Stimulation Of Intestinal Calcium Absorption Research Articles

Correction to: Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis.

There were two errors in this article. 1. In the section "Ethical considerations", the registration number of the study was incorrectly given as UMIN000024492. The correct number is UMIN0000 20267. 2. The Acknowledgments paragraph was incomplete.

Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis

SummaryIntestinal fractional calcium absorption (FCA) was assessed before and after vitamin D3 treatment. Serum 1,25(OH)2D concentration was significantly increased by plain vitamin D3 and reduced by eldecalcitol. The 1α hydroxyl calcidiol and eldecalcitol treatments increased FCA, which may be induced through direct stimulation of vitamin D receptors in the intestine.IntroductionTo assess the effects of vitamin D3 compounds on intestinal FCA and calcium-regulating hormones in post-menopausal osteoporosis, a randomized open-label prospective study was conducted.MethodsForty eligible patients were allocated randomly into four groups: eldecalcitol (ELD; 0.75 μg/day), 1α hydroxyl calcidiol (ALF; 1 μg/day), plain vitamin D3 (800 IU/day), and control. Before and after the 4-week treatment, intestinal FCA was estimated by using a double isotope method, and serum concentrations of calcium-regulating hormones and a bone turnover marker were measured.ResultsThe baseline FCA value of the participants was 21.5 ± 7.9% (mean ± SD) and was significantly correlated with serum 1,25(OH)2D (calcitriol) concentration. After the treatment, the FCA significantly increased by 59.5% (95% CI, 41.6 to 77.4%) in the ELD group and by 45.9% (27.9 to 63.8%) in the ALF group, whereas no significant change in the plain vitamin D3 group was found. Unlike the baseline FCA, post-treatment FCA exhibited no significant correlation with serum calcitriol concentration. Parathyroid hormone levels were suppressed by ALF and plain vitamin D3 but were sustained in the ELD and control groups. Serum calcitriol tended to be suppressed by ELD, whereas plain vitamin D3 treatment increased both serum 25(OH)D and calcitriol concentrations.ConclusionThese findings suggest that oral administration of vitamin D3 analogues (ALF and ELD) stimulates FCA but plain vitamin D3 does not. Those effects of vitamin D3 compounds on FCA were independent of serum calcitriol concentration, suggesting that ALF and ELD may directly stimulate intestinal vitamin D receptors.

Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the major controlling hormone of intestinal calcium absorption. As the body's demand for calcium increases from a diet deficient in calcium, from growth, pregnancy or lactation, the synthesis of 1,25(OH)(2)D(3) is increased resulting in the stimulation of intestinal calcium absorption. However a complete description of the molecular mechanisms involved in the 1,25(OH)(2)D(3) regulated calcium absorptive process remains incomplete. Intestinal calcium absorption occurs by both an active saturable transcellular pathway and a passive nonsaturable paracellular pathway. Each step in the process of transcellular calcium transport (apical entry of calcium, translocation of calcium through the interior of the enterocyte and basolateral extrusion of calcium by the plasma membrane pump) has been reported to involve a vitamin D dependent component. This article will review recent studies, including those using knockout mice, that have suggested that 1,25(OH)(2)D(3) mediated calcium absorption is more complex than the traditional three step model of transcellular calcium transport. Current concepts are reviewed and questions that remain are addressed. Evidence for a role of 1,25(OH)(2)D(3) in the regulation of the paracellular pathway is also discussed.

Comparative Effects of Vitamin K and Vitamin D Supplementation on Calcium Balance in Young Rats Fed Normal or Low Calcium Diets

We examined the effect of vitamin K and vitamin D supplementation on calcium balance in young rats fed a normal or low calcium diet. Eighty female Sprague-Dawley rats, 6 wk of age, were randomized by the stratified weight method into eight groups with 10 rats in each group: 0.5% (normal) or 0.1% (low) calcium diet, 0.5% or 0.1% calcium diet+vitamin K (vitamin K2, menatetrenone, 30 mg/100 g, food intake), 0.5% or 0.1% calcium diet+vitamin D (25 microg/100 g, food intake), and 0.5% or 0.1% calcium diet+vitamin K+vitamin D. The duration of the study was 10 wk. Vitamin K supplementation promoted the reduction in urinary calcium excretion and retarded the abnormal elevation of serum PTH level in rats fed a low calcium diet, and stimulated intestinal calcium absorption in rats fed a normal calcium diet. Vitamin D supplementation stimulated intestinal calcium absorption with prevention of the abnormal elevation of serum PTH levels and prevented hypocalcemia in rats fed a low calcium diet, and stimulated intestinal calcium absorption in rats fed a normal calcium diet. The stimulation of intestinal calcium absorption was associated with increased serum 1,25-dihydroxyvitamin D levels. An additive effect of vitamin K and vitamin D on intestinal calcium absorption was found only in rats fed a normal calcium diet. This study shows the differential effects of vitamin K and vitamin D supplementation on calcium balance in young rats fed a normal or low calcium diet.

Tissue distribution and activity studies of 1,24-dihydroxyvitamin D 2, a metabolite of vitamin D 2 with low calcemic activity in vivo

The active vitamin D compound 1α,24( S)-dihydroxyvitamin D 2 (1,24(OH) 2D 2) is under development as a therapy for disorders including cancer and secondary hyperparathyroidism. 1,24(OH) 2D 2 is a potent inhibitor of cell proliferation in vitro and, relative to calcitriol (1,25(OH) 2D 3), has reduced calcemic activity in vivo. To examine the mechanisms underlying this reduced calcemic activity, we studied the tissue distribution in rats of radiolabeled 1,24(OH) 2D 2 or 1,25(OH) 2D 3 over 24 h. Serum levels of 1,24(OH) 2D 2 were lower than those of 1,25(OH) 2D 3 at all time points; however, tissue levels of radiolabeled compounds followed different patterns. In duodenum and kidney, 1,24(OH) 2D 2 and 1,25(OH) 2D 3 rose to similar levels at early time points; 1,24(OH) 2D 2 levels then declined more rapidly. In bone marrow, 1,24(OH) 2D 2 and 1,25(OH) 2D 3 were present at similar levels at all time points. In liver, 1,24(OH) 2D 2 levels were two-fold higher than 1,25(OH) 2D 3 at 1 h post-injection, declining to similar levels by 8 h. In vitamin D-deficient rats, doses of 1,24(OH) 2D 2 30-fold higher than 1,25(OH) 2D 3 were required to produce equal stimulation of intestinal calcium absorption. In the same deficient animals, 1,24(OH) 2D 2 and 1,25(OH) 2D 3 were nearly equipotent at stimulating bone calcium mobilization. In cultured bone cells, 1,24(OH) 2D 2 and 1,25(OH) 2D 3 were equipotent at stimulating osteoclast formation and bone resorption. In summary, the reduced calcemic activity of 1,24(OH) 2D 2 may result from altered pharmacokinetics relative to 1,25(OH) 2D 3, resulting in relatively rapid decreases in 1,24(OH) 2D 2 levels and activity in target organs such as intestine. Further studies will be necessary to confirm these findings and to confirm the clinical utility of 1,24(OH) 2D 2.

Alzheimer disease and calcium

Calcium deficiency due to insufficient nutritional intake, poor intestinal absorption or excessive urinary loss leading to secondary hyperparathyroidism, increase of calcium influx into nerve cells causing cell death may lead to neuronal dysfunction and cell death as in dialysis encephalopathy with EEG changes and decrease of nerve conduction velocity in chronic renal failure and Alzheimer's disease in aging. Intracellular free calcium (Ca i) is increased in nerve cells showing neurofibrillar tangles associated with tau protein in Alzheimer's disease. Increase of Ca i facilitates presenilin mutation with consequent augmentation of short chain amyloid beta production which further increase Ca i. Peroxide radical production by amyloid beta and metals such as Fe, Cu and Mn is prompted by an increase of Ca i. Plasma membrane damage caused by lipid peroxidation further increases Ca i. Neurotoxic action of apolipoprotein E(4) increasing the risk for Alzheimer's disease may be explained by lipid peroxidation and rise of Ca i. Beneficial effect of estrogen in preventing Alzheimer's disease may also be explained by its anti-oxidant effect and stimulation of intestinal calcium absorption. By increasing calcium intake and administration of active form of vitamin D which cannot be sufficiently supplied by the aging kidney, one step forward should be made in the prevention and treatment of Alzheimer's disease.

The cecum does not participate in the stimulation of intestinal calcium absorption by calcitriol.

Intestinal Ca absorption from the diet consumed during one night was measured in male rats fed a normal (0.5%) Ca, low fiber (3% cellulose) diet by determining the decrease in 47Ca/47Sc ratio between diet and feces. One-half of the rats had been cecectomized 9 weeks previously at 14 weeks of age. Calcitriol injections, given intraperitoneally the morning of the experiment, stimulated fractional intestinal Ca absorption 2.5-fold in intact rats (16.9 +/- 2.0% to 42.2 +/- 1.8%) and 2.3-fold in cecectomized rats (20.1 +/- 1.4% to 46.8 +/- 1.2%). Similar results were obtained when the data were calculated in terms of total Ca absorption expressed as mg/day. Thus, although the cecum can absorb Ca when diets contain large amounts of digestible fiber, cecectomy does not influence the stimulation of intestinal Ca absorption induced by calcitriol in vitamin D-replete rats fed a low fiber diet.

Metabolic effects of thiazide and 1,25-(OH)2 vitamin D in postmenopausal osteoporosis

It was previously shown that the stimulation of intestinal calcium absorption by exogenous 25-hydroxyvitamin D (25-OHD) in postmenopausal women with osteoporosis was attenuated when thiazide was added, probably due to the suppression of endogenous synthesis of 1,25-(OH)2 vitamin D (1,25-(OH)2D). To test whether the above attenuation could be averted if exogenous 1,25-(OH)2D replaced 25-OHD, 10 women with postmenopausal osteoporosis participated in a three-phase study comprising control (pretreatment), treatment with 1,25-(OH)2D 0.5 microgram/day for 4 weeks, and combined 1,25-(OH)2D and trichlormethiazide (TZ) 2 mg/day for 4 weeks. The 1,25-(OH)2D treatment significantly increased serum 1,25-(OH)2D from 60 +/- 7.2 (SD) to 154 +/- 48 pmol/l, fractional intestinal calcium absorption (alpha) from 0.386 +/- 0.055 to 0.613 +/- 0.081, and urinary calcium from 3.7 +/- 0.8 to 6.6 +/- 1.9 mmol/day. Addition of TZ significantly reduced urinary calcium from 6.6 +/- 1.9 to 4.8 +/- 1.3 mmol/day, without changing alpha (0.613 +/- 0.081 to 0.584 +/- 0.070), serum calcium or 1,25-(OH)2D (154 +/- 48 to 154 +/- 38 pmol/l). Thus, estimated calcium balance (absorbed minus urinary calcium, increased marginally to +5.6 mmol/day on 1,25-(OH)2D alone (p = 0.028) and significantly to +6.8 mmol/day on 1,25-(OH)2D+TZ, from the control value of +4.0 mmol/day. Seven patients who were treated long-term with combined 1,25-(OH)2D and TZ for 11-29 months maintained their alpha (0.593 +/- 0.099) and a marginally more positive estimated calcium balance (+6.4 mmol/day, p = 0.025 from the control phase). Moreover, there was a stability of bone density of radial shaft, femoral neck, and lumbar spine.(ABSTRACT TRUNCATED AT 250 WORDS)

Ovulation-associated stimulation of intestinal calcium absorption in female rats is blunted by ovariectomy

Ovulation-associated stimulation of intestinal calcium absorption in female rats is blunted by ovariectomy

1,25-Dihydroxyvitamin D3 analog structure-function assessment of the rapid stimulation of intestinal calcium absorption (transcaltachia).

The possibility is now emerging that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] can mediate biologic responses via both genomic and nongenomic pathways. To understand the molecular basis of the nongenomic response of transcaltachia, defined as the 1,25-(OH)2D3-mediated rapid (2-10 minutes) stimulation of calcium transport from the brush border to the basal lateral membrane of the epithelial cell in vitamin D-replete chick intestine, and to address the issue of whether the same receptor for the secosteroid serves as the signal transducer for both genomic and nongenomic pathways, we carried out structure-function studies using seven analogs of 1,25-(OH)2D3 with different affinities for the classic nuclear 1,25-(OH)2D3 receptor as measured by determination in a steroid competition assay of the relative competitive index (RCI). The RCI of 1,25-(OH)2D3 is by definition 100. 1,25-(OH)2D3 initiates transcaltachia within 2-10 minutes of vascular perfusion and yields a biphase response curve. Dose-dependent stimulations of Ca2+ transport by the seven analogs indicates that different structural features are essential for initiating the transcaltachic response as contrasted with binding to the classic nuclear receptor. Vascular perfusion with analogs AT (25-OH-16-ene-23-yne-D3) and Y (25-OH-23-yne-D3), which are known to activate Ca2+ channels but bind very poorly to the classic receptor (RCI less than 0.5), are efficient in stimulating Ca2+ transport. By comparison, compounds BT [1 alpha,24S-(OH)2-22-en-26,27-dehydrovitamin D3] and V (1,25-(OH)2-16-ene-23-yne-D3], which bind very well to the classic nuclear receptor (RCI 75-111) but do not activate Ca2+ channels, are inefficient in stimulating Ca2+ transport. These results indicate that the membrane components that respond to the analogs of 1,25-(OH)2D3 with activation of Ca2+ channels have a different ligand specificity than the classic nuclear receptor.

Synthesis and biological activity of 1α,23,25,26-tetrahydroxyvitamin D 3

The metabolic pathway from 1α,25-dihydroxyvitamin D 3 [1α,25-(OH) 2D 3] to 1α,25-dihydroxyvitamin D 3-26,23-lactone includes the formation of 1α,23,25,26-tetrahydroxyvitamin D 3 [1α,23,25,26-(OH) 4D 3]. The aim of the current study was to explore the as yet unknown biological properties of this vitamin D 3 sterol. The four diastereoisomers of 1α,23,25,26-(OH) 3D 3 were chemically synthesized. They were compared to 1α,25-(OH) 2D 3 in terms of their affinity for the chick intestinal 1α,25-(OH) 2D 3 receptor and their biologic activity in vivo (stimulation of intestinal calcium absorption and mobilization of calcium from bone in vitamin D-deficient rats). The 1,25-(OH) 2D 3 receptor binding affinities of 1α,23( R)25( R)26-(OH) 4D 3, 1α,23( S)25( S)26-(OH) 4D 3, 1α,23( S)25( R)26-(OH) 4D 3, and 1α,23( R)25( S)26-(OH) 4D 3 were 11,100,216, and 443 times weaker than the binding affinity of 1α,25-(OH) 2D 3, respectively. Compared to 1α,25-(OH) 2D 3, the relative capacities of the 1α,23,25,26-(OH) 4D 3 compounds to stimulate intestinal calcium absorption were 1 4 for 1α,23( R)25( R)26-(OH) 4D 3; 1 19 for 1α,23( S)25( S)26-(OH) 4D 3; 1 90 for 1α,23( S)25( R)26-(OH) 4D 3; and 1 136 for 1α,23( R)25( S)26-(OH) 4D 3. Maximal stimulation of intestinal calcium transport occurred 8 h after administration of vitamin D 3 metabolites. Mobilization of calcium from bone was quantitated by serum calcium concentration measurements. The activities of 1α,23( R)25( R)26-(OH) 4D 3, 1α,23( S)25( S)26-(OH) 4D 3, 1α,23( S)25( R)26-(OH) 4D 3, and 1α,23( R)25( S)26-(OH) 4D 3 to increase serum calcium were estimated to be 4, 13, 43, and 69 times weaker than that of 1α,25-(OH) 2D 3, respectively. These results illustrate the stereospecificity of the chicken intestine 1α,25-(OH) 2D 3 receptor for binding of 1α,23,25,26-(OH) 4D 3 and suggest that the 1α,23,25,26-(OH) 4D 3 exerts its biological activity in the rat through an interaction with 1,25-(OH) 2D 3 receptors. In summary, the 1α,23,25,26-(OH) 4D 3 had a markedly lower biological activity than 1α,25-(OH) 2D 3.

25-Hydroxyvitamin D3Metabolism by Lipopolysaccharide-Stimulated Normal Human Macrophages*

Cultured normal human pulmonary alveolar macrophages and peripheral blood monocyte-derived macrophages were studied for their capacity to metabolize [3H]25-hydroxyvitamin D3 (25OHD3). Incubation of macrophages with bacterial lipopolysaccharide (LPS) resulted in the conversion of [3H]25OHD3 to a more polar vitamin D3 metabolite (up to 15 pmol/10(6) cells). Untreated macrophages did not synthesize this metabolite. Several findings suggested that the metabolite was the biologically active form of vitamin D3, namely 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. (1) The metabolite comigrated with chemically synthesized 1,25-(OH)2D3 on four different high performance liquid chromatographic systems. (2) The metabolite had the same affinity for the chick intestinal 1,25-(OH)2D3 receptor as authentic 1,25-(OH)2D3. (3) The biological activity of the macrophage metabolite in vivo (stimulation of intestinal calcium absorption and bone calcium mobilization in rachitic chicks) was identical to the activity of chemically synthesized 1,25-(OH)2D3. The LPS-stimulated synthesis of the 1,25-(OH)2D3-like compound by macrophages was dose dependent in a linear fashion; a half-maximal response was typically found with 100-200 ng LPS/10(6) cells. Polymyxin B abolished the effects of LPS on 25OHD3 metabolism in macrophages. Our data suggest that LPS-stimulated macrophages can modulate, on a local level, the function of 1,25-(OH)2D3-responsive cells by releasing the 1,25-(OH)2D3-like metabolite.

Aspirin inhibition of 1α-hydroxyvitamin D 3 or parathyroid hormone induced hypercalcemia in vivo in rats : A mechanism independent of prostaglandin biosynthesis inhibition

The interactions of calcium-regulating hormones, active forms of vitamin D and parathyroid hormone, and aspirin were studied in rats. Aspirin, a prostaglandin biosynthesis inhibitor, abolished the hypercalcemia induced by 1α-hydroxyvitamin D 3 at 20, 50 and 100 mg/kg p.o. in parathyroidectomized or thyroparathyroidectomized rats with or without vitamin D deficiency, and in thyroparathyroidectomized plus nephrectomized rats. Aspirin did not affect the stimulation of intestinal calcium absorption by 1α-hydroxyvitamin D 3. By contrast, indomethacin, another prostaglandin biosynthesis inhibitor, did not affect hypercalcemia or stimulation of intestinal calcium absorption by 1α-hydroxyvitamin D 3. Aspirin also abolished the hypercalcemie action of parathyroid hormone in rats with or without intact thyroparathyroid glands. Moreover, aspirin alone caused hypocalcemia in rats with intact thyroparathyroid glands. Indomethacin had no effect in either of these systems. These data suggest that aspirin may inhibit bone resorption by the active form of vitamin D or parathyroid hormone via a mechanism independent of prostaglandin biosynthesis inhibition.

An apparent 1,25-dihydroxyvitamin D-independent stimulation of intestinal calcium absorption in patients with paget disease of bone during a short-term diphosphonate therapy

Six patients with Paget disease of bone were treated with a 6-mo course of disodium-ethane-1-hydroxy-1, 1-diphosphate (EHDP) at a dosage of 5 mg/kg/day (one patient) or 20 mg/kg/day (five patients). In addition to symptomatic and biochemical improvement which persisted 3 mo after discontinuance of therapy, EHDP resulted in a significant increase in intestinal calcium absorption that was not correlated with a change in serum 1α,25-(OH) 2-vitamin D concentration. EHDP appears to stimulate intestinal calcium transport by either a vitamin D independent process or by an increased intestinal mucosal cell sensitivity to vitamin D.

Effect of 1,25-dihydroxyvitamin D 3 on intestinal calcium absorption in strontium-fed rats

These studies investigated the initial stimulation of intestinal calcium absorption in the rat by 1,25-dihydroxyvitamin D 3. To produce a functional vitamin D 3-deficiency, rats were fed a diet containing 2.4% strontium. After 10 days on the diet, intestinal calcium uptake, as measured by everted gut sacs, was significantly depressed. Strontium-fed rats were dosed orally with 1,25-dihydroxyvitamin D 3, and changes in intestinal calcium uptake, intestinal alkaline phosphatase activity, and intestinal calcium-binding protein were measured as a function of time after dose. Calcium uptake was significantly increased in the proximal 2.5 cm of the duodenum at 4 h and along the whole duodenum by 7 h. Intestinal alkaline phosphatase activity, measured in a Triton extract of the mucosal homogenate and in isolated brush border complexes, was also increased by 7 h. Using both gel electrophoresis and immunodiffusion against a specific antiserum, an increase in intestinal calcium-binding protein was detected in intestinal supernate at 4 h after dosing. Almost no calcium-binding protein was detectable in strontium-fed rats dosed with propylene glycol only. These time studies are consistent with a role for both alkaline phosphatase and calcium-binding protein in the 1,25-dihydroxyvitamin D 3-stimulated uptake of calcium by the intestine. In addition, the usefulness of strontium feeding for producing a functional vitamin D 3 deficiency in rats is demonstrated.

Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism

To understand better dietary regulation of intestinal calcium absorption, a quantitative assessment of the metabolites in plasma and duodenum of rats given daily doses of radioactive vitamin D 3 and diets differing in calcium and phosphorus content was made. All known vitamin D metabolites were ultimately identified by high-pressure liquid chromatography. In addition to the known metabolites (25-hydroxyvitamin D 3, 24,25-dihydroxyvitamin D 3, 1,25-dihydroxyvitamin D 3, 25,26-dihydroxyvitamin D 3, and 1,24,25-trihydroxyvitamin D 3), several new and unidentified metabolites were found. In addition to 1,25-dihydroxyvitamin D 3 and 1,24,25-trihydroxyvitamin D 3, the levels of some of the unknown metabolites could be correlated with intestinal calcium transport. However, whether or not any of these metabolites plays a role in the stimulation of intestinal calcium absorption by low dietary calcium or low dietary phosphorus remains unknown.

Effects of 1α-hydroxy-vitamin D 3 and 1,25-dihydroxy-vitamin D 3 on calcium and phosphorus metabolism in hypoparathyroidism

The effects of 1α-OH D 3 or 1,25-(OH) 2D 3 on calcium and phosphorus metabolism have been evaluated in five hypoparathyroid patients to establish the direct effects of these compounds in adult humans, uncomplicated by compensatory changes in parathyroid hormone secretion. Doses of 1–2.5 μg/day in four patients (5 μg/day in a fifth patient on diphenyl-hydantoin and phenobarbital) caused a marked increase in serum calcium concentration and urinary calcium excretion, without significant changes in renal calcium clearance or urinary hydroxyproline excretion. These results suggest that the correction of hypocalcemia involved primarily a stimulation of intestinal calcium absorption rather than a stimulation of skeletal calcium resorption. Simultaneously, there were increases in urinary phosphorus excretion and variable changes in serum inorganic phosphate concentration. These effects were produced by doses of 1α-OH D 3 and 1,25-(OH) 2D 3 which approach the dose needed to prevent rickets, in contrast to the very large doses of vitamin D or 25-OH D 3 required for comparable effects in hypoparathyroid patients. The increased relative effectiveness of these one-hydroxylated forms of vitamin D reveals a deficiency of vitamin D one-hydroxylation in hypoparathyroidism. The rapidity of action of 1α-OH D 3 and 1,25-(OH) 2D 3 was also striking. Apart from its physiologic implications, the potency of the one-hydroxylated forms of vitamin D offers significant therapeutic advantages in some patients whose hypoparathyroidism is difficult to control with vitamin D itself.

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.

Biologic effects of 1,25-dihydroxycholecalciferol (a highly active vitamin D metabolite) in acutely uremic rats.

The development of a vitamin D-resistant state in the course of renal failure may be responsible for reduced intestinal absorption of calcium and an impaired response of skeletal tissue. Moreover, the kidney has been shown to carry out the conversion of 25-hydroxycholecalciferol (25-OH-CC) to a highly biologically active metabolite, 1,25-dihydroxycholecalciferol (1,25-diOH-CC). In the present studies, vitamin D-deficient rats, made acutely uremic by either bilateral nephrectomy or urethral ligation, received physiological doses of cholecalciferol (vitamin D(3)) (CC), 25-OH-CC or 1,25-diOH-CC; 24 hr later intestinal calcium transport, in vitro, and bone calcium mobilization, in vivo, were assessed. Whereas CC and 25-OH-CC stimulated calcium transport in sham-operated controls, they were without effect in the uremic animals. In contrast, administration of 1,25-diOH-CC stimulated calcium transport in both groups of uremic animals. Administration of 1,25-diOH-CC also stimulated calcium mobilization from bone in each group of animals. However, CC and 25-OH-CC were only effective in the sham controls and the uremic group produced by urethral ligation and had little or no effect in animals without kidneys. These results indicate that renal conversion of calciferol to a more biologically active form is necessary for the stimulation of intestinal calcium absorption and calcium mobilization from bone, and that 1,25-diOH-CC may bypass a possible defect in vitamin D metabolism in uremia. From these studies it is likely that uremia, per se, may also impair intestinal calcium transport.