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PubMed1986

Na,K-ATPase activity and 25(OH)vitamin D3 hydroxylation in rat proximal tubules.

The proximal tubule is the target site for parathyroid hormone (PTH), and conversion of 25(OH)vitamin D3 hormones which impinge on calcium (Ca) homeostasis, as well as a major site for sodium (Na) reabsorption. The effect of changes in PTH and vitamin D status on Na,K-ATPase activity, as a measure of Na transport, were studied in the proximal tubules of adult rat kidneys where Na and Ca reabsorption rates are in parallel. Na,K-ATPase activity and 25(OH)D3 metabolism were determined in cortical and juxtamedullary proximal tubule segments from normal, parathyroidectomized (PTX), and vitamin D-deficient (-D) rats. Na,K-ATPase activity was highest in cortical segments. PTX led to a decrease in activity in convoluted segments but increased activity in straight segments. In -D rats, Na,K-ATPase activity decreased in cortical segments but increased in juxtamedullary segments. 25(OH)D3 was metabolized more to 24,25(OH)2D3 than to 1,25(OH)2D3 in all normal segments. Juxtamedullary segments were more sensitive to PTX and -D conditions. These findings suggest that cortical and juxtamedullary nephrons are inherently different in basal Na,K-ATPase activity, in conversion of 25(OH)D3 to active metabolites, and in response to altered PTH and vitamin D3 status.

Animals↗
PubMed1983

Blockade of the renal tubular effects of vitamin D by cycloheximide in the rat.

To further characterize the mechanisms by which 25(OH) vitamin D3 (25(OH)D3) and 1.25(OH)2 vitamin D3 (1,25(OH)2D3) suppress the phosphaturic action of parathyroid hormone (PTH) we have studied the effects of cycloheximide (cyclohex), a protein synthesis inhibitor, on the interaction between PTH and vitamin D metabolites in parathyroidectomized (PTX) rats, both in vivo and in vitro experiments. In clearance studies PTX PTH-infused rats were pretreated with cyclohex 2 h before the administration of vitamin D. In control, PTX PTH-infused rats not pretreated with cyclohex, the administration of 25(OH)D3 and 1,25(OH)2D3 was associated with a fall in fractional excretion of phosphate (CP/CIN) from 0.30 +/- 0.05 to 0.16 +/- 0.02 and from 0.31 +/- 0.05 to 0.13 +/- 0.01 (P less than 0.005) respectively. Cyclohex-pretreated PTX PTH-infused rats failed to respond to both 25(OH)D3 and 1,25(OH)2D3, and CP/CIN, which rose after PTH, remained 0.32 +/- 0.05 and 0.29 +/- 0.03 respectively. In vitro, both 25(OH)D3 and 1,25(OH)2D3 inhibited the PTH-induced activation of adenylate cyclase in the renal isolated membrane fractions. Pretreatment with cyclohex abolished this effect of vitamin D metabolites. These results show that cyclohex blocks the antiphosphaturic effects of both 25(OH)D3 and 1,25(OH)2D3 but does not alter the response to PTH. These findings are consistent with the possibility that the acute renal action of vitamin D depends on de novo synthesis of protein.

Adenylyl Cyclases↗
PubMed1990

Antigenic and catalytic disparity in the distribution of cytochrome P-450-dependent 25-hydroxyvitamin D3-1 alpha- and 24-hydroxylases.

Chick 25-hydroxyvitamin D3-1 alpha-hydroxylase, a cytochrome P-450 monooxygenase with a molecular weight of 57 kDa, can be isolated as described by Mandel et al. (1990 b). Under normal physiological circumstances, it occurs exclusively in kidney mitochondria. An isozyme of the 1 alpha-hydroxylase, known as the 24-hydroxylase, which uses the same substrate to yield an isomeric product, is also a cytochrome P-450 monooxygenase, has a molecular weight of 55 kDa, and like-wise occurs in kidney mitochondria. The amino-terminal sequences of the first 10 residues of the two isozymes are 100% homologous. Monoclonal antibodies of the IgM class raised against the 1 alpha-hydroxylase, which quantitatively discriminate against other P-450 cytochromes of mitochondrial or microsomal origin, recognize and interact with the 24-hydroxylase as an antigen. In the present study we show that the intestine, which is the only non-renal tissue with demonstrable 24-hydroxylase activity, gives a positive peroxidase-antiperoxidase immunohistochemical reaction using the monoclonal antibodies against the 1 alpha-hydroxylase. The reactions revealed that the antigen in the kidney is restricted to the cortical proximal tubular cells while in the intestine, the antigen is localized in the enterocytes of the villi. In kidney medullary or intestinal crypt cells, or in liver, heart and lung tissues where 1 alpha-hydroxylase or 24-hydroxylase activity could not be detected using cell or tissue homogenates, the immunohistochemical reactions were also negative.(ABSTRACT TRUNCATED AT 250 WORDS)

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1996

Effect of seasonal ultraviolet radiation fluctuations on vitamin D homeostasis during an Antarctic expedition.

Antarctica is a unique and challenging environment where members of expeditions face a range of conditions not normally experienced. Ultraviolet (uv) radiation levels show marked variation during the year. The 25-hydroxy metabolite of vitamin D [25(OH)D] is largely produced by sunlight and shows a yearly variation in concentration that corresponds to uv radiation levels. The active metabolite 1,25-dihydroxyvitamin D [1,25(OH)2D] does not generally show any such variation provided 25(OH)D concentrations are sufficient. Previous studies have shown a seasonal variation in 25(OH)D with a significant winter drop. No other study of 1,25(OH)2D has been reported on members of Antarctic expeditions. A group of 19 men wintering at Davis Station (68 degrees 34' S) had four blood samples taken at 3-monthly intervals beginning in the Antarctic summer. Analysis for 25(OH)D showed a drop in concentration for each of the latter three sampling periods (P < 0.005). This correlated with uv radiation levels and would suggest that endogenous production of 25(OH)D ceases for at least the duration of the Antarctic winter. There were no significant alterations in 1,25(OH)2D or calcium concentrations over the same period. Providing that individuals with pre-existing vitamin D deficiencies are detected before departure for Antarctica and missions are limited in duration, clinical deficiency is unlikely to occur.

Adult↗
PubMed1988

Vitamin D metabolite profiles in moderate renal insufficiency of childhood.

In a prior study, we reported vitamin D metabolite profiles in the plasma of healthy children. In view of these findings, we investigated these same profiles in children with moderate renal insufficiency. Specimens were obtained in both summer and winter in untreated patients, and before and after treatment for up to 1 year, with either 25(OH)D3 or 1,25(OH)2D3. Mean pretreatment 1,25(OH)2D levels were normal. Levels of 25(OH)D3 were also normal and continued to vary with season. Mean pretreatment 24,25(OH)2D3 levels were significantly lower in patients and, interestingly, did not show the normal seasonal variation. Treatment with 25(OH)D3 resulted in consistent and sustained rises in 25(OH)D3 and 24,25(OH)2D3 levels, but no increase in 1,25(OH)2D levels. After 1,25(OH)2D3 treatment, 25(OH)D3 levels were unchanged but still showed seasonal variation in some patients, suggesting a lack of feedback control by 1,25(OH)2D3. Levels of 24,25(OH)2D3 were not significantly different from baseline values. Levels of 1,25(OH)2D increased initially then dropped to pretreatment levels or lower. Normal 1,25(OH)2D levels and reduced 24,25(OH)2D3 levels with the loss of seasonal variation suggests in our patients that the kidney was able to maintain 1,25(OH)2D levels at the expense of 24,25(OH)2D3 levels, presumably to preserve calcium homeostasis.

24,25-Dihydroxyvitamin D 3↗
PubMed1993

Bone metabolism before and after irradiation with ultraviolet light.

The beneficial effects of ultraviolet light on cutaneous vitamin D synthesis, calcium metabolism, and bone formation are well known. Regarding the increasing fear of side effects from ultraviolet B (UV-B), lamps with less energy in the UV-B range have been developed. Two spectra with differences in the emission of UV-B have therefore been evaluated for their influence on calcium metabolism. A group of 24 healthy male volunteers was subdivided into two treatment groups. Group 1 was exposed to lamps with higher energy of total UV-B but less energy at the wavelengths below 300 nm than the lamps used in group 2. All subjects were irradiated ten times within 12 days. Exposure time was 3 min in the first session and time of exposure was increased by 10% in every following irradiation (suberythematous doses only). Before the first irradiation, 3 days after the last exposure, and after 4 more weeks, the serum parameters of bone metabolism were determined by standard laboratory methods. Significantly increased levels of 25-hydroxyvitamin D3 were found in both groups. There was only a slight increase of 1,25-dihydroxyvitamin D3. Parathyroid hormone decreased significantly in group 2 only. The data would suggest beneficial effects on bone metabolism for both regimens. The observed effects were more pronounced when shorter wavelengths (group 2) were applied, although the total energy of UV-B was lower in these lamps.

Adult↗
PubMed1988

Vitamin D metabolism and phosphate transport in developing kidney: effect of diet and mutation.

In order to obtain a better understanding of the molecular mechanisms involved in phosphate reabsorption and vitamin D hormone production by mammalian kidney, we have devoted our efforts to the study of a mutant mouse model (Hyp). Studies from our laboratory have demonstrated that Na(+)-dependent phosphate transport is significantly reduced in renal brush border membrane vesicles derived from Hyp mice and that the regulation of the renal mitochondrial enzymes which metabolize 25-hydroxyvitamin D3 (25-OH-D3) is impaired in the mutant strain. The demonstration of abnormal phosphate transport and 25-OH-D3 metabolism in proximal tubule cells derived from Hyp kidney after 6-8 days in culture indicates that the mutant renal phenotype is independent of circulating factors and, therefore, intrinsic to the kidney. However, the precise relationship between these two proximal tubular abnormalities is poorly understood. Because the Hyp mutation segregates as a Mendelian trait, it is very likely that one mutant gene is responsible for the biochemical and clinical phenotype. Several hypotheses are put forth to explain the nature of the primary mutation in the Hyp mouse.

Animals↗
PubMed1989

Active metabolites of vitamin D in patients with coxarthrosis and with aseptic loosening of total hip endoprostheses.

The blood levels of the active metabolites of vitamin D--25-hydroxycholecalciferol (25(OH)D), 1,25 dihydroxycholecalciferol (1,25(OH)2D), and 24,25 dihydroxycholecalciferol (24,25(OH)2D)--were determined in 15 patients suffering from arthrosis of the hip and in 13 patients with aseptic loosening of total hip endoprostheses. Normal values were found in all but one patient with aseptic loosening, in whom 24,25(OH)2D was not detectable. The difference between the two groups of patients was not statistically significant.

Adult↗
PubMed1993

Bone turnover in rats treated with 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D3 or 24,25-dihydroxyvitamin D3.

Female rats were given 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 0.25 microgram per 100 g body weight (bw), 25-hydroxyvitamin D3 (25(OH)D3), 1.7 micrograms/100 g bw or 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) 1.7 micrograms/100 g bw, subcutaneously three times a week for 12 weeks. Traditional variables pertaining to calcium homeostasis and growth, i.e. blood and urine calcium (Ca) and phosphate (P), serum levels of vitamin D3 metabolites parathyroid hormone, (PTH), calcitonin (CT), prolactin (PRL) and growth hormone (GH) were measured every four weeks. This data pool was correlated with bone matrix turnover parameters, i.e. serum levels of alkaline phosphatase (ALP) and urinary hydroxyproline (u-HYP) excretion. After 12 weeks of treatment, 1,25(OH)2D3 significantly enhanced serum total and ionized Ca, urine Ca and urine P, and also diminished urine cAMP due to reduced renal function (creatinine clearance). However, 25(OH)D3 administration had no such impact. 24,25(OH)2D3 opposed the effect of 1,25(OH)2D3 after 12 weeks by significantly augmenting serum P and diminishing serum levels of total Ca and ionized Ca. Cross sectional group analyses showed that circulating levels of ALP were directly related with serum 1,25(OH)2D3 and inversely related to serum 24,25(OH)2D3 and CT. Total u-HYP and per cent non-dialysable HYP (ndHYP) were reciprocally and positively correlated with serum PRL, respectively. However, no such relations were observed with serum GH. It appears that rats with elevated circulating levels of 1,25(OH)2D3 exhibit increased bone resorption, while augmented 24,25(OH)2D3 is associated with the opposite. Apparently, high bone turnover (i.e. reduced total urinary HYP and enhanced ndHYP) is associated with high serum PRL.

24,25-Dihydroxyvitamin D 3↗
PubMed1986

Biliary excretion of radioactivity after intravenous administration of [3H]25-hydroxyvitamin D3 in man.

The biliary excretion of radioactivity after intravenous [3H]25-hydroxyvitamin D3 was studied in nine patients with T-tube bile drainage. The mean +/- SD 24-hr radioactivity excretion in T-tube bile expressed as a percentage of the administered dose was 6.7 +/- 2.9%; after correction for incomplete bile collection, the value obtained was 16.0 +/- 11.1%. Chloroform solubility of biliary radioactivity increased from 27.4 +/- 8.9% to 72.9 +/- 10.1% following incubation with beta-glucuronidase. High-performance liquid chromatographic analysis of chloroform extracts of bile revealed that most of the eluted radioactivity was more polar than [3H]25-hydroxyvitamin D3. No free [3H]25-hydroxyvitamin D3 was demonstrated. Thus in man, most of the biliary radioactivity excreted following [3H]25-hydroxyvitamin D3 is in the form of water-soluble compounds, mainly glucuronides. However, our results suggest that glucuronides of metabolites other than 25-OHD3 are predominantly formed.

Adult↗
PubMed1993

Molybdenum-induced changes in the epiphyseal growth plate.

Molybdenum (Mo), at high concentrations, induces changes in the epiphyseal growth plate through its effects on copper (Cu) metabolism but it is unclear whether or not Mo can induce changes independent of its effects on copper status. To this end, the effect of Mo on longitudinal bone growth was examined in rats. Dietary Mo was given either as ammonium heptamolybdate or as ammonium tetrathiomolybdate, the latter producing a marked Cu deficiency. There was a significant reduction in longitudinal bone growth in both groups; however, growth plate width was increased only in the Cu-deficient animals due to an increase in the width of the zone of transitional/hypertrophic chondrocytes. Both glucose 6-phosphate dehydrogenase activity and cell proliferation (assessed by bromodeoxyuridine incorporation) were markedly decreased in the proliferating zone of the growth plate in both Mo-treated groups. These changes were not apparently related to changes in circulating vitamin D metabolites or insulin-like growth factor-1. The results indicate that excess Mo impairs cell proliferation within the growth plate, whereas the effects of copper deficiency are more related to chondrocyte differentiation. Thus, Mo can induce changes in longitudinal bone growth which are distinct from those resulting from Cu deficiency.

Alkaline Phosphatase↗
PubMed1989

Bone disease in vitamin D-deficient patients with Crohn's disease.

Vitamin D deficiency is frequently observed in patients with Crohn's disease and may be associated with an increased risk of development of metabolic bone disease. To estimate the incidence of metabolic bone disease by noninvasive methods, 31 patients (17-75 years old) with Crohn's disease and low 25-hydroxyvitamin D (25-OHD) levels in winter were investigated in the following summer by measuring the bone mineral content (BMC) of the distal radius by single photon absorptiometry and the cortical area ratio (CAR) calculated from radiographs of the right hand and by x-ray of the lumbar spine. Forty-five percent of the patients showed signs of metabolic bone disease. BMC and CAR correlated with 25-OHD serum levels (P less than 0.05), especially in men. Furthermore, the amount of sun exposure has an influence not only on 25-OHD serum levels both in summer and in winter (P = 0.0006), but also on the BMC (P = 0.07). Consequently, vitamin D deficiency is of major importance for the development of metabolic bone disease in patients with Crohn's disease. Vitamin D deficiency can be prevented by increasing sun exposure and long-term vitamin D supplementation.

Adolescent↗
PubMed1996

Effect of ovariectomy on bone histology and plasma parameters of bone metabolism in nulliparous and multiparous sows.

To investigate the suitability of the pig as animal model for postmenopausal osteoporosis, effects of ovariectomy (OVX) on bone metabolism and histology were studied in two groups of sows (9 months, nulliparous or 35 months, multiparous). A standard diet of about 1.5% calcium (Ca) was fed till sacrifice at either 12 or 20 months post OVX when mineral content and histology were studied in representative bone specimens of proximal tibia, iliac crest and lumbar vertebrae. At 4, 8, 12, and 18 months post OVX, total and bone-specific alkaline phosphatase (APt, APb) calcidiol, calcitriol and parathyroid hormone (PTH) were measured in plasma. In young sows OVX did not significantly affect plasma variables except for calcitriol, which was higher at 4 months post OVX. No significant differences between OVX or control animals were observed in the variables of bone chemical and histological analyses, neither 12 nor 20 months post OVX. In multiparous sows OVX significantly increased PTH plasma concentrations at 8 months post OVX and plasma calcitriol, APt and APb at 12 months post OVX. All effects were moderate and transient. OVX did not significantly affect the variables of bone chemical and histological analyses neither 12 nor 20 months post OVX. Although undoubtedly the clinical-chemical changes observed were not accompanied by any histomorphometric signs of osteopenia/osteoporosis, it must be left to future experiments as to whether this resulted from the ample calcium supply provided. This possibility is supported by recent observations showing that porcine osteopenia could be induced by OVX in animals maintained on only 0.75% dietary calcium but not on higher (0.9%) Ca regimens.

Aging↗
PubMed1993

Bone loss after cardiac transplantation: effects of calcium, calcidiol and monofluorophosphate.

Of 203 patients who underwent cardiac transplantation and were given long-term treatment with cyclosporine and 0.3 mg/kg per day prednisone, 123 were studied prospectively for at least 6 months and 46 for up to 2 years to evaluate the effects on lumbar bone mineral density (BMD) and calcium metabolism of a combined therapy with calcium, calcidiol and disodium monofluorophosphate (MFP). The population was arbitrarily assigned to one of two groups. Group I consisted of patients who had a lumbar spine BMD Z score above -1.5 SD as compared with an age- and sex-matched population and no vertebral fractures. They received daily 1 g elemental calcium and 25 micrograms (1000 IU) calcidiol. Group II consisted of patients who received daily the same doses of calcium and calcidiol combined with 200 mg MFP, and was divided into two subgroups: (a) osteopenic subjects who had a lumbar spine BMD Z score below -1.5 SD without vertebral fractures and (b) osteoporotic subjects with vertebral fractures. If serum creatinine was higher than 140 mumol/l the daily dose of MFP was tapered to 100 mg. Fifty-four and 27 patients from group I and 38 and 19 patients from group II were followed respectively for 12 and 24 months. In both groups serum parathyroid hormone levels were significantly reduced from the twelfth month in parallel with a significant increase in serum 25-OHD levels. No decline in lumbar BMD occurred in non-osteopenic and non-osteoporotic patients (group 1) who received the calcium and calcidiol supplement. In group II, where MFP was added, a significant and linear increase in lumbar BMD was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentration in elderly patients.

In 50 patients of a geriatric hospital (33 women, aged 65-96 years, mean age 80 years, and 17 men, aged 68-91, mean age 78.3 years) calcium, albumin, phosphate, urea, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were determined. Forty patients with serum creatinine levels up to 1.4 mg/dl (124 mumols/l) and 10 patients with creatinine concentrations greater than or equal to 1.5 mg/dl (132 mumols/l) were evaluated. In patients with normal creatinine, a positive correlation was found between parathyroid hormone and age (r = 0.41; P less than 0.01). In patients with elevated creatinine, negative correlations were found in 1,25-dihydroxyvitamin D and calcium (r = -0.724; P less than 0.05), 1,25-dihydroxyvitamin D and creatinine (r = -0.79; P less than 0.01) and 1,25-dihydroxyvitamin D and phosphate (r = -0.87; P less than 0.002). The best correlation was observed in patients with elevated serum creatinine for 1,25-dihydroxyvitamin D and phosphate (r = -0.91; P less than 0.001). The results suggest that low levels of calcium and phosphate stimulate the 1-hydroxylation of 25-hydroxyvitamin D even in advanced age and that the calcium metabolism of these patients is frequently disturbed. Nineteen patients had low levels of 25-hydroxyvitamin D, indicating an insufficient supply of vitamin D or rare exposure to sunlight. In 49 of 50 patients, one ore more of the parameters of calcium metabolism were outside the normal range.

Aged↗
PubMed1984

25-Hydroxyvitamin D, 24, 25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid.

Samples of CSF and plasma were obtained simultaneously from 46 adult patients who had no endocrine disorders and were undergoing routine diagnostic lumbar puncture because of suspected or proved prolapse of a disc. Concentrations of 25-OHD, 24,25(OH)2D and 1,25(OH)2D were measured. The samples were purified by column chromatography and fractionated by HPLC. In the appropriate fractions the vitamin D metabolites were measured by PBA, and cytoreceptor assay. The results were as follows (median, range in brackets): 25-OHD in CSF 8.3 ng/ml (2.0-24.8), in plasma 14.5 ng/ml (7.0-36.0). 24,25(OH)2D in CSF 1.8 ng/ml (0.3-4.6) and 2.5 ng/ml (0.4-4.7) in plasma. 1.25(OH)2 D in CSF 25.0 pg/ml (2.2-39.0) and 31.0 pg/ml (10.1-55.0) in plasma. The correlations between plasma and CSF concentrations were as follows: 25-OHD r = 0.479 (P less than 0.001); 24,25(OH)2D r = 0.815 (P less than 0.001) and for 1.25(OH)2D r = 0.497 (P less than 0.001). Our findings showed vitamin D metabolites to be present in human CSF.

24,25-Dihydroxyvitamin D 3↗