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1
Carpenter, T. O., D. L. Carnes, and C. S. Anast. "Effect of magnesium depletion on metabolism of 25-hydroxyvitamin D in rats." American Journal of Physiology-Endocrinology and Metabolism 253, no. 1 (July 1, 1987): E106—E113. http://dx.doi.org/10.1152/ajpendo.1987.253.1.e106.
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Resistance to vitamin D in magnesium depletion has been observed in humans and in animal studies. Variable levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] have been reported in patients with magnesium depletion, and studies of vitamin D metabolism in states of magnesium depletion have not yielded consistent results. We examined effects of magnesium deprivation on circulating 1,25(OH)2D levels before and after a loading dose of 25-hydroxyvitamin D3 [25(OH)D3], on in vivo conversion of small doses of radiolabeled 25(OH)D3 to 1,25(OH)2D3 in intact rats, and on in vitro 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity in rat renal mitochondria. The effects of magnesium-free media on mitochondrial 1 alpha-hydroxylase activity was examined. Magnesium depletion did not affect in vivo conversion of 25(OH)D to 1,25(OH)2D. In vitro 1 alpha-hydroxylase activity was comparable in magnesium-replete and -deplete animals and was evident in the absence of added magnesium in incubation media. Our in vivo and in vitro studies are consistent with one another and demonstrate that in the rat conversion of 25(OH)D to 1,25(OH)2D is unimpaired in magnesium deficiency. Resistance to vitamin D in magnesium depletion is likely due to the impaired skeletal responsivity to 1,25(OH)2D, as demonstrated in earlier studies.
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Turner, R. T., J. S. Graves, and N. H. Bell. "Regulation of 25-hydroxyvitamin D3 metabolism in chick embryo." American Journal of Physiology-Endocrinology and Metabolism 252, no. 1 (January 1, 1987): E38—E43. http://dx.doi.org/10.1152/ajpendo.1987.252.1.e38.
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We investigated the time course of the development of renal 25-hydroxyvitamin D-1-hydroxylase and 25-hydroxyvitamin D-24-hydroxylase in chick embryos grown in the presence and absence of the eggshell. In embryos with the eggshell, the specific activity (SA) of 25-hydroxyvitamin D-1-hydroxylase in kidney homogenates increased from 0.68 fmol X min-1 X mg protein-1 at 12 days of gestation to a peak of 2.55 +/- 0.50 fmol X min-1 X mg-1 protein-1 at 17 days. In contrast, the SA of 25-hydroxyvitamin D-24-hydroxylase decreased from 2.5 fmol X min-1 X mg protein-1 to 0.90 +/- 0.25 fmol X min-1 X mg protein-1 during the interval. The total plasma calcium was significantly reduced in embryos without shells at 14 to 15 days of gestation (1.1 +/- 0.1 mM, mean +/- SE) compared with normal embryos of the same gestation (2.3 +/- 0.3 mM, P less than 0.002). In embryos without the eggshell, renal 25-hydroxyvitamin D-1-hydroxylase increased from 6.0 to 8.2 +/- 0.6 fmol X min-1 X mg protein-1 at 17 days of gestation and was from four- to sixfold higher than corresponding enzymatic activities for intact embryos. The increased enzyme activity resulting from loss of the eggshell was due to an increase in Vmax. The findings indicate that renal 25-hydroxyvitamin D-1-hydroxylase and 25-hydroxyvitamin D-24-hydroxylase in the chick embryo exhibit activity and show a large capacity for regulation in response to changes in calcium metabolism.
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Postlind, H., and K. Wikvall. "Purification of a cytochrome P-450 from pig kidney microsomes catalysing the 25-hydroxylation of vitamin D3." Biochemical Journal 253, no. 2 (July 15, 1988): 549–52. http://dx.doi.org/10.1042/bj2530549.
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Cytochrome P-450 catalysing 25-hydroxylation of vitamin D3 was purified from pig kidney microsomes. The enzyme fraction contained 7 nmol of cytochrome P-450/mg of protein and showed only one protein band with an apparent Mr of 50,500 upon SDS/polyacrylamide-gel electrophoresis. The purified cytochrome P-450 catalysed 25-hydroxylation of vitamin D3 up to 1,000 times more efficiently, and 25-hydroxylation of 1 alpha-hydroxyvitamin D3 up to 4000 times more efficiently, than the microsomes. The cytochrome P-450 required microsomal NADPH-cytochrome P-450 reductase for catalytic activity. Mitochondrial ferredoxin and ferredoxin reductase could not replace microsomal NADPH-cytochrome P-450 reductase. The enzyme preparation showed no detectable 25-hydroxylase activity towards vitamin D2 or 1 alpha-hydroxylase activity towards 25-hydroxyvitamin D3. CO inhibited the 25-hydroxylation by more than 85%. Mannitol, hydroquinone, catalase and superoxide dismutase did not affect the 25-hydroxylation. The possible role of the kidney microsomal cytochrome P-450 in the metabolism of vitamin D3 is discussed.
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Yu, Wen-Xuan, Christina Chui-Wa Poon, Wayne Yuk-Wai Lee, and Man-Sau Wong. "Oleanolic Acid Modulates 25-Hydroxyvitamin D3 1-alpha-hydroxylase in Osteoblasts and Human Mesenchymal Stem Cells." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A237. http://dx.doi.org/10.1210/jendso/bvab048.482.
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Abstract Objectives: 25-Hydroxyvitamin D3 1-alpha-hydroxylase (CYP27B1) catalyzes the hydroxylation of 25-hydroxyvitamin D3 (25(OH)D3) to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), the bioactive form of vitamin D3. Our previous studies suggested that oleanolic acid (OA), a pentacyclic triterpenoid presents in many food and herbs, can improve circulating 1,25(OH)2D3 in ovariectomized (OVX) mice and increase CYP27B1 expression in human renal proximal tubular cells (HKC-8). However, the role of OA in regulating CYP27B1 in bone is far from clear. The present study is designed to study the effects of OA on CYP27B1 expressions and 1,25(OH)2D3 production in bone cells. Methods: The mRNA and protein expressions of CYP27B1, as well as bone metabolism markers were determined in osteoblast-like UMR-106 cells in response to treatments of parathyroid hormone (PTH) (10–7 M) or OA (10–9 - 10–5 M) for 24 hours. By using excessive 25(OH)D3 (10–6 M) as substrate, cellular production of 1,25(OH)2D3 was measured to determine CYP27B1 activity. To mimic the physiological condition, human mesenchymal stem cells (hMSCs) were pre-treated with 25(OH)D3 (10–7 M) for 12 hours, followed by OA treatment (10–9 - 10–6 M) for another 24 hours, the osteogenic effects of OA on alkaline phosphatase (ALP) activity and CYP27B1 expression were evaluated. Results: PTH (10–7 M, p<0.001) and OA (10–9 M, p<0.05) significantly upregulated mRNA and protein expressions of CYP27B1 in UMR-106 cells. 4-hour treatments of PTH (10–7 M) and OA (10–9 M) also stimulated the 1,25(OH)2D3 production by 46.02 % (p<0.001) and 17.60 % (p<0.01), respectively. Moreover, the mRNA expressions of ALP and osteocalcin (OCN) involved in osteoblast differentiation, were upregulated in response to PTH and OA in UMR-106 cells (p<0.05). The protein expression of CYP27B1 was upregulated by treatment with OA in hMSCs supplemented with 25(OH)D3 (10–8 M, p<0.05 vs. supplement alone). Furthermore, OA (10–8 M) potentiated the effects of 25(OH)D3 on osteogenesis in hMSCs by enhancing ALP activity by 47.77 % (p<0.01). Conclusions: Our results indicated that the bone anabolic effects of OA are associated with its actions to improve local bioactivation of vitamin D3 in osteoblasts and hMSCs, suggesting the involvement of paracrine or autocrine activities of 1,25(OH)2D3 in mediating the actions of OA in bone. Funding Sources: This work is supported by research studentship of Wen-Xuan Yu, The Hong Kong Polytechnic University.
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Adams, J. S., and M. A. Gacad. "Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis." Journal of Experimental Medicine 161, no. 4 (April 1, 1985): 755–65. http://dx.doi.org/10.1084/jem.161.4.755.
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We investigated the 1 alpha-hydroxylation of vitamin D3 sterols by cultured pulmonary alveolar macrophages (PAM) from patients with sarcoidosis with or without clinically abnormal calcium homeostasis. Like the naturally occurring renal 1 alpha-hydroxylase, the PAM 1 alpha-hydroxylation reaction exhibited a high affinity for 25-hydroxyvitamin D3 (25-OH-D3) and a preference for substrates containing a 25-hydroxyl group in the side chain of the sterol. Unlike the renal enzyme, the PAM 1 alpha-hydroxylating mechanism was not accompanied by 24-hydroxylating activity, even after preincubation with 75 nM 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3] or exposure to high concentrations of substrate (500 nM 25-OH-D3). The PAM 25-OH-D3-1 alpha-hydroxylation reaction was stimulated by gamma interferon and inhibited by exposure to the glucocorticoid dexamethasone. The characteristics of the PAM hydroxylation process in vitro appear to reflect the efficiency of the extrarenal production of 1,25-(OH)2-D3 and the therapeutic efficacy of glucocorticoids in patients with sarcoidosis and disordered calcium metabolism.
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Lee, Sang R., Mi-Young Park, Hyun Yang, Geun-Shik Lee, Beum-Soo An, Bae-kuen Park, Eui-Bae Jeung, and Eui-Ju Hong. "5α-dihydrotestosterone reduces renal Cyp24a1 expression via suppression of progesterone receptor." Journal of Molecular Endocrinology 60, no. 2 (February 2018): 159–70. http://dx.doi.org/10.1530/jme-17-0187.
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Androgens act in concert with vitamin D to influence reabsorption of calcium. However, it is unclear whether androgens directly regulate vitamin D homeostasis or control other cellular events that are related to vitamin D metabolism. To examine whether the expression of vitamin D-related genes in mouse kidney is driven by androgens or androgen-dependent effects, the androgen receptor and other sex steroid receptors were monitored in orchidectomized mice treated with 5α-dihydrotestosterone (DHT). Our results revealed that exposing orchidectomized mice to DHT inhibited the expression of progesterone receptor (Pgr) with or without estrogen receptor α expression, the latter was confirmed by ER-positive (MCF7 and T47D) or -negative (PCT) cells analysis. The loss of Pgr in turn decreased the expression of renal 24-hydroxylase via transcriptional regulation because Cyp24a1 gene has a progesterone receptor-binding site on promoter. When male kidneys preferentially hydroxylate 25-hydroxyvitamin D3 using 24-hydroxylase rather than 25-hydroxyvitamin D3-1-alpha hydroxylase, DHT suppressed the Pgr-mediated 24-hydroxylase expression, and it is important to note that DHT increased the blood 25-hydroxyvitamin D3 levels. These findings uncover an important link between androgens and vitamin D homeostasis and suggest that therapeutic modulation of Pgr may be used to treat vitamin D deficiency and related disorders.
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Vieth, R., K. McCarten, and K. H. Norwich. "Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D3 production." American Journal of Physiology-Endocrinology and Metabolism 258, no. 5 (May 1, 1990): E780—E789. http://dx.doi.org/10.1152/ajpendo.1990.258.5.e780.
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To understand the relationships among 1) the dose of 25-hydroxyvitamin D [25(OH)D] in vivo, 2) the activity of 1-hydroxylase in renal mitochondria, and 3) the production of 1,25-dihydroxyvitamin D [1,25(OH)2D] in vivo, we gave rats different chronic or acute doses of 25-hydroxyvitamin D3 [25(OH)D3]. We followed the metabolism of intracardially administered [25-hydroxy-26,27-methyl-3H]cholecalciferol [25(OH)[3H]D3] for 24 h before killing by measuring extracts of serum by chromatography. Specific activity of 1-hydroxylase in kidney was measured at death. In rats given 0-2,000 pmol 25(OH)D3 chronically by mouth, there was a dose-dependent decline in the percent of serum radioactivity made up of 1,25-dihydroxy-[26,27-methyl-3H]cholecalciferol [1,25(OH)2[3H]D3] as well as a decline in mitochondrial 1-hydroxylase, and these correlated significantly (r = 0.83, P less than 0.001). Serum %1,25(OH)2[3H]D3 in this experiment ranged from 0.8 to 42%. A small part of this range could be accounted for by a faster metabolic clearance rate (MCR) of 1,25(OH)2D3 from rats supplemented with 25(OH)D3 (MCR, 2.12 +/- 0.10 ml/min) compared with rats restricted in vitamin D (MCR, 0.94 +/- 0.06 ml/min, P less than 0.001). The activity of 1-hydroxylase was by far the major factor determining serum %1,25(OH)2[3H]D3. When different acute doses of 25(OH)D3 were given to rats with identical specific activities of 1-hydroxylase, the resulting 1,25(OH)2D3 concentrations in serum correlated with the 25(OH)D3 dose (r = 0.99, P less than 0.001). We conclude that the behavior of 1-hydroxylase in vivo is analogous to the classic behavior in vitro of an enzyme functioning below its Michaelis constant (Km). The amount of 1-hydroxylase present in renal mitochondria determines the fraction (not simply the quantity) of 25(OH)D metabolized to 1,25(OH)2D3 in vivo.
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Carpenter, T. O., and T. Shiratori. "Renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity and mitochondrial phosphate transport in Hyp mice." American Journal of Physiology-Endocrinology and Metabolism 259, no. 6 (December 1, 1990): E814—E821. http://dx.doi.org/10.1152/ajpendo.1990.259.6.e814.
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The Hyp mouse is a homologue of the X chromosome-linked human disease, familial hypophosphatemic rickets (FHR). In FHR, reduced renal tubular brush-border membrane transport of phosphate results in hypophosphatemia and rickets. Both humans with FHR and Hyp mice have abnormal regulation of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase), a mitochondrial enzyme found in proximal renal tubular cell epithelia, the apparent site of defective brush-border membrane phosphate transport. No common pathophysiology for these defects has been demonstrated. We hypothesized that phosphate transport may be present in renal mitochondria from Hyp mice and that its regulation may be deranged in parallel with the mitochondrial 1 alpha-hydroxylase. Using inhibitor-stop techniques described for measurement of phosphate transport in liver mitochondria, we examined mitochondria in normal and Hyp mouse kidney and found them to be comparable. We performed manipulations known to alter 1 alpha-hydroxylase differentially in normal and Hyp mice, i.e., phosphorus deprivation and phosphorus loading, and found no effect on mitochondrial phosphate transport. We also subjected Hyp and normal mice to calcium and vitamin D deprivation; this maneuver resulted in no significant changes in mitochondrial phosphate transport in Hyp or normal mice but confirmed the earlier observation that 1 alpha-hydroxylase activity is stimulated to a greater degree in normal mice than Hyp mice after this diet. Furthermore, administration of 1,25-hydroxyvitamin D3 depresses 1 alpha-hydroxylase activity in mitochondria from both normal and Hyp mice but has no effect on mitochondrial phosphate transport. We conclude that the mechanism of abnormal vitamin D metabolism in Hyp mice is not related to a primary defect in renal mitochondrial phosphate transport.
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Carpenter, T. O., M. L. Pendrak, and C. S. Anast. "Metabolism of 25-hydroxyvitamin D in copper-laden rat: a model of Wilson's disease." American Journal of Physiology-Endocrinology and Metabolism 254, no. 2 (February 1, 1988): E150—E154. http://dx.doi.org/10.1152/ajpendo.1988.254.2.e150.
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Wilson's disease results in excess tissue accumulation of copper and is often complicated by skeletal and mineral abnormalities. We investigated vitamin D metabolism in rats fed a copper-laden diet rendering hepatic copper content comparable with that found in Wilson's disease. Injection of 25-hydroxyvitamin D3 [25(OH)D3] resulted in reduced 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in copper-intoxicated rats. In vitro 25(OH)D-1 alpha-hydroxylase activity was impaired in renal mitochondria from copper-intoxicated animals. Activity was also inhibited in mitochondria from controls when copper was added to incubation media. Impaired conversion of 25(OH)D to 1,25(OH)2D occurs in copper intoxication and suggests that altered vitamin D metabolism is a potential factor in the development of bone and mineral abnormalities in Wilson's disease.
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Lobaugh, B., A. Boass, G. E. Lester, and S. U. Toverud. "Regulation of serum 1,25-dihydroxyvitamin D3 in lactating rats." American Journal of Physiology-Endocrinology and Metabolism 259, no. 5 (November 1, 1990): E665—E671. http://dx.doi.org/10.1152/ajpendo.1990.259.5.e665.
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To characterize further the mechanism(s) underlying the increased serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] concentration associated with lactation in the rat, we examined hormone biosynthesis [i.e., renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity] and hormone disappearance in groups of lactating Holtzman rats and age- and sex-matched nonlactating controls. 1 alpha-Hydroxylase activity was significantly greater in kidneys from lactating rats (4.0 +/- 0.42 fmol.mg-1.min-1) on a basal diet than in those from nonmated females (1.4 +/- 0.08 fmol.mg-1.min-1), an increment sufficient to account for the observed fourfold elevation of 1,25(OH)2D3 in the dams. The increase occurs despite the lower serum 1,25(OH)2D3 levels in lactating than in nonlactating rats at 12 and 24 h after a bolus injection of 1,25(OH)2D3 (2 ng/g body wt). Elevation of serum 1,25(OH)2D3 is not a requisite consequence of lactation, however, because dams receiving supplemental calcium from food (1.6%) and water (0.3%) exhibited no increase of either serum 1,25(OH)2D3 or 1 alpha-hydroxylase activity compared with controls. In contrast, lactating rats that received a diet with only 0.1% calcium had 5-fold higher serum 1,25(OH)2D3 levels and 20-fold higher 1 alpha-hydroxylase activity than nonlactating rats on the same diet. We conclude that other factors in conjunction with lactation, but not the lactating state per se, promote the changes in 1,25(OH)2D3 metabolism observed.
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Koyama, H., M. Inaba, Y. Nishizawa, E. Ishimura, Y. Imanishi, M. Hini, T. Furuyama, H. Takagi, and H. Morii. "Potentiated 1,25(OH)2D3-induced 24-hydroxylase gene expression in uremic rat intestine." American Journal of Physiology-Renal Physiology 267, no. 6 (December 1, 1994): F926—F930. http://dx.doi.org/10.1152/ajprenal.1994.267.6.f926.
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24-Hydroxylase has been considered a major enzyme regulating metabolism of circulating 1 alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3]. To understand the metabolism of 1,25(OH)2D3 in chronic renal failure, we examined 1,25(OH)2D3-induced 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase) gene expression in the intestine of uremic rats. Northern blot and dot blot analyses showed that the induction of duodenal 24-hydroxylase gene expression was 2.0- to 3.8-fold greater in uremic rats than in sham-operated rats (P < 0.05, Student's t-test) at 6 h after 1,25(OH)2D3 administration. Gene induction of calbindin D9k by 1,25(OH)2D3 was not augmented in uremic group. In situ hybridization analysis revealed that the induction of 24-hydroxylase mRNA by 1,25(OH)2D3 was observed exclusively in the columnar epithelium of the crypt and the lower part of the villi, suggesting that the stage of epithelial cell differentiation is a major determinant of 1,25(OH)2D3-induced 24-hydroxylase gene expression. In uremia, 1,25(OH)2D3-induced 24-hydroxylase gene expression was accelerated selectively, possibly because of poorly differentiated epithelial cells.
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Iwata, K., A. Yamamoto, S. Satoh, Y. Ohyama, Y. Tashiro, and T. Setoguchi. "Quantitative immunoelectron microscopic analysis of the localization and induction of 25-hydroxyvitamin D3 24-hydroxylase in rat kidney." Journal of Histochemistry & Cytochemistry 43, no. 3 (March 1995): 255–62. http://dx.doi.org/10.1177/43.3.7868855.
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25-Hydroxyvitamin D3 24(R)-hydroxylase (24-hydroxylase) is involved in the metabolism and regulation of vitamin D3 and is markedly induced by administration of vitamin D3. We detected this enzyme by electron microscopy and an immunogold technique along nephrons of normal and vitamin D3-administered rats. After the rats were administered vitamin D3, 50,000 IU/day for 1 week, they were perfusion-fixed with a paraformaldehyde solution. The fixed kidneys were then removed and embedded in LR White resin. Ultrathin sections were prepared and labeled by the immunogold technique using a mouse anti-rat 25-hydroxyvitamin D3 24-hydroxylase monoclonal antibody. We counted the number of gold particles bound per micron 2 of the mitochondria (particle density) of the tubule epithelial cells along the nephrons. In normal and vitamin D3-administered rats, gold particles were observed in the mitochondria of epithelial cells along the tubules. In normal rats, gold labeling for 24-hydroxylase was statistically significant (p < 0.05), in the S1-S2 segments, the S3 segment of the proximal tubules, and in the distal convoluted tubules. In the rats administered vitamin D3, the particle density increased significantly (p < 0.05) by about 12-fold in the S1-S2 segments of the proximal tubules, whereas it increased less markedly in other parts of the nephron. The marked induction of the S1-S2 segments of the proximal tubules suggests that these segments play an important role in the regulation of vitamin D3 metabolism.
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Segersten, U. "25-Hydroxyvitamin D3-1 -Hydroxylase Expression in Normal and Pathological Parathyroid Glands." Journal of Clinical Endocrinology & Metabolism 87, no. 6 (June 1, 2002): 2967–72. http://dx.doi.org/10.1210/jc.87.6.2967.
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Buffenstein, R., I. N. Sergeev, and J. M. Pettifor. "Vitamin D hydroxylases and their regulation in a naturally vitamin D-deficient subterranean mammal, the naked mole rat (Heterocephalus glaber)." Journal of Endocrinology 138, no. 1 (July 1993): 59–64. http://dx.doi.org/10.1677/joe.0.1380059.
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ABSTRACT The vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is generated by a series of hydroxylation steps in the liver and kidneys. We investigated whether naturally vitamin D-deficient subterranean mammals (naked mole rats, Heterocephalus glaber) employ the same enzymatic pathways, and whether these are regulated in a similar manner to that established for other mammals. Vitamin D3-25-hydroxylase in the liver and both 25-hydroxyvitamin D3-l-hydroxylase and 25-hydroxyvitamin D3-24 hydroxylase (1-OHase and 24-OHase) in the kidney were detectable in mole rats. As expected for vitamin D-deficient mammals, the 1-OHase activity predominated over the 24-OHase. After mole rats received a supraphysiological supplement of vitamin D3, 1-OHase activity was suppressed and 24-OHase activity was enhanced. Irrespective of vitamin D status, forskolin (a protein kinase A activator) and dibutyryl cyclic AMP did not alter the activity of either 1-OHase or 24-OHase. These findings suggest that the response of renal hydroxylases to parathyroid hormone was blunted. Phorbol esters, 12-O-tetradecanoylphorbol 13-acetate (TPA) and 1-oleoyl-2-acetylglycerol (OAG) (protein kinase C activators), suppressed 1-OHase activity. 24-OHase activity was induced by TPA but not by OAG. These effects were similar to those illicited by vitamin D3 supplementation but were additive in that they increased the responses shown in vitamin D-replete mole rats. These data confirm that naturally vitamin D-deficient mole rats can convert vitamin D3 to the hormone, 1,25(OH)2D3. Furthermore, the enzymes 1-OHase and 24-OHase present in the kidneys of these mammals are regulated independently by 1,25(OH)2D3 and protein kinase C-mediated pathways of intracellular signalling, but are not regulated by the cyclic AMP–protein kinase A signal transduction pathway. Journal of Endocrinology (1993) 138, 59–64
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Dahlbäck, H., and K. Wikvall. "25-Hydroxylation of vitamin D3 by a cytochrome P-450 from rabbit liver mitochondria." Biochemical Journal 252, no. 1 (May 15, 1988): 207–13. http://dx.doi.org/10.1042/bj2520207.
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A cytochrome P-450 catalysing 25-hydroxylation of vitamin D3 was purified from liver mitochondria of untreated rabbits. The enzyme fraction contained 9 nmol of cytochrome P-450/mg of protein and showed only one protein band with an apparent Mr of 52,000 upon SDS/polyacrylamide-gel electrophoresis. The preparation showed a single protein spot with an apparent isoelectric point of 7.8 and an Mr of approx. 52,000 upon two-dimensional isoelectric-focusing-polyacrylamide-gel electrophoresis. The purified cytochrome P-450 catalysed 25-hydroxylation of vitamin D3 up to 5000 times more efficiently than did the mitochondria. The cytochrome P-450 required both ferredoxin and ferredoxin reductase for catalytic activity. Microsomal NADPH-cytochrome P-450 reductase could not replace ferredoxin and ferredoxin reductase. The cytochrome P-450 catalysed, in addition to 25-hydroxylation of vitamin D3, the 25-hydroxylation of 1 alpha-hydroxyvitamin D3 and the 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol. The enzyme did not catalyse side-chain cleavage of cholesterol, 11 beta-hydroxylation of deoxycorticosterone, 1 alpha-hydroxylation of 25-hydroxyvitamin D3, hydroxylations of lauric acid and testosterone or demethylation of benzphetamine. The results raise the possibility that the 25-hydroxylation of vitamin D3 and the 26-hydroxylation of C27 steroids are catalysed by the same species of cytochrome P-450 in liver mitochondria. The possible role of the liver mitochondrial cytochrome P-450 in the metabolism of vitamin D3 is discussed.
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Martineau, Adrian R., Kenneth E. Thummel, Zhican Wang, David A. Jolliffe, Barbara J. Boucher, Simon J. Griffin, Nita G. Forouhi, and Graham A. Hitman. "Differential Effects of Oral Boluses of Vitamin D2 vs Vitamin D3 on Vitamin D Metabolism: A Randomized Controlled Trial." Journal of Clinical Endocrinology & Metabolism 104, no. 12 (June 14, 2019): 5831–39. http://dx.doi.org/10.1210/jc.2019-00207.
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Abstract Context Vitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism. Objective To compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3. Methods We measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups. Results Vitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4β,25(OH)2D3 to 25(OH)D3 did not differ between groups. Conclusions Bolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3.
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Hayes, M. E., D. Bayley, and E. B. Mawer. "Metabolism of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 and its sensitivity to ketoconazole in 1α,25-dihydroxyvitamin D3-differentiated HL60 cells." Journal of Molecular Endocrinology 3, no. 3 (November 1989): 199–205. http://dx.doi.org/10.1677/jme.0.0030199.
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ABSTRACT Regulation of the metabolism of [3H]25-hydroxyvitamin D3 ([3H]25-(OH)D3) in vitro to material with the characteristics of [3H]24,25-dihydroxyvitamin D3 ([3H]24,25-(OH)2D3) has been studied in the human promyelocytic cell line HL60. Synthesis of 24,25-(OH)2D3 was induced in a dose-dependent manner in cells pretreated with 0·1–100 nm 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) for 4 days. This treatment also inhibited cell proliferation and stimulated differentiation to a macrophage phenotype that was characterized by staining for non-specific esterase (NSE) activity. The ability to synthesize [3H]24,25-(OH)2D3 from [3H]25-(OH)D3 and the expression of NSE activity both responded to changes in concentration of 1α,25-(OH)2D3 in the culture medium in a parallel manner. Synthesis of [3H]24,25-(OH)2D3 was linear when the incubation time was between 1 and 8 h and the cell number between 1 and 12×106 cells/incubation. The optimum substrate concentration for its synthesis was 125 nm, giving an apparent Michaelis constant of 360 nm. The identity of the [3H]24,25-(OH)2D3 synthesized by these cells was confirmed by co-chromatography with authentic 24,25-(OH)2D3 on normal-phase and reverse-phase high-performance liquid chromatography systems and by its reaction to sodium-m-periodate. Cells that had been exposed to 100 nm 1α,25-(OH)2D3 for 4 days synthesized 2·17±0·07 (s.e.m.) pmol 24,25-(OH)2D3/106 cells per h. This synthesis was inhibited in a dose-dependent manner over a concentration range of 0·01–1 μm by the drug ketoconazole, an antimycotic imidazole which is a known inhibitor of certain cytochrome P-450 enzyme systems, suggesting that the HL60 25-(OH)D3-24-hydroxylase is also a P-450-dependent enzyme system.
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Fox, John, Uwe Kollenkirchen, and Marian R. Walters. "Deficiency of vitamin D metabolites directly stimulates renal 25-hydroxyvitamin D3-1-hydroxylase activity in rats." Metabolism 40, no. 4 (April 1991): 438–41. http://dx.doi.org/10.1016/0026-0495(91)90157-r.
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Pitcher, T., I. N. Sergeev, and R. Buffenstein. "Vitamin D metabolism in the Damara mole-rat is altered by exposure to sunlight yet mineral metabolism is unaffected." Journal of Endocrinology 143, no. 2 (November 1994): 367–74. http://dx.doi.org/10.1677/joe.0.1430367.
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Abstract Vitamin D may be endogenously synthezised in the skin in the presence of sunlight or, alternatively, acquired from dietary sources. Cryptomys damarensis appear to have a naturally impoverished vitamin D status with low plasma concentrations of both 25-hydroxyvitamin D (25(OH)D; <5 ng/ml) and 1,25-dihydroxyvitamin D (1,25(OH)2D; <20 pg/ml). We attribute this to their underground habitat and herbivorous habits. We questioned whether these subterranean mammals could utilize sunlight-mediated pathways and therefore compared vitamin D metabolism and function when animals were (a) housed naturally (control), (b) given an oral vitamin D3 (D3) supplement (1 IU/g dry matter food eaten per day) and (c) exposed to 10 h of sunlight. Control animals exhibited a highly efficient apparent fractional absorption of both calcium (Ca) and inorganic phosphorus (Pi) (>90%), passive mode of intestinal mineral uptake, yet tightly regulated serum ionized calcium (Ca2+). The ratio of 25(OH)D-1α-hydroxylase (1-OHase) to 25(OH)D-24R-hydroxylase (24-OHase) activity in the kidney, corresponded with a state of vitamin D deficiency. Cryptomys damarensis responded to both oral D3 supplementation and sun exposure by an increase in plasma concentration of 1,25(OH)2D with a commensurate decline (P<0·05) in 1-OHase activity, and a resulting decrease (P<0·05) in the ratio of 1-OHase:24-OHase activity. Despite these changes, the intestinal mode of Ca uptake and plasma total Ca, Ca2+ and Pi remained unchanged with either treatment. Responses to sunlight were less pronounced than that of oral D3 supplementation. These data confirm that naturally vitamin D-deficient mole-rats can convert vitamin D to the active hormone 1,25(OH)2D, and indicate that mole-rats function optimally at the low concentrations of vitamin D metabolites found naturally. Furthermore, these animals exhibit a highly efficient vitamin D-independent mode of intestinal Ca absorption. Journal of Endocrinology (1994) 143, 367–374
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Hayes, M. E., D. Bayley, and E. B. Mawer. "Studies on an adherent variant of the human promyelomonocytic HL60 leukaemia cell line that constitutively expresses 25-hydroxyvitamin D3-24-hydroxylase activity which is inhibited by 1α,25-dihydroxyvitamin D3." Journal of Molecular Endocrinology 7, no. 3 (December 1991): 185–95. http://dx.doi.org/10.1677/jme.0.0070185.
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ABSTRACT The constitutive expression of 25-hydroxyvitamin D3-24-hydroxylase (25-(OH)D3-24-hydroxylase) activity has been studied in an adherent variant (Ad-HL60) of the human promyelomonocytic leukaemia cell line HL60. The Ad-HL60 cells have a more differentiated phenotype than the non-adherent cells from which they were derived, and synthesized 1.88±0.07 (±s.e.m.) pmol 24,25-(OH)2D3/h per 106 cells following culture in RPMI-1640 medium containing <0.02 nm 1α,25-(OH)2D3. They also synthesized 1.66±0.05 pmol 24,25-(OH)2D3/h per 106 cells following culture in 1α,25-(OH)2D3-free medium supplemented with 1 g bovine serum albumin/l instead of 10% serum. In contrast, non-adherent HL60 cells required exposure to 10–100 nm 1α,25-(OH)2D3 to induce equivalent 24,25-(OH)2D3 synthesis. The 25-(OH)D3-24-hydroxylase expressed by Ad-HL60 cells had an apparent Michaelis constant of 1 μm and maximal rate of 20 pmol/h per 106 cells with substrate concentrations from 0.012 to 1.2 μm/incubation (5–500ng/ml). Furthermore, 24,25-(OH)2D3 synthesis was inhibited in a dose-dependent manner by ketoconazole (0.01–10 μm), suggesting that the enzyme is cytochrome P-450 dependent. Ad-HL60 cells expressed approximately 3500 specific receptors for 1α,25-(OH)2D3/cell with a dissociation constant of 40 pm. Following exposure to 0.1–100 nm 1α,25-(OH)2D3, Ad-HL60 cell proliferation was significantly inhibited compared with controls grown in medium containing <0.02 nm 1α,25-(OH)2D3 for 96h. Expression of 25-(OH)D3-24-hydroxylase was also inhibited in a dose- and time-dependent manner; however, expression of non-specific esterase was not induced. Both of these findings are contrary to those previously demonstrated for non-adherent HL60 cells, whereas the dose-dependent inhibition of cell proliferation by 1α,25-(OH)2D3 occurs in both adherent and non-adherent phenotypes. These observations on Ad-HL60 cells represent the first description of a cell type in which 1α,25-(OH)2D3 appears to inhibit 25-(OH)D3-24-hydroxylase activity. The Ad-HL60 cells also constitutively metabolized 1α,25-(OH)2D3 in a manner consistent with formation of 1α,24,25-(OH)3D3 without previous exposure to 1α,25-(OH)2D3. In contrast, many other cell types, including non-adherent HL60 cells, require exposure to 1α,25-(OH)2D3 to induce metabolism of 1α,25-(OH)2D3 to 1α,24,25-(OH)3D3, a reaction that represents the initial step for catabolism of 1α,25-(OH)2D3 to calcitroic acid.
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Hazell, Tom J., Sina Gallo, llze Berzina, Catherine A. Vanstone, Celia Rodd, and Hope A. Weiler. "Plasma 25-hydroxyvitamin D, more so than its epimer, has a linear relationship to leaner body composition across infancy in healthy term infants." Applied Physiology, Nutrition, and Metabolism 39, no. 10 (October 2014): 1137–43. http://dx.doi.org/10.1139/apnm-2013-0586.
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Vitamin D status positively associates with skeletal muscle mass and function in adolescents. The C-3 alpha epimer of 25-hydroxyvitamin D3 (3-epi-25(OH)D3) is high in infants, yet the potential impacts of 25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25(OH)D3 on skeletal muscle development are largely unexplored. The objective of this study was (i) to explore how the concentrations of 25(OH)D3 and 3-epi-25(OH)D3 track with body composition (lean mass (LM) and fat mass (FM)) and (ii) to determine the association between 25(OH)D3 and 3-epi-25(OH)D3 in infancy. Healthy breastfed infants (n = 132) were followed from 1 to 12 months of age as part of a vitamin D dose–response study (NCT00381914). Anthropometry and diet were assessed. Body composition was measured with dual-energy X-ray absorptiometry. Plasma 25(OH)D3 and 3-epi-25(OH)D3 concentrations were evaluated using liquid chromatography tandem mass spectrometry. Plasma 25(OH)D3 and 3-epi-25(OH)D3 increased from 1 to 3 months of age and decreased thereafter (p < 0.05). Infants with 25(OH)D3 concentrations above 75 nmol/L did not have a higher LM (g or %; p > 0.273) than those below this cutoff. LM was not associated with 25(OH)D3, whereas LM% was positively associated with 25(OH)D3 (β = 0.03; CI: 0.01 to 0.06; p = 0.006), while accounting for sex, weight-for-age Z-score, protein and fat intake, and age. For FM, the variables accounting for a significant amount of the variation were plasma 25(OH)D3 concentration (β = −2.38; CI: −4.35, −0.41; p = 0.019), weight-for-age Z-score, protein and fat intake, and time. In healthy infants, higher vitamin D status associates with leaner body composition, though the effect is smaller in magnitude relative to growth.
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Jovičić, Snežana, Svetlana Ignjatović, and Nada Majkić-Singh. "Biochemistry and metabolism of vitamin D / Biohemija i metabolizam vitamina D." Journal of Medical Biochemistry 31, no. 4 (October 1, 2012): 309–15. http://dx.doi.org/10.2478/v10011-012-0028-8.
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Summary Vitamin D is not technically a vitamin, since it is not an essential dietary factor. It is rather a prohormone produced photochemically in the skin from 7-dehydrocholesterol. Vitamin D and its metabolites may be categorized as either cholecalciferols or ergocalciferols. Cholecalciferol (vi - tamin D3) is the parent compound of the naturally occurring family and is produced in the skin from 7-dehydrocholesterol on exposure to the ultraviolet B portion of sunlight. Vitamin D2 (ergocalciferol), the parent compound of the other family, is manufactured by irradiation of ergosterol produced by yeasts and its potency is less than one-third of vitamin D3’s potency. The steps in the vitamin D endocrine system include the following: 1) the photoconversion of 7- dehydrocholesterol to vitamin D3 in the skin or dietary intake of vitamin D3; 2) metabolism of vitamin D3 by the liver to 25-hydroxyvitamin-D3 [25(OH)D3 ], the major form of vitamin D circulating in the blood compartment; 3) conversion of 25(OH)D3 by the kidney (functioning as an endocrine gland) to the hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]; 4) systemic transport of the dihydroxylated metabolite 1,25(OH)2D3 to distal target organs; and 5) binding of 1,25(OH)2D3 to a nuclear receptor (VDR) at target organs, followed by generation of appropriate biological responses. The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hy - droxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1a-hy - dro xylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1,25(OH)2D3. A five-step inactivation pathway from 1,25(OH)2D3 to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally in du - ced in vitamin D target cells by the action of 1,25(OH)2D3. An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein (DBP), which carries vitamin D3 and its metabolites to their metabolism and target organs. DBP is a specific, high-affinity transport protein. It is synthesized by the liver and circulates in great excess, with fewer than 5% of the binding sites normally occupied. 1,25(OH)2D3, acts as a ligand for a nuclear transcription factor, vitamin D receptor - VDR, which like all other nuclear receptors, regulates gene transcription and cell function. The widespread presence of VDR, and the key activating (1a-hydroxylase, CYP27B1) and inactivating (24-hydroxylase, CYP24A1) en - zy mes in most mammalian cells means that the cells in these tissues have the potential to produce biological res pon ses, depending on the availability of appropriate amounts of vi - tamin D3. Thanks to this widespread presence of elements of vitamin D endocrine system, its biological features are being recognized outside bone tissue, i.e. calcium and pho - sphate metabolism.
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Diaz, L. "Identification of a 25-Hydroxyvitamin D3 1 -Hydroxylase Gene Transcription Product in Cultures of Human Syncytiotrophoblast Cells." Journal of Clinical Endocrinology & Metabolism 85, no. 7 (July 1, 2000): 2543–49. http://dx.doi.org/10.1210/jc.85.7.2543.
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Matsumoto, T., K. Ikeda, H. Yamato, K. Morita, I. Ezawa, M. Fukushima, Y. Nishii, and E. Ogata. "Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 metabolism in calcium-deficient rats." Biochemical Journal 250, no. 3 (March 15, 1988): 671–77. http://dx.doi.org/10.1042/bj2500671.
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The effect of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] on 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolism was examined in rats fed on a low-calcium diet. These rats exhibit hypocalcaemia, high urinary cyclic AMP excretion, a markedly elevated serum 1,25(OH)2D concentration and low serum concentrations of both 24,25(OH)2D and 25(OH)D. When the rats are treated orally with 1, 5 or 10 micrograms of 24,25(OH)2D3/100 g every day, there is a dramatic decrease in serum 1,25(OH)2D concentration in a dose-dependent manner concomitant with an increase in serum 24,25(OH)2D concentration. Serum calcium concentration and urinary cyclic AMP excretion are not significantly affected by the 24,25(OH)2D3 treatment, which suggests that parathyroid function is not affected by the 24,25(OH)2D3 treatment. The 25(OH)D3 1 alpha-hydroxylase activity measured in kidney homogenates is markedly elevated in rats on a low-calcium diet but is not affected by any doses of 24,25(OH)2D3. In contrast, recovery of intravenously injected [3H]1,25(OH)2D3 in the serum is decreased in 24,25(OH)2D3-treated rats. Furthermore, when [3H]1,25(OH)2D3 is incubated in vitro with kidney or intestinal homogenates of 24,25(OH)2D3-treated rats there is a decrease in the recovery of radioactivity in the total lipid extract as well as in the 1,25(OH)2D3 fraction along with an increase in the recovery of radioactivity in the water-soluble phase. These results are consistent with the possibility that 24,25(OH)2D3 has an effect on 1,25(OH)2D3 metabolism, namely that of enhancing the degradation of 1,25(OH)2D3. However, because a considerable proportion of the injected 24,25(OH)2D3 is expected to be converted into 1,24,25(OH)3D3 by renal 1 alpha-hydroxylase in 24,25(OH)2D3-treated rats, at least a part of the decrease in serum 1,25(OH)2D concentration may be due to a competitive inhibition by 24,25(OH)2D3 of the synthesis of 1,25(OH)2D3 from 25(OH)D3. Thus the physiological importance of the role of 24,25(OH)2D3 in regulating the serum 1,25(OH)2D concentration as well as the mechanism and metabolic pathway of degradation of 1,25(OH)2D3 remain to be clarified.
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Kim, Chan Jong, Larry E. Kaplan, Farzana Perwad, Ningwu Huang, Amita Sharma, Yong Choi, Walter L. Miller, and Anthony A. Portale. "Vitamin D 1α-Hydroxylase Gene Mutations in Patients with 1α-Hydroxylase Deficiency." Journal of Clinical Endocrinology & Metabolism 92, no. 8 (August 1, 2007): 3177–82. http://dx.doi.org/10.1210/jc.2006-2664.
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Abstract Context: Vitamin D 1α-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1α-hydroxylase (1α-hydroxylase, CYP27B1) gene. The human gene encoding the 1α-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns. We previously isolated the human 1α-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1α-hydroxylase deficiency. Objectives, Patients, and Methods: We analyzed the 1α-hydroxylase gene of 10 patients, five from Korea, two from the United States, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1,25-dihydroxyvitamin D3. Results: Direct sequencing identified the responsible 1α-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included a nonsense mutation in exon 6, substitution of adenine for guanine (2561G→A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C→T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G→A) causing a frameshift. Conclusions: Mutations in the 1α-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1α-hydroxylase mutations and the clinical findings of 1α-hydroxylase deficiency.
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Chau, Tsui-Shan, Wan-Ping Lai, Pik-Yuen Cheung, Murray J. Favus, and Man-Sau Wong. "Age-related alteration of vitamin D metabolism in response to low-phosphate diet in rats." British Journal of Nutrition 93, no. 3 (March 2005): 299–307. http://dx.doi.org/10.1079/bjn20041325.
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The responses of renal vitamin D metabolism to its major stimuli alter with age. Previous studies showed that the increase in circulating 1,25-dihydroxyvitamin D (1,25(OH)2D3) as well as renal 25-hydroxyvitamin D3 1-α hydroxylase (1-OHase) activity in response to dietary Ca or P restriction reduced with age in rats. We hypothesized that the mechanism involved in increasing circulating 1,25(OH)2D3 in response to mineral deficiency alters with age. In the present study, we tested the hypothesis by studying the expression of genes involved in renal vitamin D metabolism (renal 1-OHase, 25-hydroxyvitamin D 24-hydroxylase (24-OHase) and vitamin D receptor (VDR)) in young (1-month-old) and adult (6-month-old) rats in response to low-phosphate diet (LPD). As expected, serum 1,25(OH)2D3 increased in both young and adult rats upon LPD treatment and the increase was much higher in younger rats. In young rats, LPD treatment decreased renal 24-OHase (days 1–7, P<0·01) and increased renal 1-OHase mRNA expression (days 1–5, P<0·01). LPD treatment failed to increase renal 1-OHase but did suppress 24-OHase mRNA expression (P<0·01) within 7 d of LPD treatment in adult rats. Renal expression of VDR mRNA decreased with age (P<0·001) and was suppressed by LPD treatment in both age groups (P<0·05) Feeding of adult rats with 10 d of LPD increased 1-OHase (P<0·05) and suppressed 24-OHase (P<0·001) as well as VDR (P<0·05) mRNA expression. These results indicate that the increase in serum 1,25(OH)2D3 level in adult rats during short-term LPD treatment is likely to be mediated by a decrease in metabolic clearance via the down-regulation of both renal 24-OHase and VDR expression. The induction of renal 1-OHase mRNA expression in adult rats requires longer duration of LPD treatment than in younger rats.
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Wehmeier, Kent, Luisa M. Onstead-Haas, Norman C. W. Wong, Arshag D. Mooradian, and Michael J. Haas. "Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells." Journal of Molecular Endocrinology 57, no. 2 (August 2016): 87–96. http://dx.doi.org/10.1530/jme-16-0009.
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The vitamin D metabolite 24,25-dihydroxyvitamin D3(24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25-[OH]2D3but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3resulted in decreased peroxisome proliferator-activated receptor alpha (PPARα) expression and retinoid-X-receptor alpha (RXRα) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3for 1–3 h induced PKCα activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-junphosphorylation, an increase in AP-1-dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3increased IL-1β, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function.
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Tebben, Peter J., Ravinder J. Singh, and Rajiv Kumar. "Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment." Endocrine Reviews 37, no. 5 (September 2, 2016): 521–47. http://dx.doi.org/10.1210/er.2016-1070.
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AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.
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Kitanaka, S. "No Enzyme Activity of 25-Hydroxyvitamin D3 1 -Hydroxylase Gene Product in Pseudovitamin D Deficiency Rickets, Including That with Mild Clinical Manifestation." Journal of Clinical Endocrinology & Metabolism 84, no. 11 (November 1, 1999): 4111–17. http://dx.doi.org/10.1210/jc.84.11.4111.
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Yang, Wen, Peter A. Friedman, Rajiv Kumar, John L. Omdahl, Brian K. May, Mei-Ling Siu-Caldera, G. Satyanarayana Reddy, and Sylvia Christakos. "Expression of 25(OH)D324-hydroxylase in distal nephron: coordinate regulation by 1,25(OH)2D3and cAMP or PTH." American Journal of Physiology-Endocrinology and Metabolism 276, no. 4 (April 1, 1999): E793—E805. http://dx.doi.org/10.1152/ajpendo.1999.276.4.e793.
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Previous studies using microdissected nephron segments reported that the exclusive site of renal 25-hydroxyvitamin D3-24-hydroxylase (24OHase) activity is the renal proximal convoluted tubule (PCT). We now report the presence of 24OHase mRNA, protein, and activity in cells that are devoid of markers of proximal tubules but express characteristics highly specific for the distal tubule. 24OHase mRNA was undetectable in vehicle-treated mouse distal convoluted tubule (DCT) cells but was markedly induced when DCT cells were treated with 1,25 dihydroxyvitamin D3[1,25(OH)2D3]. 24OHase protein and activity were also identified in DCT cells by Western blot analysis and HPLC, respectively. 8-Bromo-cAMP (1 mM) or parathyroid hormone [PTH-(1—34); 10 nM] was found to potentiate the effect of 1,25(OH)2D3on 24OHase mRNA. The stimulatory effect of cAMP or PTH on 24OHase expression in DCT cells suggests differential regulation of 24OHase expression in the PCT and DCT. In the presence of cAMP and 1,25(OH)2D3, a four- to sixfold induction in vitamin D receptor (VDR) mRNA was observed. VDR protein, as determined by Western blot analysis, was also enhanced in the presence of cAMP. Transient transfection analysis in DCT cells with rat 24OHase promoter deletion constructs demonstrated that cAMP enhanced 1,25(OH)2D3-induced 24OHase transcription but this enhancement was not mediated by cAMP response elements (CREs) in the 24OHase promoter. We conclude that 1) although the PCT is the major site of localization of 24OHase, 24OHase mRNA and activity can also be localized in the distal nephron; 2) both PTH and cAMP modulate the induction of 24OHase expression by 1,25(OH)2D3in DCT cells in a manner different from that reported in the PCT; and 3) in DCT cells, upregulation of VDR levels by cAMP, and not an effect on CREs in the 24OHase promoter, is one mechanism involved in the cAMP-mediated modulation of 24OHase transcription.
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Buskermolen, Joost, Karen van der Meijden, Regula Furrer, Dirk-Jan Mons, Huib W. van Essen, Annemieke C. Heijboer, Paul Lips, Richard T. Jaspers, and Nathalie Bravenboer. "Effects of different training modalities on phosphate homeostasis and local vitamin D metabolism in rat bone." PeerJ 7 (January 24, 2019): e6184. http://dx.doi.org/10.7717/peerj.6184.
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Objectives Mechanical loading may be an important factor in the regulation of bone derived hormones involved in phosphate homeostasis. This study investigated the effects of peak power and endurance training on expression levels of fibroblast growth factor 23 (FGF23) and 1α-hydroxylase (CYP27b1) in bone. Methods Thirty-eight rats were assigned to six weeks of training in four groups: peak power (PT), endurance (ET), PT followed by ET (PET) or no training (control). In cortical bone, FGF23 was quantified using immunohistochemistry. mRNA expression levels of proteins involved in phosphate and vitamin D homeostasis were quantified in cortical bone and kidney. C-terminal FGF23, 25-hydroxyvitamin D3, parathyroid hormone (PTH), calcium and phosphate concentrations were measured in plasma or serum. Results Neither FGF23 mRNA and protein expression levels in cortical bone nor FGF23 plasma concentrations differed between the groups. In cortical bone, mRNA expression levels of sclerostin (SOST), dental matrix protein 1 (DMP1), phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and matrix extracellular phosphoglycoprotein (MEPE) were lower after PT compared to ET and PET. Expression levels of CYP27b1 and vitamin D receptor (VDR) in tibial bone were decreased after PT compared to ET. In kidney, no differences between groups were observed for mRNA expression levels of CYP27b1, 24-hydroxylase (CYP24), VDR, NaPi-IIa cotransporter (NPT2a) and NaPi-IIc cotransporter (NPT2c). Serum PTH concentrations were higher after PT compared to controls. Conclusion After six weeks, none of the training modalities induced changes in FGF23 expression levels. However, PT might have caused changes in local phosphate regulation within bone compared to ET and PET. CYP27b1 and VDR expression in bone was reduced after PT compared to ET, suggesting high intensity peak power training in this rat model is associated with decreased vitamin D signalling in bone.
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Ajibade, Dare V., Puneet Dhawan, Adam J. Fechner, Mark B. Meyer, J. Wesley Pike, and Sylvia Christakos. "Evidence for a Role of Prolactin in Calcium Homeostasis: Regulation of Intestinal Transient Receptor Potential Vanilloid Type 6, Intestinal Calcium Absorption, and the 25-Hydroxyvitamin D3 1α Hydroxylase Gene by Prolactin." Endocrinology 151, no. 7 (May 12, 2010): 2974–84. http://dx.doi.org/10.1210/en.2010-0033.
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Increased calcium transport has been observed in vitamin D-deficient pregnant and lactating rats, indicating that another factor besides 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is involved in intestinal calcium transport. To investigate prolactin as a hormone involved in calcium homeostasis, vitamin D-deficient male mice were injected with 1,25(OH)2D3, prolactin, or prolactin + 1,25(OH)2D3. Prolactin alone (1 μg/g body weight 48, 24, and 4 h before termination) significantly induced duodenal transient receptor potential vanilloid type 6 (TRPV6) mRNA (4-fold) but caused no change in calbindin-D9k. Combined treatment with 1,25(OH)2D3 and prolactin resulted in an enhancement of the 1,25(OH)2D3 induction of duodenal TRPV6 mRNA, calbindin-D9k mRNA, and an induction of duodenal calcium transport [P < 0.05 compared with 1,25(OH)2D3 alone]. Because lactation is associated with an increase in circulating 1,25(OH)2D3, experiments were done to determine whether prolactin also has a direct effect on induction of 25-hydroxyvitamin D3 1α hydroxylase [1α(OH)ase]. Using AOK B-50 cells cotransfected with the prolactin receptor and the mouse 1α(OH)ase promoter −1651/+22 cooperative effects between prolactin and signal transducer and activator of transcription 5 were observed in the regulation of 1α(OH)ase. In addition, in prolactin receptor transfected AOK B-50 cells, prolactin treatment (400 ng/ml) and signal transducer and activator of transcription 5 significantly induced 1α(OH)ase protein as determined by Western blot analysis. Thus, prolactin, by multiple mechanisms, including regulation of vitamin D metabolism, induction of TRPV6 mRNA, and cooperation with 1,25(OH)2D3 in induction of intestinal calcium transport genes and intestinal calcium transport, can act as an important modulator of vitamin D-regulated calcium homeostasis.
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Liu, Nancy, Lisa Nguyen, Rene F. Chun, Venu Lagishetty, Songyang Ren, Shaoxing Wu, Bruce Hollis, Hector F. DeLuca, John S. Adams, and Martin Hewison. "Altered Endocrine and Autocrine Metabolism of Vitamin D in a Mouse Model of Gastrointestinal Inflammation." Endocrinology 149, no. 10 (June 5, 2008): 4799–808. http://dx.doi.org/10.1210/en.2008-0060.
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The active form of vitamin D, 1,25-dihydroxyvitamin D3, [1,25(OH)2D3] has potent actions on innate and adaptive immunity. Although endocrine synthesis of 1,25(OH)2D3 takes place in the kidney, the enzyme that catalyzes this, 25-hydroxyvitamin D-1α-hydroxylase (CYP27b1 in humans, Cyp27b1 in mice), is expressed at many extra-renal sites including the colon. We have shown previously that colonic expression of CYP27b1 may act to protect against the onset of colitis. To investigate this further, we firstly characterized changes in Cyp27b1 expression in a mouse model of colitis. Mice treated with dextran sodium sulfate (DSS) showed weight loss, histological evidence of colitis, and increased expression of inflammatory cytokines. This was associated with decreased renal expression of Cyp27b1 (5-fold, P = 0.013) and lower serum 1,25(OH)2D3 (51.8 ± 5.9 pg/nl vs. 65.1 ± 1.6 in controls, P < 0.001). However, expression of CYP27b1 was increased in the proximal colon of DSS mice (4-fold compared with controls, P < 0.001). Further studies were carried out using Cyp27b1 null (−/−) mice. Compared with +/− controls the Cyp27b1 −/− mice showed increased weight loss (4.9% vs. 22.8%, P < 0.001) and colitis. This was associated with raised IL-1 in the distal colon and IL-17 in the proximal and distal colon. Conversely, DSS-treated Cyp27b1−/− mice exhibited lower IL-10 in the proximal colon and toll-like receptors 2 and 4 in the distal colon. These data indicate that both local and endocrine synthesis of 1,25(OH)2D3 affect colitis in DSS-treated mice. Lack of Cyp27b1 exacerbates disease in this model, suggesting that similar effects may occur with vitamin D deficiency.
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Zhang, Yan, Wan-Ping Lai, Chun-Fu Wu, Murray J. Favus, Ping-Chung Leung, and Man-Sau Wong. "Ovariectomy worsens secondary hyperparathyroidism in mature rats during low-Ca diet." American Journal of Physiology-Endocrinology and Metabolism 292, no. 3 (March 2007): E723—E731. http://dx.doi.org/10.1152/ajpendo.00445.2006.
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Estrogen deficiency impairs intestinal Ca absorption and induces bone loss, but its effects on the vitamin D-endocrine system are unclear. In the present study, calciotropic hormones levels, renal vitamin D metabolism, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-dependent intestinal calcium absorption, and bone properties in 3-mo-old sham-operated (sham) or ovariectomized (OVX) rats fed either a normal-Ca (NCD; 0.6% Ca, 0.65% P) or a low-Ca (LCD; 0.1% Ca, 0.65% P) diet for 2 wk were determined. LCD increased serum 1,25(OH)2D3 levels in both sham and OVX rats. Serum parathyroid hormone [PTH(1–84)] levels were highest in OVX rats fed LCD. Renal 25-hydroxyvitamin D1α-hydroxylase (1-OHase) protein expression was induced in both sham and OVX rats during LCD, while renal 1-OHase mRNA expression was highest in OVX rats fed LCD. Renal vitamin D receptor (VDR) and mRNA expressions in rats were induced by ovariectomy in rats fed NCD but suppressed by ovariectomy in rats fed LCD. The induction of intestinal calcium transporter-1 and calbindin-D9k mRNA expressions by LCD were not altered by ovariectomy. As expected, bone Ca content, cancellous bone mineral density, and bone strength index in proximal metaphysis of rat tibia were reduced by both ovariectomy and LCD ( P < 0.05) as analyzed by two-way ANOVA. Taken together, the data demonstrate that ovariectomy alters the responses of circulating PTH levels, renal 1-OHase mRNA expression, and renal VDR expression to LCD. These results suggest that estrogen is necessary for the full adaptive response to LCD mediated by both PTH and 1,25(OH)2D3.
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Nobre, J. L., P. C. Lisboa, A. P. Santos-Silva, N. S. Lima, A. C. Manhães, J. F. Nogueira-Neto, A. Cabanelas, C. C. Pazos-Moura, E. G. Moura, and E. de Oliveira. "Calcium supplementation reverts central adiposity, leptin, and insulin resistance in adult offspring programed by neonatal nicotine exposure." Journal of Endocrinology 210, no. 3 (June 16, 2011): 349–59. http://dx.doi.org/10.1530/joe-11-0172.
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Obesity is a worldwide epidemic. Calcium influences energy metabolism regulation, causing body weight loss. Because maternal nicotine exposure during lactation programs for obesity, hyperleptinemia, insulin resistance (IR), and hypothyroidism, we decided to evaluate the possible effect of dietary calcium supplementation on these endocrine dysfunctions in this experimental model. Osmotic minipumps containing nicotine solution (N: 6 mg/kg per day for 14 days) or saline (C) were s.c. implanted in lactating rats 2 days after giving birth (P2). At P120, N and C offspring were subdivided into four groups: 1) C – standard diet; 2) C with calcium supplementation (CCa, 10 g calcium carbonate/kg rat chow); 3) N – standard diet; and 4) N with calcium supplementation (NCa). Rats were killed at P180. As expected, N offspring showed higher visceral and total body fat, hyperleptinemia, lower hypothalamus leptin receptor (OB-R) content, hyperinsulinemia, and higher IR index. Also, higher tyrosine hydroxylase (TH) expression (+51%), catecholamine content (+37%), and serum 25-hydroxyvitamin D3(+76%) were observed in N offspring. Dietary calcium supplementation reversed adiposity, hyperleptinemia, OB-R underexpression, IR, TH overexpression, and vitamin D. However, this supplementation did not reverse hypothyroidism. In NCa offspring,Sirt1mRNA was lower in visceral fat (−37%) and higher in liver (+42%). In conclusion, dietary calcium supplementation seems to revert most of the metabolic syndrome parameters observed in adult offspring programed by maternal nicotine exposure during lactation. It is conceivable that the reduction in fat massper se, induced by calcium therapy, is the main mechanism that leads to the increment of insulin action.
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Gallieni, M., S. Kamimura, A. Ahmed, E. Bravo, J. Delmez, E. Slatopolsky, and A. Dusso. "Kinetics of monocyte 1 alpha-hydroxylase in renal failure." American Journal of Physiology-Renal Physiology 268, no. 4 (April 1, 1995): F746—F753. http://dx.doi.org/10.1152/ajprenal.1995.268.4.f746.
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In chronic uremia, the requirement of supraphysiological doses of serum 25-hydroxyvitamin D3 [25(OH)D3] for the normalization of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels has been attributed to impaired substrate availability to renal 1 alpha-hydroxylase. Because serum 1,25(OH)2D3 can also be corrected by 25(OH)D3 supplementation in bilaterally nephrectomized patients, we examined the role of substrate availability on 1,25(OH)2D3 production by peripheral blood monocytes (PBM). In hemodialysis patients (HP), 25(OH)D3 uptake was 50% lower than normal, and the maximal velocity (Vmax) and apparent Michaelis constant (Km) for 25(OH)D3 of 1 alpha-hydroxylase were 2.7- and 4-fold above normal, respectively. When serum 1,25(OH)2D3 of HP was corrected by intravenous 1,25(OH)2D3, 25(OH)D3 uptake, Km, and Vmax returned to normal values. The effect of 25(OH)D3 supplementation was also examined. In normal adults, 25(OH)D3 administration had no effect on serum 1,25(OH)2D3 levels nor on the Km or the Vmax of PBM 1 alpha-hydroxylase but caused a 11-fold increase in serum 24R,25-dihydroxyvitamin D3[24R, 25(OH)2D3]. In HP, 25(OH)D3 therapy raised serum 1,25(OH)2D3 and reduced the Km and Vmax of PBM 1 alpha-hydroxylase, which correlated negatively with serum 1,25(OH)2D3. However, serum 24R,25(OH)2D3 only increased slightly above basal. These results demonstrate that, in HP, 1) impaired uptake of 25(OH)D3 and low affinity for substrate determine the need for high 25(OH)D3 levels to normalize serum 1,25(OH)2D3, despite higher enzymatic activity; 2) 1,25(OH)2D3 deficiency plays a role in enhanced 1,25(OH)2D3 synthesis and impaired access of 25(OH)D3 to PBM 1 alpha hydroxylase; and 3) abnormal 25(OH)D3 delivery also affects 24-hydroxylation.
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Mandel, M. L., B. Moorthy, and J. G. Ghazarian. "Reciprocal post-translational regulation of renal 1α- and 24-hydroxylases of 25-hydroxyvitamin D3 by phosphorylation of ferredoxin. mRNA-directed cell-free synthesis and immunoisolation of ferredoxin." Biochemical Journal 266, no. 2 (March 1, 1990): 385–92. http://dx.doi.org/10.1042/bj2660385.
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We have used a cell-free rabbit reticulocyte translational system programmed with polyadenylated [poly(A)+] RNA prepared from chick kidney tissue to study the synthesis of nascent ferredoxin, a class of iron-sulphur-containing proteins functional in the renal mitochondrial 1 alpha- and 24-hydroxylases of 25-hydroxyvitamin D3. The synthesis of ferredoxin was monitored by determining [35S]methionine incorporation into ferredoxin and quantified by SDS/PAGE and autoradiography after immunoprecipitation from the total translation products. Compared with normal controls, vitamin D deprivation caused a significant increase in the net synthesis of nascent ferredoxin with an Mr of 12,000-13,000. [3H]Orotate incorporation as uridine into kidney poly(A)+ RNA was stimulated by aminophylline, a potent inducer of 25-hydroxyvitamin D3 24-hydroxylase; however, the amount of nascent ferredoxin synthesis was the same as in normal controls. Also, partially purified chick kidney mitochondrial cyclic AMP-stimulated protein kinase catalysed the phosphorylation of ferredoxin in vitro. The catalytic activity of the ferredoxin in 1 alpha- and 24-hydroxylations of 25-hydroxyvitamin D3 in reconstituted systems consisting of cytochrome P-450 and ferredoxin reductase was altered with ferredoxin phosphorylation. The phosphorylation caused inhibition of the 1 alpha-hydroxylase activity while at the same time it stimulated the 24-hydroxylase. Authentic 1 alpha,25- and 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 were used as standards to monitor the separation of the enzymic products by h.p.l.c. using methanol/water (4:1, v/v) as solvent. These results indicate that, in the absence of vitamin D or its metabolites in the deficient state, the synthesis of ferredoxin necessary for the 1 alpha-hydroxylase is accentuated, whereas the stimulation of the 24-hydroxylase requires the phosphorylation of existing ferredoxin without a net gain in its synthesis. This would suggest a post-translational regulation of the 1 alpha- and 24-hydroxylases. A model delineating the various aspects of this study is presented.
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Hagenfeldt, Y., J. I. Pedersen, and I. Björkhem. "Properties of guinea-pig kidney 25-hydroxyvitamin D3 1α-hydroxylase assayed by isotope dilution-mass spectrometry." Biochemical Journal 250, no. 2 (March 1, 1988): 521–26. http://dx.doi.org/10.1042/bj2500521.
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1. A highly specific and accurate method based on isotope dilution-mass spectrometry was used for characterization of the renal 25-hydroxyvitamin D3 1 alpha-hydroxylase in untreated guinea pigs with a normal vitamin D status. In previous work, the properties of the enzyme had been determined in rachitic animals only. 2. With intact mitochondria, the reaction required the presence of citric acid-cycle intermediates. The uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone had an inhibitory effect on the isocitrate-supported reaction, indicating that energy-dependent transhydrogenation is of importance. Mitochondrial respiratory-chain inhibitors (cyanide, rotenone, antimycin A) had no effect on the hydroxylation. CO had an inhibitory effect, suggesting participation of a species of cytochrome P-450 in the reaction. A fraction solubilized from mitochondria by cholate became catalytically active in 1 alpha-hydroxylation of 25-hydroxyvitamin D3 after addition of ferredoxin and ferredoxin reductase. The isocitrate-supported reaction catalysed by crude mitochondria had an apparent Km of about 1 microM. 3. An atmosphere containing 50% O2 was found to be necessary for optimal activity. It is thus possible that O2 may be a limiting factor under normal conditions in vivo. 4. The results demonstrate that the mammalian renal 25-hydroxyvitamin D3 1 alpha-hydroxylase is a cytochrome P-450-dependent mixed-function oxidase with properties similar to those previously reported for the same enzyme system in chicken. The present assay and animal system seem to be suitable for further studies on the mechanism of regulation of the mammalian renal 25-hydroxyvitamin D3 1 alpha-hydroxylase under conditions when the vitamin D status is normal.
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Paulson, Susan K., Mary Phelps, and Hector F. DeLuca. "Assay and properties of rat yolk sac 25-hydroxyvitamin D3 1.alpha.-hydroxylase." Biochemistry 25, no. 22 (November 4, 1986): 6821–26. http://dx.doi.org/10.1021/bi00370a014.
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Paulson, S. K., and H. F. DeLuca. "Subcellular location and properties of rat renal 25-hydroxyvitamin D3-1 alpha-hydroxylase." Journal of Biological Chemistry 260, no. 21 (September 1985): 11488–92. http://dx.doi.org/10.1016/s0021-9258(17)39055-5.
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Gray, R. W., and J. G. Ghazarian. "Solubilization and reconstitution of kidney 25-hydroxyvitamin D3 1 α- and 24-hydroxylases from vitamin D-replete pigs." Biochemical Journal 259, no. 2 (April 15, 1989): 561–68. http://dx.doi.org/10.1042/bj2590561.
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Pig kidney mitochondrial 25-hydroxyvitamin D3 1 alpha- and 24-hydroxylase activities have been solubilized with cholate/Emulgen 911 and reconstituted with NADPH, ferredoxin reductase and ferredoxin. All three of these components are required for full catalytic activity of both enzymes. Both products were identified by co-chromatography with authentic metabolites on both normal and reverse-phase h.p.l.c. using solvent systems which were shown to separate 10-oxo-19-nor-25-hydroxyvitamin D3 from 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3]. In addition, periodate treatment of the 24,25-(OH)2-D3 product resulted in complete loss of the product as measured by protein-binding assay. Further purification by p-chloroamphetamine-Sepharose chromatography of a solubilized extract from a pig fed a normal diet increased the specific content of the cytochrome P-450 from 0.019 to 0.239 nmol/mg and the 1 alpha-hydroxylase activity from 4.75 to 268 pmol/h per mg. Activity of the 24-hydroxylase in the crude solubilized extract was 6.3 pmol/h per mg, but was undetectable after partial purification by a p-chloroamphetamine-Sepharose column. However, further fractionation of this material by DEAE-Sepharose chromatography resulted in a further increase in 1 alpha-hydroxylase activity to 430 pmol/h per mg and detection of 24-hydroxylase in a separate fraction at a level of 53 pmol/h per mg. Production of 1,25-(OH)2-D3 was linear with time up to 2 h and was dependent upon ferredoxin concentration as well as cytochrome P-450 concentration in the range of 0-40 nM. In the presence of excess ferredoxin and adequate amounts of cytochrome P-450, 1,25-(OH)2-D3 production was also dependent upon substrate concentrations in the range of 0.25 to 2.5 microM yielding an estimated Km of 1 microM. In the presence of excess substrate and ferredoxin, the catalytic-centre activity of the enzyme was estimated to be 1 h-1.
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Matsumoto, T., K. Ikeda, K. Morita, S. Fukumoto, H. Takahashi, and E. Ogata. "Blood Ca2+ modulates responsiveness of renal 25(OH)D3-1 alpha-hydroxylase to PTH in rats." American Journal of Physiology-Endocrinology and Metabolism 253, no. 5 (November 1, 1987): E503—E507. http://dx.doi.org/10.1152/ajpendo.1987.253.5.e503.
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To clarify whether extracellular Ca2+ modulates renal 25-hydroxyvitamin D3 [25(OH)D3]-1 alpha-hydroxylase, thyroparathyroidectomized rats were infused with 15 mM CaCl2, 20 mM EGTA, and/or 2.5 U/h parathyroid hormone (PTH), and blood Ca2+, serum 1,25-dihydroxyvitamin D [1,25(OH)2D], and renal 1 alpha-hydroxylase activity were determined. Rats with CaCl2, EGTA, or PTH infusion (group 1) exhibited low blood Ca2+, serum 1,25(OH)2D, and 1 alpha-hydroxylase activities. Infusion of CaCl2 alone (group 2) caused a significant increase in blood Ca2+ and a reduction in serum 1,25(OH)2D and 1 alpha-hydroxylase compared with group 1. Administration of PTH alone (group 3) markedly elevated blood Ca2+, serum 1,25(OH)2D, and 1 alpha-hydroxylase activity. When EGTA was infused along with PTH (group 4), blood Ca2+ was significantly reduced compared with group 3, and serum 1,25(OH)2D and renal 1 alpha-hydroxylase were further elevated. In contrast, when CaCl2 was infused with PTH (group 5), blood Ca2+ was higher than that in group 3, and serum 1,25(OH)2D and 1 alpha-hydroxylase activities were significantly reduced compared with group 3. No significant difference in serum inorganic phosphate or urinary cAMP excretion was observed by CaCl2 or EGTA infusion in both PTH-treated and nontreated rats. These results demonstrate that extracellular Ca2+ modulates the responsiveness of renal 1 alpha-hydroxylase to PTH as well as the base-line activity of the enzyme in the absence of PTH. These effects of extracellular Ca2+ on renal 1 alpha-hydroxylase may serve to offer an efficient way of regulating 1,25(OH)2D production and serum 1,25(OH)2D concentration by altering the responsiveness of 1 alpha-hydroxylase to PTH and possibly other stimulations depending on the demand for Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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Bergman, T., and H. Postlind. "Characterization of pig kidney microsomal cytochrome P-450 catalysing 25-hydroxylation of vitamin D3 and C27 steroids." Biochemical Journal 270, no. 2 (September 1, 1990): 345–50. http://dx.doi.org/10.1042/bj2700345.
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The cytochrome P-450 enzyme which catalyses 25-hydroxylation of vitamin D3 (cytochrome P-450(25] from pig kidney microsomes [Postlind & Wikvall (1988) Biochem. J. 253, 549-552] has been further purified. The specific content of cytochrome P-450 was 15.0 nmol.mg of protein-1, and the protein showed a single spot with an apparent isoelectric point of 7.4 and an Mr of 50,500 upon two-dimensional isoelectric-focusing/SDS/PAGE. The 25-hydroxylase activity towards vitamin D3 was 124 pmol.min-1.nmol of cytochrome P-450-1 and towards 1 alpha-hydroxyvitamin D3 it was 1375 pmol.min-1.nmol-1. The preparation also catalysed the 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol at a rate of 1000 pmol.min-1.nmol of cytochrome P-450-1 and omega-1 hydroxylation of lauric acid at a rate of 200 pmol.min-1.nmol of cytochrome P-450-1. A monoclonal antibody raised against the 25-hydroxylating cytochrome P-450, designated mAb 25E5, was prepared. After coupling to Sepharose, the antibody was able to bind to cytochrome P-450(25) from kidney as well as from pig liver microsomes, and to immunoprecipitate the activity for 25-hydroxylation of vitamin D3 and 5 beta-cholestane-3 alpha,7 alpha-diol when assayed in a reconstituted system. The hydroxylase activity towards lauric acid was not inhibited by the antibody. By SDS/PAGE and immunoblotting with mAb 25E5, cytochrome P-450(25) was detected in both pig kidney and pig liver microsomes. These results indicate a similar or the same species of cytochrome P-450 in pig kidney and liver microsomes catalysing 25-hydroxylation of vitamin D3 and C27 steroids. The N-terminal amino acid sequence of the purified cytochrome P-450(25) from pig kidney microsomes differed from those of hitherto isolated mammalian cytochromes P-450.
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Saarem, K., and J. I. Pedersen. "Effect of age, gonadectomy and hypophysectomy on mitochondrial hydroxylation of vitamin D3 (cholecalciferol) and of 5β-cholestane-3α,7α,12α-triol in female and male rat liver." Biochemical Journal 251, no. 2 (April 15, 1988): 475–81. http://dx.doi.org/10.1042/bj2510475.
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In a previous study we found that liver mitochondrial side-chain hydroxylation of vitamin D3 (cholecalciferol) and of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was higher in female than in male rats [Saarem & Pedersen (1987) Biochem. J. 247, 73-78]. The present paper describes the effects of age, gonadectomy and hypophysectomy on these activities. The sex difference became manifest above the age of 7 weeks. Ovariectomy and/or injection of oestradiol valerate had no effect on the hydroxylase activities in adult females. Castration increased, and subsequent testosterone treatment decreased, the hydroxylase activities in adult males. Hypophysectomy had no effect in females, but increased the hydroxylase activities in males. Testosterone treatment had no effect in hypophysectomized females or males. Injection of oestradiol valerate had no effect on the hydroxylase activities in hypophysectomized females. In hypophysectomized males this treatment had no effect on the vitamin D3 25-hydroxylase activity, but decreased the C27-steroid 27-hydroxylase activity in males. Microsomal 1 alpha-hydroxyvitamin D3 25-hydroxylase activity was lower in females than in males in all age groups. Castration or hypophysectomy decreased the activity in male rats. It is concluded that, in adult female rats, the mitochondrial side-chain hydroxylation of vitamin D3 and of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol is independent of sex hormones. In males these activities are regulated by influence of sex hormones on the hypophysis, probably by the presence of androgens in the neonatal period. Different effects on the two hydroxylases indicate the presence of at least two different cytochromes P-450 in rat liver mitochondria.
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Chemouny, Jonathan Maurice, Aurélie Sannier, Guillaume Hanouna, Laure Champion, Francois Vrtovsnik, and Eric Daugas. "Malakoplakia as a cause of severe hypercalcemia through ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase expression." Medicine 97, no. 40 (October 2018): e12090. http://dx.doi.org/10.1097/md.0000000000012090.
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Walker, A. T., A. F. Stewart, E. A. Korn, T. Shiratori, M. A. Mitnick, and T. O. Carpenter. "Effect of parathyroid hormone-like peptides on 25-hydroxyvitamin D-1 alpha-hydroxylase activity in rodents." American Journal of Physiology-Endocrinology and Metabolism 258, no. 2 (February 1, 1990): E297—E303. http://dx.doi.org/10.1152/ajpendo.1990.258.2.e297.
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The role of vitamin D metabolism in the humoral hypercalcemia of malignancy syndrome (HHM) is unclear. We studied in vivo and in vitro effects of synthetic parathyroid hormone-like peptides (PTH-LPs) on rodent renal 25-OHD-1 alpha-hydroxylase activity. Infusion of mice with PTH-LP-(1-36) at 10 pmol/h for 12 and 24 h showed significant (429 +/- 139% and 937 +/- 413%, respectively) stimulation of control enzyme activity. Infusion for 36 h demonstrated diminution of activity to levels nearer to the unstimulated state (228 +/- 36% of control). In that maximal activity was observed after 24 h of infusion, we examined 1 alpha-hydroxylase activity after variable dosages of PTH-LP-(1-36) at this time point. Animals infused with PTH-LP-(1-36) at dosages of 2.5, 10, and 30 pmol/h for 24 h demonstrated 1 alpha-hydroxylase activities of 0.71 +/- 0.12, 4.74 +/- 2.09, and 9.91 +/- 1.01 ng.mg protein-1.20 min-1 (means +/- SD), respectively, all significantly greater than control activity (0.51 +/- 0.20 ng.mg protein-1.20 min-1). PTH-LP-(1-36) and PTH-LP-(1-74) were comparable in potency to bovine (b)PTH-(1-34) in stimulating 1 alpha-hydroxylase. Direct in vitro incubation of PTH-LP-(1-36) with renal slices resulted in stimulation of 1 alpha-hydroxylase activity up to 200% of control levels, comparable to that seen with equimolar concentrations of bPTH-(1-34).(ABSTRACT TRUNCATED AT 250 WORDS)
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Hollis, B. W. "25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes." Proceedings of the National Academy of Sciences 87, no. 16 (August 1, 1990): 6009–13. http://dx.doi.org/10.1073/pnas.87.16.6009.
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Pedersen, J. I., Y. Hagenfeldt, and I. Björkhem. "Assay and properties of 25-hydroxyvitamin D3 23-hydroxylase. Evidence that 23,25-dihydroxyvitamin D3 is a major metabolite in 1,25-dihydroxyvitamin D3-treated or fasted guinea pigs." Biochemical Journal 250, no. 2 (March 1, 1988): 527–32. http://dx.doi.org/10.1042/bj2500527.
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Incubation of 25-hydroxyvitamin D3 with kidney cortex mitochondria from 1,25-dihydroxyvitamin D3-treated guinea pigs resulted in the formation of 23,25-dihydroxyvitamin D3 as the major product. The identity of the product was verified by g.c.-m.s. and quantification was performed by h.p.l.c. The rates of the reaction were in the range 1.0-1.8 pmol/min per mg of mitochondrial protein (at 37 degrees C), which were 5-10 times the rates of formation of 24,25-dihydroxyvitamin D3. In mitochondrial preparations from untreated guinea pigs, the rate of 23-hydroxylation was below detection limit (0.02 pmol/min per mg of mitochondrial protein). Fasting the animals for 24 h induced the 23-hydroxylase almost as efficiently as treatment with 1,25-dihydroxyvitamin D3, with a concomitant depression of the 1 alpha-hydroxylase. The 23-hydroxylase reaction required oxidizable substrate, was decreased by low O2 partial pressures and inhibited by CO or the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone. It was stimulated by the respiratory-chain inhibitors rotenone, antimycin A and KCN. These results indicate that the guinea-pig renal mitochondrial 23-hydroxylase is a cytochrome P-450 and that the reducing equivalents are primarily supplied by NADPH via the energy-dependent transhydrogenase.
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Kumar, R., J. Schaefer, J. P. Grande, and P. C. Roche. "Immunolocalization of calcitriol receptor, 24-hydroxylase cytochrome P-450, and calbindin D28k in human kidney." American Journal of Physiology-Renal Physiology 266, no. 3 (March 1, 1994): F477—F485. http://dx.doi.org/10.1152/ajprenal.1994.266.3.f477.
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The precise localization of the calcitriol (1 alpha,25-dihydroxyvitamin D3) receptor (VDR) and the 25-hydroxyvitamin D3 [25(OH)D3] 24-hydroxylase cytochrome P-450 in the human kidney is unknown. Using newly developed polyclonal antibodies against the human VDR, we demonstrate that the receptor is present in cells of the distal tubule, the collecting duct, the proximal tubule, and in the parietal epithelial cells of the glomerulus. In the distal tubule and collecting duct not all cells contain epitopes for the receptor. The protein is not detected in glomerular capillaries, in the glomerular mesangium, in the interstitium, or in blood vessels. Specific polyclonal antibodies directed against the 25(OH)D3 24-hydroxylase cytochrome P-450 demonstrate epitopes for the cytochrome in cells of the proximal tubule, the distal tubule, glomerular parietal epithelial cells, and mesangial cells. The protein is absent from interstitial cells. Calbindin D28k is present exclusively in principal cells of the distal tubule and collecting duct. In the human kidney, the VDR is present in cells where vitamin D-inducible proteins are found; conversely it is absent from cells where vitamin D-dependent proteins are not present.
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Shinki, T., C. H. Jin, A. Nishimura, Y. Nagai, Y. Ohyama, M. Noshiro, K. Okuda, and T. Suda. "Parathyroid hormone inhibits 25-hydroxyvitamin D3-24-hydroxylase mRNA expression stimulated by 1 alpha,25-dihydroxyvitamin D3 in rat kidney but not in intestine." Journal of Biological Chemistry 267, no. 19 (July 1992): 13757–62. http://dx.doi.org/10.1016/s0021-9258(18)42278-8.
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