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PubMed1988

The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects.

Vitamin D deficiency is common in the elderly and may lead to secondary hyperparathyroidism, cortical bone loss, and hip fractures. The effect of vitamin D supplementation for 1 yr was studied in 72 people living in a nursing home and 70 people living in an aged people's home. The subjects were randomized into 3 groups: control, and 400 or 800 IU vitamin D3/day. The initial vitamin D status of each subject was classified as deficient or borderline [serum 25-hydroxyvitamin D (25OHD) less than 30 nmol/L] in 79% and adequate (serum 25OHD greater than or equal to 30 nmol/L) in 21%. Serum 25OHD concentrations increased about 3-fold in both groups receiving vitamin D supplementation. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations increased slightly but significantly, and the increase was inversely related to the initial serum 25OHD concentration. Serum intact PTH-(1-84) concentrations decreased about 15% during supplementation in both nursing home and aged people's home residents, whereas serum osteocalcin significantly decreased in the nursing home residents only. We conclude that a vitamin D3 supplement of 400 IU/day adequately improves vitamin D status in elderly people and increases 1,25-(OH)2D concentrations in those with vitamin D deficiency. Supplementation decreases parathyroid function and may depress bone turnover to some degree.

Aged↗

PubMed1994

Renal and intestinal calcium transport: roles of vitamin D and vitamin D-dependent calcium binding proteins.

A model has been presented here for vitamin D-dependent Ca transport, based on observations of the intestinal Ca absorption process. In this model of vitamin D-dependent Ca transport, processes that occur in different areas of the intestinal epithelial cell combine to result in active transport of Ca2+ from the intestinal lumen to the bloodstream. At the brush-border membrane, 1,25(OH)2D3 causes a rapid opening of Ca2+ channels and transport of Ca2+ into the cell in a matter of seconds to minutes by a process that is independent of gene transcription. Inside the cell, 1,25(OH)2D3 stimulates transcription of the CaBP-D9k/28k mRNA and protein in 1 or more hours after 1,25(OH)2D3 treatment. The CaBP-D9k/28k has greater affinity for Ca2+ than do the brush-border membrane components, so Ca2+ movement through the cytosol is facilitated, with Ca2+ carried by CaBP-D9k/28k. At the BLM, 1,25(OH)2D3 causes an increase in concentration of the PMCA, and stimulates Ca(2+)-pumping activity. The PMCA has still greater affinity for Ca2+ than does the CaBP-D9k/28k. The combination of these vitamin D-dependent events results in active transport of Ca across the intestinal epithelia. Vitamin D sufficiency is necessary for this response to vitamin D treatment. This model may apply to renal DT cells as well as to intestinal absorptive cells. Vitamin D-regulated factors that are involved in vitamin D-dependent active Ca transport and are present in both renal DT and intestinal epithelial cells include VDR, CaBP-D9k/28k and the PMCA. The PMCA is localized to the BLM in both cell types. Both kidney and intestine respond similarly to changes in vitamin D, Ca, or P status. The many similarities between renal DT cells and intestinal epithelia strongly support the application of this model for vitamin D-dependent Ca transport in both tissues.

Animals↗

PubMed2006

The impact of over-the-counter vitamin D supplements on vitamin D and parathyroid hormone levels in chronic kidney disease.

BACKGROUND: In addition to the known disturbances in mineral metabolism and vitamin D activation, the majority of patients with chronic kidney disease (CKD) do not have sufficient vitamin D stores. The impact of supplementation with low-dose, nonactive forms of vitamin D (calciferol) on parathyroid hormone (PTH) levels in this population is unknown, however. METHODS: A cross-sectional evaluation of vitamin D levels, intact parathyroid hormone (iPTH) and other laboratory results in 108 stage 3 and stage 4 CKD patients according to their intake of over-the-counter vitamin D. RESULTS: 37 patients took 400 IU of vitamin D daily with supplemental calcium and 71 did not. Compared to subjects who did not take it, patients who were on the supplement had higher 25(OH)D (31 +/- 15 vs. 17 +/- 9) ng/ml, higher 1,25(OH)D (21 +/- 12 vs. 16 +/- 9) pg/ml, lower iPTH (75 +/- 48 vs. 144 +/- 100) pg/ml and were more likely to meet K-DOQI PTH guidelines. However, these subjects were more likely to have oversuppressed iPTH values. The groups did not differ with regard to demographics, glomerular filtration rate and calcium and phosphorus levels. CONCLUSIONS: Vitamin D supplements may be a valuable tool in the prevention and treatment of hyperparathyroidism in patients with stages 3 and 4 CKD. CKD patients who have oversuppressed PTH need to be asked about their vitamin supplement intake.

Aged↗

PubMed2003

Food contents and biological activity of 25-hydroxyvitamin D: a vitamin D metabolite to be reckoned with?

Only a limited number of foods naturally contain vitamin D such as fish, meat and offal, and eggs, and milk and dairy products. However, all these foods in addition contain the metabolite 25-hydroxyvitamin D (25OHD). From the few systematic studies which have been performed the food contents of 25OHD in animal foods are usually low but vary. Contents are typically very low in milk and fish (<0.1 microg/100 g), somewhat higher in meat and offal (0.2-0.4 microg/100 g) and up to 1 microg/100 g in egg yolk. It has been demonstrated that 25OHD is absorbed better and faster from the diet than native vitamin D and has metabolic effects of its own in regulating cell growth and calcium metabolism. Thus, the biological activity of 25OHD is greater than that of native vitamin D. However, there is as yet no consensus on the conversion factor that should be used for 25OHD to calculate vitamin D activity. Depending on the testing system used the factor varies from 1.5 to 5. If food contents and the higher potency of 25OHD are not included in dietary intake surveys, true vitamin D intake will be underestimated.

Animals↗

PubMed1984

Vitamin D, 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D in cow's milk, infant formulas and breast milk during different stages of lactation.

Vitamin D and its metabolites were determined in cow's milk, infant formulas, and colostrum, transitional and mature breast milk by specific protein-binding assays following HPLC (high-pressure liquid chromatography). Cow's milk contains (mean +/- SEM) 50.4 +/- 4.1 pg/ml vitamin D (n = 10), 499 +/- 47 pg/ml 25-OH D (n = 10) and 9.7 +/- 1.0 pg/ml 1,25 (OH)2D (n = 3). 86.6% of the added vitamin D3 was recovered from infant formulas. The mean content (mean +/- SEM) of 25-OH D and 1,25(OH)2D of infant formulas are 299 +/- 35 pg/ml and 5.4 +/- 0.9 pg/ml (n = 9), respectively. Vitamin D concentration of colostrum and mature breast milk is 122 +/- 3.4 pg/ml (n = 7, mean +/- SEM) and 38 +/- 3.3 pg/ml (n = 9) respectively; the 25-OH D content increases from 294 +/- 50.6 pg/ml (n = 10) to 845 +/- 190 pg/ml (n = 14) during lactation. The increase of 1,25-(OH)2D from early to mature breast milk (3.2 +/- 0.6 pg/ml, n = 8 versus 5.3 +/- 0.7 pg/ml, n = 20) is still statistically significant.

Animals↗

PubMed1995

[The effects of long-term intake of restricted calcium, vitamin D, and vitamin E and cadmium-added diets on the bone mass of mouse femoral bone: a microdensitometrical study].

Effects of undernutrition on development of cadmium (Cd) poisoning were investigated in mice over a long experimental period ranging from 29 days to 24 months. The study was designed to examine low in calcium, low in vitamin D and low in vitamin E diets, which were considered neither to induce lesions of Ca, vitamin D and vitamin E deficiency nor in nutrition. Twenty-nine-day-old female ICR strain mice were separated into 7 groups and different diets were given to each group. Group I a commercial diet (Intact), Group II a low in Ca and low in D diet, Group III a low in Ca, low in D and low in E diet, Group IV a low in Ca, low in D and 20ppm Cd diet, Group V a low in Ca, low in D and 40ppm Cd diet, Group VI a low in Ca, low in D, low in E and 20ppm Cd diet and Group VII a low in Ca, low in D, low in E and 40ppm Cd diet. Using X-rays of the hind legs, the bone density was measured at the middle of the femur employing a densitometer; effects of the undernutrition and the cadmium-added diet on bone density were investigated referring to five indices: 1) peaks of the density of the middle of the bone cortex (h1, h2) (the maximum density of the bone cortex (h1 + h2)/2 [hmax]), 2) the lowest density of the middle of the bone marrow (h3) (the minimum density of the bone marrow [hmin]), 3) the bone cortical width (d1 + d2), 4) the bone marrow width (d) and 5) the cortical bone index (the ratio of cortical bone width to bone width. [CBI]). The long-term effects of cadmium. a) Comparisons among groups II, IV and V.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗

PubMed1990

Effects of growth hormone administration on vitamin D metabolism and vitamin D receptors in the pig.

Twelve 36-kg pigs were given either 100 micrograms/kg porcine pituitary growth hormone (pGH) or placebo injections daily for 33 days. Serum was obtained weekly for analysis of minerals and vitamin D metabolites. On day 34, the pigs were sacrificed and renal and duodenal tissue were obtained for analysis of vitamin D receptor content (VDR). Animals treated with pGH grew faster and had a higher rate of bone accretion than did control animals. Serum concentrations of 1,25-dihydroxyvitamin D (1,25-(OH)2D) were significantly higher in pGH-treated pigs than in control pigs at all time points following initiation of treatment, with the greatest difference observed at day 28 (42.4 +/- 4.9 pg/ml in controls vs. 65.4 +/- 4.7 pg/ml in pGH-treated pigs). Serum 24,25-dihydroxy-vitamin D tended to be lower in pGH-treated pigs than in control pigs, being significantly lower on day 21 of the experiment (3.22 +/- .52 vs. 6.73 +/- 1.22 ng/ml, respectively). Serum concentrations of 25-hydroxyvitamin D and calcium were unaffected by pGH treatment. Kidneys of control pigs contained significantly more unoccupied vitamin D receptors than did kidneys from pGH-treated pigs (73.3 +/- 4.3 vs. 58.3 +/- 4.1 fmoles/mg protein). Duodenal tissue unoccupied vitamin D receptor content was similar in both pGH-treated (245 +/- 17.9 fmoles/mg protein) and control (263 +/- 21.8 fmoles/mg protein) pigs. Duodenal occupied vitamin D receptor concentration was similar in both pGH-treated (6.8 +/- .75 fmoles/mg protein) and control pigs (5.32 +/- .77 fmoles/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

[The effects of long-term intake of restricted calcium, vitamin D, and vitamin E and cadmium-added diets on various organs and bones of mice: a histological and the roentgenological study].

The toxic effects of long-term administration of cadmium (Cd) on the kidneys, liver, and hind leg bones were studied histologically and roentgenologically in 29-day-old female ICR-strain mice separated into groups variously fed 1) a commercial (calcium [1.17%], vitamin D [220IU/100g], vitamin E [10mg/100g]) diet, 2) a low Ca (0.18% diet, 3) a low Ca and low D (50IU/100g) diet, and 4) a low Ca, low D and low E (5mg/100g) diet. Though the levels of vitamin D and vitamin E were designed to be low in each diet, their amounts fulfilled the nutritional requirements. Three subgroups in each category were fed Cd at dietary concentrations of 0, 20 or 40 ppm. After 12, 18 or 24 months on these diets the mice were sacrificed. 1) In the groups fed the commercial diet containing Cd, prominent swelling of the glomerulus and thickening of the basement membrane of glomerulus were observed. This did not occur in the groups fed the commercial diet without Cd. 2) In the groups fed the Cd-added low-Ca diet the following findings were more prominent compared with the low-Ca diet group. In the kidneys, swelling of the glomerulus, hyaline casts in tubular lumina and cellular infiltration of the interstitial tissue were present. In the liver, cellular infiltration on the interstitial tissue were present. In the liver, cellular infiltration of the interstitial tissue occurred. In the hind leg bones, thinning of trabeculae and ossification of the Achilles's tendon were seen. 3) In the Cd-added low-Ca, D diet groups, there was atrophy of glomerulus, thickening of basement membrane of glomerulus, and atrophy of tubular epithelial cells in the kidneys, while in the liver, binuclate cells, anisonucleosis and enlargement of Kupffer cells were seen. In the hind leg bones, thinning of the cortex and trabeculae were present. All of these findings were more prominent in this group than in the low-Ca, group. 4) In the Cd-added low-Ca, D, E, diet groups subjects the following findings were more prominent than in the low-Ca, D, E, diet group. In the kidneys, there was swelling of glomerulus and in the liver, there were binuclate cells, anisonucleosis, and cellular infiltration into interstitial tissue. In the hind leg bones, thinning of the cortex and trabeculae, a decrease of cartilage cells and a decrease of osteocytes were seen. These histological and roentgenological changes were seen to increase in a dose-dependent manner with the amount of dietary Cd.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Molecular cloning of complementary DNA encoding the avian receptor for vitamin D.

Vitamin D3 receptors are intracellular proteins that mediate the nuclear action of the active metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Two receptor-specific monoclonal antibodies were used to recover the complementary DNA (cDNA) of this regulatory protein from a chicken intestinal lambda gt11 cDNA expression library. The amino acid sequences that were deduced from this cDNA revealed a highly conserved cysteine-rich region that displayed homology with a domain characteristic of other steroid receptors and with the gag-erbA oncogene product of avian erythroblastosis virus. RNA selected via hybridization with this DNA sequence directed the cell-free synthesis of immunoprecipitable vitamin D3 receptor. Northern blot analysis of polyadenylated RNA with these cDNA probes revealed two vitamin D receptor messenger RNAs (mRNAs) of 2.6 and 3.2 kilobases in receptor-containing chicken tissues and a major cross-hybridizing receptor mRNA species of 4.2 kilobases in mouse 3T6 fibroblasts. The 4.2-kilobase species was substantially increased by prior exposure of 3T6 cells to 1,25(OH)2D3. This cDNA represents perhaps the rarest mRNA cloned to date in eukaryotes, as well as the first receptor sequence described for an authentic vitamin.

Amino Acid Sequence↗

PubMed1997

Dietary 1,25-dihydroxycholecalciferol has variable effects on the incidences of leg abnormalities, plasma vitamin D metabolites, and vitamin D receptors in chickens divergently selected for tibial dyschondroplasia.

Three experiments were conducted to examine the efficacy of dietary 1,25-dihydroxycholecalciferol [(1,25-(OH)2D3)] on the development of tibial dyschondroplasia (TD) in chickens divergently selected for high (HTD) and low (LTD) incidences of TD. In Experiment 1, chickens from the two lines were fed two calcium levels (0.75 and 1.0%), with and without 5 micrograms/ kg dietary 1,25-(OH)2D3. In Experiment 2, both lines were fed diets containing 1.0% calcium and 0, 5, 10, or 15 micrograms/kg 1,25-(OH)2D3. The addition of 1,25-(OH)2D3 did not reduce the overall incidence of TD in Experiment 1, but did reduce the incidence of severe TD from 69 to 48% in the chickens receiving the 0.75% calcium diet. In this experiment, LTD chickens had higher plasma phosphorus and bone ash. No line differences were noted between plasma vitamin D metabolites or intestinal vitamin D receptors. In Experiment 2, 5 micrograms/kg of 1,25-(OH)2D3 decreased the incidence of TD from 94 to 76% and number three scores from 69 to 44% (P < or = 0.001). Higher amounts of 1,25-(OH)2D3 further decreased TD, but there was a reduction in body weight above 5 micrograms/kg. Plasma 25-hydroxycholecalciferol [25-(OH)D3] and 1,25-(OH)2D3 were higher and intestinal vitamin D receptors were lower in HTD chickens than in LTD chickens. Plasma 1,25-(OH)2D3 was not affected by dietary treatment, but 25-(OH)D3 was reduced by dietary 1,25-(OH)2D3. Experiment 3 was conducted to examine effects of line and dietary 1,25-(OH)2D3 on plasma vitamin D metabolites and intestinal and growth plate receptors. No effect of genetic line or dietary 1,25-(OH)2D3 was observed for vitamin D receptors concentration or plasma 1,25-(OH)2D3 levels. Plasma 25-(OH)D3 was reduced when 1,25-(OH)2D3 was fed. These results indicate that HTD chickens are somewhat responsive to dietary 1,25-(OH)2D3, but this treatment failed to prevent the lesion in a large portion of the population.

Animal Feed↗

PubMed2005

Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis.

It has been suggested that early postmenopausal women and patients treated with steroids should receive preventive therapy (calcium, vitamin D, vitamin D analogs, estrogens, or bisphosphonates) to preserve their bone mineral density (BMD) and to avoid fragility fractures. We designed the present study to compare the effects of native vitamin D to its hydroxylated analogs alfacalcidol 1-alpha(OH)D and calcitriol 1,25(OH)(2)D. All randomized, controlled, double-blinded trials comparing oral native vitamin D and its analogs, alfacalcidol or calcitriol, to placebo or head-to-head trials in primary or corticosteroids-induced osteoporosis were included in the meta-analysis. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, and a hand search of abstracts and references lists. The study period January 1985 to January 2003. Data were abstracted by two investigators, and methodological quality was assessed in a similar manner. Heterogeneity was extensively investigated. Results were expressed as effect-size (ES) for bone loss and as rate difference (RD) for fracture while allocated to active treatment or control. Publication bias was investigated. Fourteen studies of native vitamin D, nine of alfacalcidol, and ten of calcitriol fit the inclusion criteria. The two vitamin D analogs appeared to exert a higher preventive effect on bone loss and fracture rates in patients not exposed to glucocorticoids. With respect to BMD, vitamin D analogs versus placebo studies had an ES of 0.36 (P < 0.0001), whereas native vitamin D versus placebo had an ES of 0.17 (P = 0.0005), the interclass difference being highly significant (ANOVA-1, P < 0.05). When restricted to the lumbar spine, this intertreatment difference remained significant: ES = 0.43 (P = 0.0002) for vitamin D analogs and ES = 0.21 (P = 0.001) for native vitamin D (analysis of variance [ANOVA-1], P = 0.047). There were no significant differences regarding their efficacies on other measurement sites (ANOVA-1, P = 0.36). When comparing the adjusted global relative risks for fracture when allocated to vitamin D analogs or native vitamin D, alfacalcidol and calcitriol provided a more marked preventive efficacy against fractures: RD = 10% (95% Confidence interval [CI-2] to 17) compared to RD = 2% (95% CI, 1 to 2), respectively. The analysis of the spinal and nonspinal showed that fracture rates differed between the two classes, thereby confirming the benefits of vitamin D analogs, with significant 13.4% (95% CI 7.7 to 19.8) and. 6% (95% CI 1 to 12) lower fracture rates for vitamin D analogs, respectively. In patients receiving corticosteroid therapy, both treatments provided similar global ESs for BMD: ES = 0.38 for vitamin D analogs and ES = 0.41 for native vitamin D (ANOVA-1, P = 0.88). When restriced to spinal BMD, D analogs provided significant effects, whereas native vitamin D did not: ES = 0.43 (P < 0.0001) and ES = 0.33 (P = 0.21), respectively. The intertreatment difference was nonsignificant (ANOVA-1, P = 0.52). Neither D analogs for native vitamin D significantly prevented fractures in this subcategory of patients: RD = 2.6 (95%CI, -9.5 to 4.3) and RD = 6.4 (95%CI, -2.3 to 10), respectively. In head-to-head studies comparing D analogs and native vitamin D in patients receiving corticosteroids, significant effects favoring D analogs were found for femoral neck BMD: ES = 0.31 at P = 0.02 and spinal fractures: RD = 15% (95%CI, 6.5 to 25). Publication bias was not significant. Our analysis demonstrates a superiority of the D analogs atfacalcidol and calcitriol in preventing bone loss and spinal fractures in primary osteoporosis, including postmenopausal women. In corticosteroid-induced osteoporosis, the efficacy of D analogs differed depending on the comparative approach: indirect comparisons led to nonsignificant differences, whereas direct comparison did provide significant differences. In this setting, D analogs seem to prevent spinal fractures to a greater extent than do native vitamin D, but this assumption should be confirmed on a comprehensive basis in multiarm studies including an inactive comparator.

Adrenal Cortex Hormones↗

PubMed1999

Prostaglandin E2 regulates vitamin D receptor expression, vitamin D-24-hydroxylase activity and cell proliferation in an adherent human myeloid leukemia cell line (Ad-HL60).

The effects of prostaglandin E2, forskolin, and phorbol 12-myristate 13-acetate on cell proliferation, cell surface antigen expression, vitamin D-24-hydroxylase activity and vitamin D receptor (VDR) expression have been studied in an adherent variant (Ad-HL60) of the human HL60 promyelomonocytic leukemia cell line. Ad-HL60 cells have a more differentiated phenotype than the nonadherent HL60 cells from which they were derived and, unlike the parent cell line, constitutively express vitamin D-24-hydroxylase activity. Treatment of Ad-HL60 cells with 1 microM PGE2 resulted in a decrease in the rate of cell proliferation (cell numbers were approximately 23% of control values after 72 h treatment), a change in expression of leukocyte surface antigens (decreased CD13 and CD14, increased CD11b and CD49d expression), an increase in the synthesis of 24,25-dihydroxyvitamin D3 from substrate 25-hydroxyvitamin D3 (control 5.76 +/- 0.17, 72 h PGE2-treated cells 12.10 +/- 1.90 pmol/h/10(6) cells), and an increase in receptors for the active metabolite of vitamin D, 1 alpha,25-dihydroxyvitamin D3, from 3910 to 11285 receptors per cell in control and 7-day treated cells, respectively. Prostaglandin E2 may be acting via a mechanism involving cyclic AMP in these cells, as we have also demonstrated that 10 microM forskolin, an adenylate cyclase activator, has similar effects. Phorbol 12-myristate 13-acetate had little effect on any of the parameters measured in this cell line.

24,25-Dihydroxyvitamin D 3↗

PubMed1984

Skin calcium-binding protein: effect of vitamin D deficiency and vitamin D treatment.

The amount of skin calcium-binding protein, evaluated using a sensitive radioimmunoassay and indirect immunofluorescence, was decreased in vitamin-D deficient rats and increased after one week vitamin D3 or 1 alpha-hydroxyvitamin D3 treatment. In vitamin D replete and in vitamin D-deficient animals, skin calcium-binding protein was not sensitive to changes in dietary and/or serum calcium concentrations. These results indicate that this protein is different from other calcium-binding proteins such as parvalbumin and calmodulin which are not vitamin D-dependent, and also different from intestinal calcium-binding protein which, in D replete animals, is sensitive to changes in dietary and serum calcium concentrations. Skin calcium-binding protein may, therefore, represent a new class of vitamin D-dependent protein.

Animals↗

PubMed2001

The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II.

In vitro studies and animal experiments suggest that the production of 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] and 24,25-(OH)(2)D is reciprocally controlled by 1,25-(OH)(2)D. To investigate the role of the vitamin D receptor (VDR) in controlling vitamin D metabolism in humans, we studied 10 patients with vitamin D-dependent rickets type II due to a defective VDR. After a period of high dose calcium therapy, 7 of the patients had normal serum calcium, phosphorus, alkaline phosphatase, and plasma PTH levels (PTH-N), and 3 showed increased serum alkaline phosphatase and plasma PTH (PTH-H). Serum calcium, phosphorus, alkaline phosphatase, PTH, vitamin D metabolites, urinary calcium/creatinine, and renal phosphate threshold concentration were compared with unaffected family members that comprised the control group. Vitamin D metabolites were measured before and after an oral load of 50,000 U/m(2) cholecalciferol. Compared with the control group, 1,25-(OH)(2)D levels were significantly higher and 24,25-(OH)(2)D levels were lower in the PTH-N group and even more so in the PTH-H group. 1alpha-Hydroxylase (1-OHase) and 24-OHase activities were estimated by the product/substrate ratio. In the PTH-N group, 1-OHase activity was higher and 24-OHase activity was lower than in controls. In the PTH-H group, 1-OHase activity was even higher, probably due to an additive effect of PTH. Thus, 1,25-(OH)(2)D-liganded VDR is a major control mechanism for vitamin D metabolism, and PTH exerts an additive effect. Assessment of the influence of 1,25-(OH)(2)D shows reciprocal control of enzyme activity in man, suppressing 1-OHase and stimulating 24-OHase activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1975

The kidney as an endocrine organ involved in the function of vitamin D.

Vitamin D3 must be metabilically altered first in the liver to 25-hydroxyvitamin D3 (25 OH-D3) and subsequently in the kidney to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) before it can function. Because 1,25-(OH)2D3 is formed in the kidney and acts in intestine and bone to elevate serum calcium and phosphate concentrations, it can be considered a hormone. The production of 1,25-(OH)2D3 is feedback regulated either directly or indirectly by serum calcium and serum phosphate concentrations. The hypocalcemic regulation is mediated by the parathyroid glands. The hypophosphatemic stimulus, however, does not involve either the parathyroid or thyroid glands. Under conditions whereby the synthesis of 1,25-(OH)2D3 is repressed, 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3 is formed. This metabolite can be converted further to 1,24,25-trihydroxyvitamin D3 (1,24,25-(OH)3D3), which stimulate intestinal calcium transport but not bone calcium mobilization or phosphate transport reactions. A number of vitamin D-resistant bone diseases may be related to defective vitamin D metabolism. For example, bone disease related to choric renal failure likely results from defective formation of 1,25-(OH)2D3 in the kidney. Treatment of this disease with intravenously administered 1,25-(OH)2D3 is effective in correcting the bone lesions. 1Alpha-hydroxyvitamin D3 (1alpha-OH-D3), a new synthetic analog of 1,25-(OH)2D3 which is less expensive to produce than 1,25-(OH)2D3, is effective in anephric animals and may have several advantages over 1,25-(OH)2D3 in treating bone diseases.

Biological Transport↗

PubMed2005

22-ene-25-oxa-vitamin D: a new vitamin D analogue with profound immunosuppressive capacities.

BACKGROUND: The biologic role of 1,25-dihydroxyvitamin D(3), such as anti-inflammatory functions, reduction of cytokine production by T cells and immunoglobulin production by B cells, is well established. However, its clinical use as an immunosuppressive agent is limited because of the hypercalcemic toxicity occurring after systemic application. The purpose of this study was to investigate the immunmodulatory effects of 22-ene-25-oxa-vitamin D (ZK156979), a novel low calcemic vitamin D analogue. MATERIALS AND METHODS: Human peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated using the Ficoll Hypaque technique, cultured for 24 h and treated with different concentrations of ZK156979 ranging from 10(-5) to 10(-10) mol L(-1) compared with 1,25-dihydroxyvitamin D(3)[10(-5)-10(-10) mol L(-1)] following phytohaemagglutinin (PHA) stimulation. Interferon gamma (IFNgamma), tumour necrosis factor alpha (TNFalpha), interleukin 1 beta (IL-1beta), interleukin 10 (IL-10) and interleukin 4 (IL-4) secretion in supernatants were measured by ELISA. RESULTS: ZK156979 inhibited the PHA-induced Th1-response (IFNgamma and TNFalpha levels) and the macrophage-product IL-1beta in a concentration-dependent manner (10(-10)-10(-5) mol L(-1)) with the efficiency on cytokine expression compared with 1,25-dihydroxyvitamin D(3) being slightly reduced. In contrast, ZK156979 and 1,25-dihydroxyvitamin D(3) both affected the Th2 response, leading to significantly increased IL-10- and IL-4 secretion. CONCLUSIONS: ZK156979 is a member of novel vitamin D analogues revealing prominent immunomodulatory and suppressive characteristics with distinctive inhibition of Th1-cytokines whereas the Th2 compartment is augmented, thus providing a considerable therapeutic potential in T-cell -mediated diseases.

Calcitriol↗

PubMed2000

1,25-Dihydroxy-19-nor-vitamin D(2), a vitamin D analog with reduced bone resorbing activity in vitro.

1,25-Dihydroxy-19-nor-vitamin D(2) (19-norD(2)), a new analog of 1,25(OH)(2)D(3), suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)(2)D(3). Although 19-norD(2) has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)(2)D(3), it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D(3) (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD(2), as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)(2)D(3)-stimulated osteoclasts (P < 0. 05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD(2) in cultures was approximately 20% greater than 1, 25(OH)(2)D(3), not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD(2) and 1,25(OH)(2)D(3). In summary, 19-norD(2) is less effective than 1,25(OH)(2)D(3) in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD(2) compared with 1,25(OH)(2)D(3).

Animals↗

PubMed2000

Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study.

BACKGROUND: Susceptibility to disease after infection by Mycobacterium tuberculosis is influenced by environmental and host genetic factors. Vitamin D metabolism leads to activation of macrophages and restricts the intracellular growth of M. tuberculosis. This effect may be influenced by polymorphisms at three sites in the vitamin D receptor (VDR) gene. We investigated the interaction between serum vitamin D (25-hydroxycholecalciferol) concentrations and VDR genotype on susceptibility to tuberculosis. METHODS: This study was a hospital-based case-control analysis of Asians of Gujarati origin, a mainly vegetarian immigrant population with a high rate of tuberculosis. We typed three VDR polymorphisms (defined by the presence of restriction endonuclease sites for Taq1, Bsm1, and Fok1) in 91 of 126 untreated patients with tuberculosis and 116 healthy contacts who had been sensitised to tuberculosis. Serum 25-hydroxycholecalciferol was recorded in 42 contacts and 103 patients. FINDINGS: 25-hydroxycholecalciferol deficiency was associated with active tuberculosis (odds ratio 2.9 [95% CI 1.3-6.5], p=0.008), and undetectable serum 25-hydroxycholecalciferol (<7 nmol/L) carried a higher risk of tuberculosis (9.9 [1.3-76.2], p=0.009). Although there was no significant independent association between VDR genotype and tuberculosis, the combination of genotype TT/Tt and 25-hydroxycholecalciferol deficiency was associated with disease (2.8 [1.2-6.5]) and the presence of genotype ff or undetectable serum 25-hydroxycholecalciferol was strongly associated with disease (5.1 [1.4-18.4]). INTERPRETATION: 25-hydroxycholecalciferol deficiency may contribute to the high occurrence of tuberculosis in this population. Polymorphisms in the VDR gene also contribute to susceptibility when considered in combination with 25-hydroxycholecalciferol deficiency.

Calcifediol↗