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During detoxication processes of DDT, there is, in the Rat, interference between vitamins A and E (D.1.alpha-tocopherol acetate). Vitamin E spares retinal and has a slighter but significant influence on P 450 cytochrome induction. These results are discussed.
Numerous vitamin D3 analogs (VDAs) can inhibit the proliferation of cells from several types of human malignancies. The physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3(1,25D3), is formed by successive hydroxylations of cholecalciferol at the 25 and 1 alpha positions. In this study we examined the effects of the absence of the 1 alpha (OH) group, introduction of a double bond in position 16, and further modifications at the 23, 26, and 27 positions in the side chain on the potency of the VDAs. The parameters studied were the rapidity of the induction of monocytic differentiation, the cell cycle traverse, and the effects of VDAs on intracellular calcium homeostasis in HL60 cells. The results show that (1) 1,25D3 derivatives which lace the 1 alpha (OH) group have little differentiation-inducing activity, (2) hexafluorination (6F) of the terminal methyl groups in the side chain partially restores the activity of 1 alpha-desoxy compounds and potentiates the activity of 1 alpha hydroxylated compounds, and (3) 25-(OH)-16,23E-diene-26,27-hexafluoro-vitamin D2 (Ro25-9887) alone among the twelve compounds tested induces differentiation with only minimal changes in the basal levels of intracellular calcium and store-dependent calcium influx in HL60 cells. Addition of 1 alpha (OH) group to this compound increases its differentiation-inducing activity but also elevates basal calcium level. The results suggest that altered calcium homeostasis is not an obligatory component of HL60 leukemia cell differentiation, and that Ro25-9887 and related VDAs may be suitable for testing as components of anti-leukemic therapy.
1 alpha-25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], together with vitamin D receptor (VDR), directly activates human osteocalcin (hOC) gene expression through a vitamin D-responsive element (VDRE) located in the promoter of the hOC gene. We investigated the effect of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] on the regulation of the hOC gene promoter and compared it with that of 1 alpha,25(OH)2D3. 24R,25(OH)2D3 did not activate the natural promoter in VDR-negative CV-1 cells. 24R,25(OH)2D3, however, induced the activation of this promoter following cotransfection with an hVDR expression vector. In VDR-positive MC3T3-E1 cells, 24R,25(OH)2D3 activated not only the natural hOC promoter but also a chimeric promoter composed of a synthetic hOC VDRE sequence linked to the thymidine kinase promoter. In combination with 1 alpha-25(OH)2D3, 24R,25(OH)2D3 did not exhibit any antagonist activity on the hOC promoter. These results suggest that under conditions of high 24R,25(OH)2D3 levels in vivo, this metabolite of vitamin D3 may activate hOC gene expression through receptor mechanisms identical to that for 1 alpha,25(OH)2D3.
1,25-dihydroxy-vitamin D(3) (1,25(OH)(2)D(3)), the hormonally active form of vitamin D(3), acts through two different mechanisms. In addition to regulating gene expression via the specific intracellular vitamin D receptor (VDR), 1,25(OH)(2)D(3) induces rapid, non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. The activation of second messengers supports the hypothesis that a membrane-bound steroid receptor similar to those that mediate peptide hormone biology exists. Skeletal muscle is a target tissue for 1,25(OH)(2)D(3). Avian embryonic skeletal muscle cells (myoblasts/myotubes) have been shown to respond both genomically and non-genomically to the hormone. The present study provides evidence indicating that short-term treatment (1-10 min) with 1,25(OH)(2)D(3) induces translocation of the VDR from the nuclear to the microsomal fraction in chick myoblasts. This translocation is blocked by colchicine, genistein, or herbimycin, suggesting the involvement of microtubular transport and tyrosine kinase/s in the relocation of the receptor. By isolation of plasma membranes, it was demonstrated that the hormone increases the amounts of VDR specifically in this fraction. These results suggest that the nuclear VDR may be the receptor that mediates the non-genomic effects of 1,25(OH)(2)D(3) in chick myoblasts.
In a comparative slaughter experiment the thiamin, vitamin B6 and pantothenic acid content of lean tissue of foreloin of growing cattle was determined by whole body analyses. 54 bulls, 45 heifers and 45 steers were fed until a live mass of 200 kg, 350 kg, 425 kg (only heifers) 500 kg and 575 kg, 650 kg, respectively (only bulls and steers). One half of each carcass was divided into 13 cuts and afterwards the cuts were each divided into lean, adipose and bone tissue and tendons. The lean tissue of the foreloin was subjected to analysis of thiamin, vitamin B6 and pantothenic acid. The mean thiamin content of 0.75 mg kg-1 fresh matter (200 kg live mass) decreased with rising live mass and under intensive feeding conditions in bulls and steers to 0.53 mg and in heifers to 0.61 mg. Restrictively feeding caused a mean thiamin content of 0.60 mg per kg fresh matter in bulls, steers and heifers. Under both feeding conditions in the lean tissue of the foreloin on average a vitamin B6 content of 2.6 mg (bulls), 3.1 mg (heifers) and 3.0 mg kg-1 fresh matter (steers) was analysed. A mean content of pantothenic acid of 2.6 mg kg-1 fresh matter was determined in bulls independent of live mass and feeding intensity. In heifers the content of pantothenic acid on average was 3.0 mg under intensive feeding system and 2.6 mg under low feeding conditions, whereas steers reached contents of 2.7 mg (high feeding) and 2.2 mg kg-1 fresh matter (low feeding).
The natural biologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), possesses antiproliferative, prodifferentiating and immunomodulatory properties. The actions of 1,25(OH)2D3 are mediated through the intracellular vitamin D receptor (VDR), and the level of VDR is believed to determine the cellular responsiveness to vitamin D3. In the present study we examined the effects of 1,25(OH)2D3 on the expression of VDR and its message in cultured human keratinocytes. Western analysis showed the mean VDR content to be higher in undifferentiated cultures (175 pg/microgram protein) than in differentiated cultures (90 pg/microgram protein). Incubation with 1,25(OH)2D3 induced an increase in the VDR in both undifferentiated and differentiated keratinocytes. The VDR increase was detectable after 2 h and maximal (approximately two-fold stimulation) after 8 h. The 1,25(OH)2D3-induced stimulation of VDR levels was dose dependent with a maximum at 10(-7) M. The VDR mRNA levels as determined by the ribonuclease protection assay showed a peak (50% stimulation) after approximately 2 h. Although this increase in VDR mRNA was not statistically significant, the results indicate that the ligand-induced upregulation of VDR involves increased transcription. The upregulation of VDR levels may increase the responsiveness to 1,25(OH)2D3 and may, therefore, be an important mechanism for regulating the effects of 1,25(OH)2D3 on keratinocyte proliferation and differentiation.
Normal male rats received six subcutaneous injections of 8.0 pmoles of tritiated 25-hydroxy vitamin D3 ([3H]25(OH)D3) or one intrajugular injection of 8.0 pmoles of high specific radioactivity [3H]-25(OH)D3. Lipid extracts of several tissues including the reproductive organs were subjected to sephadex LH-20 chromatography to determine the tissue distribution of the injected material and of the in vivo produced dihydroxylated cholecalciferol metabolites. The nature of the putative 25(OH)D3 and the 24,25-dihydroxy vitamin D3 (24,25(OH)2D3) from epididymis tissue was confirmed by high performance liquid chromatography (HPLC). The epididymis levels of 24,25(OH)2D3 were considerably higher in the cauda epididymis compared to kidney and caput epididymis levels. The other metabolites levels in this tissue were similar to those determined in the kidneys. The amounts of the three metabolites found in all other tissues were well below the cauda epididymis or kidney levels. The findings suggest a possible physiological role for 24,25(OH)2D3 in the epididymis, and are also consistent with data of others which indicated a possible action of 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) in rat reproductive tissues.
Twenty four hours after dosing of pregnant rats with 3H vitamin D3 i.v. the sulfoconjugate was detected only in the kidney. In contrast, 24 or 48 hours after 3H vitamin D3 i.v. dosing the vitamin D3 sulfoconjugate was detected in the plasma, liver, kidney and mammary glands of lactating mother rats.
A model of low-phosphate, vitamin D-deficient rachitic rats was used to compare the effects of 1 alpha(OH)D3, 1,25(OH)2D3, and 24,25(OH)2D3 on cartilage and bone. The rats were maintained for 3 weeks on a high-calcium, low-phosphate, vitamin D-deficient diet, during which period they developed severe rickets. The rachitic rats were injected for 2 or 3 consecutive days with a physiologic dose of either metabolite. Other littermates were given a single dose of 50,000 IU of cholecalciferol in combination with a normal diet. Samples of cartilage fluid (Cfl) and of blood were removed prior to sacrifice for biochemical studies of some parameters of calcification. These parameters were correlated with the results of light and electron microscopic studies of the growth plate cartilage and bone. Treatment with 1 alpha (OH)D3 or with 1,25(OH)2D3, in spite of increasing Ca and P levels in the Cfl, induced only partial healing of the rickets. In contrast, 24,25(OH)2D3 or vitamin D with a normal diet resulted in complete morphologic and biochemical healing of the rickets. Transmission electron microscopic (TEM) studies have shown partial mineralization of the wide hypertrophic zone of the growth plate following treatment with 1 alpha(OH)D3 or with 1,25(OH)2D3. Mineralization was more complete with 24,25(OH)2D3 treatment. The results of this study emphasize the importance of 24,25(OH)2D3 for normal endochondral bone formation and mineralization.
BACKGROUND: The active form of vitamin D, 1,25(OH)(2)D(3), exerts important effects on proliferation and differentiation of many cell types, and immunoregulatory activities in particular on T cell-mediated immunity. AIM: The aim of this study was to investigate whether KH 1060, a vitamin D analogue, could decrease tumor necrosis factor-alpha (TNF-alpha) levels in patients with inflammatory bowel disease (IBD). METHODS: PBMC proliferation was determined by [(3)H]thymidine incorporation. TNF-alpha levels were measured by ELISA kit; VDR, Bcl-2 and Bax protein levels with Western blot analysis. RESULTS: KH 1060 inhibited PBMC proliferation and decreased TNF-alpha levels in IBD patients and this effect was synergistic with anti-TNF-alpha. VDR protein levels were significantly increased by PBMC treatment with KH 1060 or anti-TNF-alpha or their combination in ulcerative colitis (UC) patients, and decreased in Crohn's disease (CD) patients, treating the cells with KH 1060. In UC patients an increase in Bcl-2 and Bax levels was observed incubating, PBMC with KH 1060 or anti-TNF-alpha or their combination. In CD patients a slight decrease in Bcl-2 levels was registered when anti-TNF alone or in association with KH 1060 was used. Bax protein levels were slightly increased in the presence of KH 1060 alone or in combination with anti-TNF. CONCLUSION: This study shows that KH 1060 acts as an immunomodulator on PBMC, acting as TNF-alpha inhibitor. This finding provides strong evidence that vitamin D status could be an important regulator of immunity IBD.
OBJECTIVES: We sought to determine whether lipid-lowering therapy and antioxidants retard the progression of coronary calcification and prevent atherosclerotic cardiovascular disease (ASCVD) events. BACKGROUND: The electron beam computed tomography-derived coronary calcium score predicts coronary disease events. Small, uncontrolled studies suggest that vigorous lipid-lowering therapy slows progression of coronary calcification and prevents coronary artery disease events, but controlled, scientific demonstration of these effects is lacking. METHODS: We conducted a double-blind, placebo-controlled randomized clinical trial of atorvastatin 20 mg daily, vitamin C 1 g daily, and vitamin E (alpha-tocopherol) 1,000 U daily, versus matching placebos in 1,005 asymptomatic, apparently healthy men and women age 50 to 70 years with coronary calcium scores at or above the 80th percentile for age and gender. All study participants also received aspirin 81 mg daily. Mean duration of treatment was 4.3 years. RESULTS: Treatment reduced total cholesterol by 26.5% to 30.4% (p < 0.0001), low-density lipoprotein cholesterol by 39.1% to 43.4% (p < 0.0001), and triglycerides by 11.2% to 17.0% (p < or = 0.02) but had no effect (p = 0.80) on progression of coronary calcium score (Agatston method). Treatment also failed to significantly reduce the primary end point, a composite of all ASCVD events (6.9% vs. 9.9%, p = 0.08). Event rates were related to baseline calcium score (pre-specified analysis) and may have been reduced in a subgroup of participants with baseline calcium score >400 (8.7% vs. 15.0%, p = 0.046 [not a pre-specified analysis]). CONCLUSIONS: Treatment with alpha-tocopherol, vitamin C, and low doses of atorvastatin (20 mg once daily) did not affect the progression of coronary calcification. Treatment may have reduced ASCVD events, especially in subjects with calcium scores >400, but these effects did not achieve conventional levels of statistical significance.
The effect of oral vitamin C has been examined in elderly long-stay inpatients known to have low levels of vitamin C in their plasma and leucocytes. 1 g of vitamin C given daily for 28 days was shown to be associated with slight, but significant, clinical improvement and weight-gain when compared with placebo therapy.
The plethora of actions of 1alpha,25(OH)(2)D(3) in various systems suggested wide clinical applications of vitamin D nuclear receptor (VDR) ligands in treatments of inflammation, dermatological indication, osteoporosis, cancers, and autoimmune diseases. More than 3000 vitamin D analogues have been synthesized in order to reduce the calcemic side effects while maintaining the transactivation potency of these ligands. Here, we report the crystal structures of VDR ligand binding domain bound to two vitamin D agonists of therapeutical interest, calcipotriol and seocalcitol, which are characterized by their side chain modifications. These structures show the conservation of the VDR structure and the adaptation of the side chain anchored by hydroxyl moieties. The structure of VDR-calcipotriol helps us to understand the structural basis for for the switching of calcipotriol to a receptor antagonist by further side chain modification. The VDR-seocalcitol structure, in comparison with the structure of VDR-KH1060, a superagonist ligand closely related to seocalcitol, shows adaptation of the D ring and position of C-21 in order to adapt its more rigid side chain.
[formula: see text] Vitamin D3-resistant rickets (VDRR) is associated with mutations to the Vitamin D receptor (VDR) which effect ligand-dependent transactivation. Some VDRR associated mutants directly disrupt ligand binding. Using the reported VDR-1,25-dihydroxy vitamin D3 (1,25(OH)2D3) cocrystal structure, three 1,25(OH)2D3 analogues were designed to uniquely complement the rickets associated mutant VDR(Arg274-->Leu). The three analogues were 17 to 286 times more potent than 1,25(OH)2D3 with the mutant in cell-based assays and did not substantially activate cellular calcium influx.
BACKGROUND: Treatment of hyperparathyroidism includes the use of 1,25-dihydroxy-vitamin D3 (1,25D3) to suppress parathyroid hormone (PTH), but dosing of 1,25D3 is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product because of gut absorption of calcium and phosphorus and enhanced bone resorption. The vitamin D analogue 19-nor-1,25(OH)2-vitamin D2 (19-Nor) causes less hypercalcemia and elevated Ca x P, whereas it still suppresses PTH in rats. METHODS: To determine whether 19-Nor had similar effects in humans, we performed a prospective crossover study to assess bone mobilization. Ten hemodialysis patients on a low-calcium low-phosphorus diet were administered 20 microg of 1,25D3 and 120 and 160 microg of 19-Nor, and changes in calcium, phosphorus, and intact and whole PTH levels were measured over 36 hours. RESULTS: Ca x P product increased more after 1,25D3 administration than after a six- or eightfold greater dose of 19-Nor and was significantly greater at 6, 12, and 24 hours. Ca x P product at 36 hours was 60.9 +/- 3.4 (4.91 +/- 0.27 mmol2/2) after 1,25D3 administration, 53.2 +/- 2.7 (4.29 +/- 0.22 mmol2/L2) after administration of 120 microg of 19-Nor, and 54.2 +/- 2.7 (4.37 +/- 0.22 mmol2/L2) after administration of 160 microg of 19-Nor. Suppression of intact PTH at 36 hours was similar after administration of 1,25D3 (54.1% +/- 6.0%) and 120 microg of 19-Nor (54.4% +/- 3.4%) and significantly greater after administration of 160 microg of 19-Nor (63.6% +/- 2.3%). The whole PTH assay yielded values approximately 25% to 30% lower than the intact PTH assay, and the percentage of suppression was virtually identical. CONCLUSION: Consistent with animal studies, 19-Nor provides profound PTH suppression while stimulating bone resorption and/or intestinal absorption less than 1,25D3, resulting in less elevation of serum calcium and phosphorus levels.
Because sex steroids regulate the life span of bone cells by modulating cytoplasmic kinase activity via a nongenotropic action of their classical receptors, we have explored the possibility that the vitamin D nuclear receptor (VDR) might exhibit similar nongenotropic actions. We report that the conformationally flexible full VDR agonist, 1alpha,25(OH)2-vitamin D3 (1alpha,25(OH)2D3), and the 6-s-cis-locked 1alpha,25(OH)2-lumisterol3 (JN) analog, also acting through the VDR but with poor transcriptional activity, protected murine osteoblastic or osteocytic cells from apoptosis. This effect was reproduced in HeLa cells transiently transfected with either wild type VDR or a mutant consisting of only the VDR ligand binding domain. The VDR ligand binding domain bound [3H]1alpha,25(OH)2D3 as effectively as wild type VDR but did not induce vitamin D response element-mediated transcription. The anti-apoptotic effects of 1alpha,25(OH)2D3 and the 6-s-cis-locked 1alpha,25(OH)2-lumisterol3 analog in calvaria cells were blocked by three cytoplasmic kinase inhibitors: Src kinase inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), phosphatidylinositol 3 kinase inhibitor Wortmannin, and the JNK kinase inhibitor SP600125. However, inhibition of p38 with SB203580 or ERK with either U0126 or a transfected dominant negative MEK did not interfere with these anti-apoptotic actions. Further, 1alpha,25(OH)2D3 induced rapid (5 min) association of VDR with Src kinase in OB-6 cells. Finally, actinomycin D or cycloheximide prevented the anti-apoptotic effect of 1alpha,25(OH)2D3, indicating that transcriptional events are also required. These findings suggest that nongenotropic modulation of kinase activity is also a general property of the VDR and that ligands that activate nongenotropic signals, but lack transcriptional activity, display different biological profiles from the steroid hormone 1alpha,25(OH)2D3.
Vitamin E, selenium and polyunsaturated fatty acids (PUFAs) were determined in feed used at three piggeries over.a four week period and compared with corresponding concentrations in clinically normal grower pigs at slaughter. Mean values were vitamin E: 59 IU/kg (feed), 6 micromol/kg (liver), 1.7 micromol/l (serum); and selenium: 310 microg/kg (feed), 5200 nmol/kg (liver), 1700 nmol/l (blood). Alpha-tocopherol accounted for 80% of the mean vitamin E activity in the feed and over 95% that in the liver and serum. The mean ratio of PUFA to total fatty acid (FA) in the feed (38%) was similar to that in the serum (36%) and liver (39%), but the ratio of peroxidisable PUFA (PPUFA) to FA increased from 1.7% in the feed to 4.2% in the serum and 10.8% in the liver. The ratio of alpha-tocopherol (mmol) to PPUFA (mol) in the liver varied from 0.16 to 0.48. The relationship of these data to the VESD syndrome is discussed in the light of other published data.
To determine the effect of varying levels of dietary protein with a constant intake of vitamin B-6 (B-6) on B-6 status, nine women were fed diets providing daily intakes of 1.25 mg B-6 and 0.5, 1.0 and 2.0 g protein/kg body weight. After an 8-d adjustment period, the women consumed each level of dietary protein for 14 d in a Latin-square design. Several direct and indirect B-6 status indicators were measured in blood and urine. Significant differences among protein levels were found for urinary 4-pyridoxic acid (4-PA) excretion (P < 0.01), plasma pyridoxal 5'-phosphate (PLP) concentration (P < 0.05), and urinary excretion of volatile amines (VA, kynurenine plus acetylkynurenine) after a 2-g L-tryptophan load (P < 0.05). Nitrogen intake was significantly negatively correlated with urinary 4-PA excretion (r = -0.619, P < 0.001) and plasma PLP concentration (r = -0.549, P < 0.01), and positively correlated with erythrocyte alanine aminotransferase percentage stimulation (r = 0.418, P < 0.05) and urinary post-tryptophan load excretion of xanthurenic acid (r = 0.535, P < 0.05), kynurenic acid (r = 0.563, P < 0.05) and VA (r = 0.626, P < 0.01). Compared with men consuming diets with similar B-6 to protein ratios In a previous study, the women excreted a greater percentage of the B-6 intake as 4-PA, had lower plasma PLP concentrations and excreted greater amounts of postload urinary tryptophan metabolites at all three protein levels. If the Recommended Dietary Allowance (RDA) of vitamin B-6 is to be based on the dietary B-6 to protein ratio, gender differences in response to varying protein intakes should be considered. For the levels of protein intake used in this study and a B-6 intake of 1.25 mg/d, a B-6 to protein ratio of greater than 0.020 mg/g is required for adequate vitamin B-6 status in women.