women ◽  
Infusion Technique

We have developed a rapid primed-infusion technique for the measurement of the metabolic clearance and production rate of 1,25-dihydroxyvitamin D3 in normal human subjects and experimental animals. With this method, an estimate of the metabolic clearance rate of 1,25-dihydroxyvitamin D3 can generally be made within 3 to 4 h. Initial studies in five dogs using 1,25-[3H]-dihydroxyvitamin D3 (180 Ci/mmol) allowed us to determine the optimal ratio of loading dose to infusion rate that resulted in the most rapid attainment of steady-state levels of plasma radioactivity. By use of this technique we found that the metabolic clearance rate of 1,25-dihydroxyvitamin D3 in dogs was 6.3 +/- 1.2 ml/min (mean +/- SD); the production rate of the hormone was 0.40 +/- 0.25 microgram/day (20.4 +/- 14.4 ng . kg-1 . day-1). In eight normal women, aged 28-51 yr, the metabolic clearance rate for 1,25-dihydroxyvitamin D3 was 25.9 +/- 4.7 ml/min; the production rate was 1.38 +/- 0.45 microgram/day (20.7 ng . kg-1 . day-1). The advantages of this method relative to ones used in the past are that it can be performed quickly (generally within 3-4 h) with the use of only tracer amounts of this hormone (equivalent to 1.1% of the production rate). With this method, no assumptions about the most appropriate model to which to fit the data need to be made. Because of its rapidity, no metabolites of the injected 1,25-dihydroxyvitamin D3 are formed during the study interval.

Elevated metabolic clearance rate of 1α,25-dihydroxyvitamin D3 in hyperthyroidism

1985 ◽  
Vol 110 (1) ◽  
pp. 70-74 ◽  
Author(s):  
Gérard Karsenty ◽  
Philippe Bouchard ◽  
André Ulmann ◽  
Gilbert Schaison
Keyword(s):  
Clearance Rate ◽  
Single Injection ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Daily Production ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Control Subjects ◽  
Significant Difference ◽  
Hyperthyroid Patients

Abstract. Metabolic clearance rate (MCR) and daily production rate (DPR) of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) were measured in 7 hyperthyroid patients and 8 control subjects after a single injection of tritiated 1,25(OH)2D3. Using a bicompartmental analysis, MCR of 1,25(OH)2D3 was found to be significantly higher in hyperthyroid than in control subjects (11.5 ± 4.4 vs 5.9 ± 2.4 ml/min (sd), P < 0.01). No significant difference in plasma 1,25(OH)2D and DPR of 1,25(OH)2D3 was demonstrated. MCR was again measured 1 month after initiation of treatment in 4 hyperthyroid patients and remained elevated. In 2 of these patients, MCR was once more determined 6 months later and had declined towards normal. No correlation was found between MCR and DPR and either plasma calcium, phosphate, immunoreactive PTH, 1,25(OH)D and T3 values. In conclusion, MCR of 1,25(OH)2D3 is elevated in hyperthyroidism, but this finding is probably unrelated to the effect of thyroid hormones on bone metabolism.

scholarly journals 1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle

2003 ◽  
Vol 10 (6) ◽  
pp. 1129-1135 ◽  
Author(s):  
S. G. Rhodes ◽  
L. A. Terry ◽  
J. Hope ◽  
R. G. Hewinson ◽  
H. M. Vordermeier
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Proliferation ◽  
Accessory Cell ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Cell Responses ◽  
1,25 Dihydroxyvitamin D ◽  
Accessory Cells

ABSTRACT This report describes the presence and activity of 1,25-dihydroxyvitamin D3 (1,25-D3) in experimental bovine tuberculosis. Animals that went on to develop tuberculous lesions exhibited a rapid transient increase in serum 1,25-D3 within the first 2 weeks following infection with Mycobacterium bovis. 1,25-D3-positive mononuclear cells were later identified in all tuberculous granulomas by immunohistochemical staining of postmortem lymph node tissue. These results suggest a role for 1,25-D3 both at the onset of infection and in the development of the granuloma in these infected animals. Using a monoclonal antibody to the vitamin D receptor (VDR) as a VDR agonist, we confirmed that activation of the vitamin D pathway profoundly depresses antigen-specific, but not mitogenic, bovine peripheral blood T-cell responses (proliferation and gamma interferon production). Investigation of the mechanism of this suppression showed that the VDR antibody modified the expression of CD80 by accessory cells, such that a significant positive correlation between T-cell proliferation and accessory cell CD80 emerged.

scholarly journals Vitamin D-Dependent Rickets Type 1 Caused by Mutations in CYP27B1 Affecting Protein Interactions With Adrenodoxin

2016 ◽  
Vol 101 (9) ◽  
pp. 3409-3418 ◽  
Author(s):  
Adam Zalewski ◽  
Nina S. Ma ◽  
Balazs Legeza ◽  
Nora Renthal ◽  
Christa E. Flück ◽  
...  
Keyword(s):  
Vitamin D ◽  
Structural Analysis ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Luciferase Assay ◽  
Compound Heterozygous ◽  
Dihydroxyvitamin D3 ◽  
Severe Loss ◽  
1,25 Dihydroxyvitamin D3

Abstract Context: CYP27B1 converts 25-hydroxyvitamin D3 to active 1,25-dihydroxyvitamin D3, playing a vital role in calcium homeostasis and bone growth. Vitamin D-dependent rickets type 1 (VDDR-1) is a rare autosomal recessive disorder caused by mutations in CYP27B1. Objective: The objective of the study was an enzymatic and structural analysis of mutations in a patient with calcipenic rickets. Design, Setting, Patient, and Intervention: Two siblings presented with calcipenic rickets and normal 1,25-dihydroxyvitamin D3 levels. CYP27B1 gene analysis showed compound heterozygous mutations confirming VDDR-1. We studied wild-type CYP27B1 and mutations H441Y and R459L by computational homology modeling, molecular dynamics simulations, and functional studies using a luciferase assay. The patients were successfully treated with calcitriol. Main Outcome: The main outcomes of the study were novel mutations leading to a severe loss of CYP27B1 activities for metabolism of 25-hydroxyvitamin D3. Results: Mitochondrial cytochrome P450s require adrenodoxin (FDX1) and adrenodoxin reductase. We created models of CYP27B1-FDX1 complex, which revealed negative effects of mutations H441Y and R459L. Upon structural analysis, near-identical folds, protein contact areas, and orientations of heme/iron-sulfur cluster suggested that both mutations may destabilize the CYP27B1-FDX1 complex by negating directional interactions with adrenodoxin. This system is highly sensitive to small local changes modulating the binding/dissociation of adrenodoxin, and electron-transporting efficiency might change with mutations at the surface. Functional assays confirmed this hypothesis and showed severe loss of activity of CYP27B1 by both mutations. Conclusions: This is the first report of mutations in CYP27B1 causing VDDR-1 by affecting protein-protein interactions with FDX1 that results in reduced CYP27B1 activities. Detailed characterization of mutations in CYP27B1 is required for understanding the novel molecular mechanisms causing VDDR-1.

Effects of 1,25-dihydroxyvitamin D3 and cortisol on bovine and human parathyroid cells

1989 ◽  
Vol 123 (1) ◽  
pp. 137-142 ◽  
Author(s):  
R. Karmali ◽  
S. Farrow ◽  
M. Hewison ◽  
S. Barker ◽  
J. L. H. O'Riordan
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D3 ◽  
Cytosolic Protein

ABSTRACT Incubation of bovine parathyroid cells with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) decreased both preproparathyroid mRNA levels and parathyroid hormone (PTH) secretion. There was a fall to 56·6 ± 13·7% (mean ± s.e.m.) and 65·1 ± 9·3% in mRNA levels and PTH secretion respectively at 1 nmol 1,25-(OH)2D3/l, and 41·1 ± 13·6% and 42·0 ± 12·1% at 10 nmol 1,25-(OH)2D3/l after 24 h. After 48 h in 0·1 nmol 1,25-(OH)2D3/l, mRNA levels had fallen to 35·3 ± 12·6% and PTH secretion to 32·1 ± 5·0%. In human adenomatous cells, however, incubation with 1,25-(OH)2D3 (10 nmol/l) had no effect on either mRNA levels or PTH secretion even after 48 h. This lack of sensitivity of adenomatous cells to 1,25-(OH)2D3 was not due to an absence of receptors (3847 ± 39 receptors/ng cytosolic protein in adenomatous cells compared with 4068 ± 371 in bovine cells) or receptors being of low affinity. Cortisol (1 μmol/l) caused a reduction in the number of receptors for 1,25-(OH)2D3 in bovine parathyroid cells of approximately 20% within 24 h of incubation, but no change in affinity. This decrease was accompanied by abolition of the response to 1,25-(OH)2D3 and was reversible, in that withdrawal of cortisol for the final 24 h of incubation was sufficient for the response to return, the number of receptors having returned to control values. These results suggest that only a small percentage of receptors for 1,25-(OH)2D3 in bovine parathyroid cells may be functional at any one time. Furthermore, the insensitivity of human adenomatous cells to 1,25-(OH)2D3 does not seem to be due to a lack of receptors but may be due to a defect in the interaction between the receptor protein and the PTH gene. Journal of Endocrinology (1989) 123, 137–142

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