C-3 epimerization of vitamin D3 metabolites and further metabolism of C-3 epimers: 25-hydroxyvitamin D3 is metabolized to 3-epi-25-hydroxyvitamin D3 and subsequently metabolized through C-1alpha or C-24 hydroxylation.
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Recently, it was revealed that 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and 24R,25-dihydroxyvitamin D3 (24,25(OH)2D3) were metabolized to their respective epimers of the hydroxyl group at C-3 of the A-ring. We now report the isolation and structural assignment of 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3 as a major metabolite of 25-hydroxyvitamin D3 (25(OH)D3) and the further metabolism of C-3 epimers of vitamin D3 metabolites. When 25(OH)D3 was incubated with various cultured cells including osteosarcoma, colon adenocarcinoma, and hepatoblastoma cell lines, 3-epi-25(OH)D3 and 24,25 (OH)2D3 were commonly observed as a major and minor metabolite of 25(OH)D3, respectively. 25(OH)D3 was at least as sensitive to C-3 epimerization as 1alpha, 25(OH)2D3 which has been reported as a substrate for the C-3 epimerization reaction. Unlike these cultured cells, LLC-PK1 cells, a porcine kidney cell line, preferentially produced 24,25(OH)2D3 rather than 3-epi-25(OH)D3. We also confirmed the existence of 3-epi-25(OH)D3 in the serum of rats intravenously given pharmacological doses of 25(OH)D3. The cultured cells metabolized 3-epi-25OHD3 and 3-epi-1alpha,25(OH)2D3 to 3-epi-24,25(OH)2D3 and 3-epi-1alpha,24,25(OH)3D3, respectively. In addition, we demonstrated that 3-epi-25(OH)D3 was metabolized to 3-epi-1alpha,25(OH)2D3 by CYP27B1 and to 3-epi-24,25(OH)2D3 by CYP24 using recombinant Escherichia coli cell systems. 3-Epi-25(OH)D3, 3-epi-1alpha,25(OH)2D3, and 3-epi-24,25(OH)2D3 were biologically less active than 25(OH)D3, 1alpha,25(OH)2D3, and 24,25(OH)2D3, but 3-epi-1alpha,25(OH)2D3 showed to some extent transcriptional activity toward target genes and anti-proliferative/differentiation-inducing activity against human myeloid leukemia cells (HL-60). These results indicate that C-3 epimerization may be a common metabolic pathway for the major metabolites of vitamin D3. (+info)
Maternal vitamin D deficiency and vitamin D supplementation in healthy infants.
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The objective of this study was to evaluate the common effects of maternal vitamin D deficiency, various doses of vitamin D given to newborns and the effects of these on vitamin D status in early childhood. Seventy-eight pregnant women and 65 infants who were followed up in various health centers were included in the sudy. 25-hydroxyvitamin-D (25-OHvitD), calcium (Ca), phosphorus (P) and alkaline phosphatase levels were measured in blood samples drawn from pregnant women in the last trimester. Infants born to these mothers were given 400 or 800 IU of vitamin D subsequently at the start of the second week. 25-OHvitD, Ca, P and alkaline phosphatase levels of the 65 infants who were brought in for controls (May-September 2000) were measured and hand-wrist X-rays were evaluated. We analyzed the relationship between vitamin D status of the mothers and infants and socio-economic status; mothers' dressing habits (covered vs uncovered), educational level, and number of pregnancies; and sunlight exposure of the house. Covered as a dressing habit meant covering the hair and sometimes part of the face and wearing dresses that completely cover the arms and legs. In 40 infants who were breast-fed and received the recommended doses of vitamin D on a regular basis, the relationship between serum vitamin D levels and supplementation doses given was analyzed. Serum 25-OHvitD level of the mothers was 17.50 +/- 10.30 and 94.8% of the mothers had a 25-OHvitD level below 40 nmol/L (below 25 nmol/L in 79.5%). The risk factors associated with low maternal 25-OHvitD were low educational level (p = 0.042), insufficient intake of vitamin D within diet (p = 0.020) and "covered" dressing habits (p = 0.012). 25-OHvitD level of the infants was 83.70 +/- 53.70 nmol/L, and 24.6% of the infants had 25-OHvitD levels lower than 40 nmol/L. Risk factors for low 25-OHvitD levels in infants were a) not receiving recommended doses of vitamin D regularly (p = 0.002) and b) insufficient sunlight exposure of the house (p = 0.033). There was a pour but significant correlation between maternal vitamin D levels and infants' 25-OHvitD levels at four months (r = 0.365, p < 0.05). No significant correlation was found between 25-OHvitD levels and supplementation doses of vitamin D (19 infants were supplemented with 400 IU/day and 21 with 800 IU/day of vitamin D) (p = 0.873). Severe maternal vitamin D deficiency remains a commonly seen problem in Turkey. However, vitamin D deficiency can be prevented by supplementation of vitamin D to newborns (at least 400 IU). Supplementation of 800 IU vitamin D in the areas of maternal vitamin D deficiency has no greater benefits for the infants. (+info)
Studies on the influence of vitamin D3 metabolites on apoptosis induction in human neoplastic cells.
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The vitamin D is involved in essential cell regulatory processes such as proliferation and differentiation in a number of different cell types including cancer cells. Adriamycin is one of the most effective agents in the treatment of many types of solid tumours and leukemias. The common features in the biological activity, expressed by vitamin D family members and adriamycin such as: apoptosis induction, influence on antioxidant enzymes activity etc., created the suggestion of synergistic effects of these compounds combination. In the earlier studies the antiproliferative activity of vitamin D3 metabolites was shown in ME18 cells, but without any correlation with sensitivity of the cells to adriamycin. In the current work the possible role of 25-hydroxycholecalciferol (calcidiol) and 1,25-dihydroxycholecalciferol (calcitriol) as the apoptotic inducers was studied in human melanoma cells. As was shown in these experiments, vitamin D3 metabolites did not stimulate apoptotic events in the cells studied and did not influence apoptosis induction in the cells treated with adriamycin. (+info)
Rat serum osteocalcin concentration is determined by food intake and not by inflammation.
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Osteocalcin, or bone gla protein, is the major noncollagenous protein in bone. Previous findings of decreased serum osteocalcin concentrations in children with Kwashiorkor led us to analyze the respective influence of nutritional status and inflammation on circulating osteocalcin in growing rats. Food deprivation for 72 h induced a significant 24% decrease in serum osteocalcin. Refeeding produced a rapid rise in serum osteocalcin, which reached control concentrations after 24 h of refeeding. Bone osteocalcin was not affected by these dietary manipulations. The changes in serum osteocalcin were not correlated with serum 1,25-dihydroxycholecalciferol, whereas they could be related to serum 25-hydroxycholecalciferol concentrations. Turpentine injection reduced serum osteocalcin concentration, but pair-feeding showed that this decrease was entirely attributable to spontaneous food restriction and not to inflammation. By contrast, the sensitive nutritional marker, serum transthyretin, was affected by both inflammation and food restriction. These results indicate that serum osteocalcin is closely related to food intake but not to inflammation, suggesting that the dramatic decrease in serum osteocalcin that we previously observed in children with Kwashiorkor is due to malnutrition per se. (+info)
Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.
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The synthesis of bioactive vitamin D requires hydroxylation at the 1 alpha and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1 alpha-hydroxylation in the kidney but the identity of the hepatic 25-hydroxylase has remained unclear for >30 years. We previously identified the microsomal CYP2R1 protein as a potential candidate for the liver vitamin D 25-hydroxylase based on the enzyme's biochemical properties, conservation, and expression pattern. Here, we report a molecular analysis of a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity. These data identify CYP2R1 as a biologically relevant vitamin D 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency. (+info)
Feeding 25-hydroxyvitamin D3 to improve beef tenderness.
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The objective of this trial was to determine if a single oral bolus of 25-hydroxyvitamin D3 (25-OH D3) given at various times before slaughter would enhance the tenderness of beef loin steaks. One hundred eight crossbred steers were allotted to 18 pens so that the mean weight of the cattle in each pen was similar. Treatments (25-OH D3 dose [62.5 or 125 mg]) and time of administration of the single oral bolus (4, 7, 21, or 35 d before slaughter) were assigned randomly to each pen of steers. Serial plasma samples were collected at each bolus administration time for control animals. For steers assigned to a treatment group, a baseline blood sample was collected before bolus administration and at each subsequent administration when other treatment groups received their bolus. Plasma samples were assayed for 25-OH D3 and calcium concentrations. Troponin-T degradation and Warner-Bratzler shear force were measured as indicators of tenderness for loin steaks collected at slaughter and aged for 6 or 14 d postmortem. Muscle samples, collected concurrently, were assayed for 25-OH D3 and calcium concentrations. A single oral bolus of 25-OH D3 was sufficient to increase plasma 25-OH D3 concentrations (P < 0.001) through slaughter, regardless of dose or time of bolus administration. The single oral bolus of 25-OH D3, however, did not increase plasma calcium concentrations (P > 0.05). As a result, neither troponin-T degradation nor Warner-Bratzler shear force was improved (P > 0.05) by treatment. Muscle 25-OH D3 concentrations were increased (P > 0.001) by treatment with 25-OH D3. Although sustained plasma 25-OH D3 concentrations did not increase plasma or muscle calcium at slaughter nor influence tenderness, the use of 25-OH D3 as a nutritional means of improving beef tenderness is in its infancy, and more research to delineate an effective dose and the potential interaction of seasonal exposure to ultraviolet light is warranted. (+info)
Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population.
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BACKGROUND: Periodontal disease (PD) is a common chronic inflammatory disease and an important risk factor for tooth loss. Vitamin D might affect periodontal disease risk via an effect on bone mineral density (BMD) or via immunomodulatory effects. OBJECTIVE: The objective was to evaluate whether serum 25-hydroxyvitamin D(3) [25(OH)D(3)] concentrations are associated with PD in the third National Health and Nutrition Examination Survey. DESIGN: We analyzed data on periodontal attachment loss (AL) and serum 25(OH)D(3) concentrations from 11 202 subjects aged > or =20 y. Mean AL was modeled in a multiple linear regression with quintile of serum 25(OH)D(3) concentration as an independent variable. The model was stratified by age and sex and was adjusted for age within age groups, race or ethnicity, smoking, diabetes, poverty income ratio, body mass index, estrogen use, and gingival bleeding. RESULTS: 25(OH)D(3) concentrations were significantly and inversely associated with AL in men and women aged > or =50 y. Compared with men in the highest 25(OH)D(3) quintile, those in the lowest quintile had a mean AL that was 0.39 mm (95% CI: 0.17, 0.60 mm) higher; in women, the difference in AL between the lowest and highest quintiles was 0.26 mm (0.09, 0.43 mm). In men and women younger than 50 y, there was no significant association between 25(OH)D(3) and AL. The BMD of the total femoral region was not associated with AL and did not mediate the association between 25(OH)D(3) and AL. CONCLUSIONS: Low serum 25(OH)D(3) concentrations may be associated with PD independently of BMD. Given the high prevalence of PD and vitamin D deficiency, these findings may have important public health implications. (+info)
Supplemental vitamin D3 concentration and biological type of steers. II. Tenderness, quality, and residues of beef.
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Vitamin D3 was orally supplemented to determine the supplemental dose that improved beef tenderness in different cattle breed types. Feedlot steers (n = 142) were arranged in a 4 x 3 factorial arrangement consisting of four levels of supplemental vitamin D3 (0, 0.5, 1, and 5 million IU/steer daily) administered for eight consecutive days antemortem using three biological types (Bos indicus, Bos Taurus-Continental, and Bos Taurus-English). Warner-Bratzler shear force (WBSF) was measured at 3, 7, 10, 14, and 21 d postmortem, and trained sensory analysis was conducted at 7 d postmortem on LM, semimembranosus, gluteus medius, and supraspinatus steaks. Concentrations of vitamin D3 and the metabolites 25-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3 were determined in the LM, liver, kidney, and plasma. Biological type of cattle did not interact (P > 0.10) with vitamin D3 supplementation for sensory or tenderness traits, suggesting that feeding vitamin D3 for 8 d before slaughter affected the different biological types of cattle similarly. Supplementing steers with 0.5, 1, or 5 million IU/(steer(d) decreased (P < 0.05) LM WBSF at 7, 10, 14, and 21 d postmortem compared with controls, and vitamin D3 treatments of 0.5, 1, and 5 million IU decreased (P < 0.05) semimembranosus WBSF at 3, 7, and 14 d postmortem. In general, vitamin D3-induced improvements in WBSF were most consistent and intense in LM steaks. Sensory panel tenderness was improved (P < 0.05) by all vitamin D3 treatments in LM steaks. Sensory traits ofjuiciness, flavor, connective tissue, and off-flavor were not (P > 0.05) affected by vitamin D3 treatments. All vitamin D3 treatments decreased micro-calpain activity and increased muscle Ca concentrations (P < 0.05). Vitamin D3 concentrations were increased (P < 0.05) by supplementation in all tissues tested (liver, kidney, LM, and plasma); however, cooking steaks to 71 degrees C decreased (P < 0.05) treatment residue effects. The vitamin D metabolite 1,25-dihydroxyvitamin D3 was increased (P < 0.05) only in plasma samples as a result of the vitamin D3 treatments. These results indicate that supplementation with vitamin D3 at 0.5 million IU/steer daily for eight consecutive days before slaughter improved tenderness in steaks from different subprimal cuts by affecting muscle Ca concentrations, micro-calpain activities, and muscle proteolysis, with only a small effect on tissue residues of vitamin D3. (+info)