1,25 Dihydroxyvitamin D increases hepatocyte cytosolic calcium levels. A potential regulator of vitamin D-25-hydroxylase.

Baran, Daniel T.; Milne, Moira

doi:10.1172/jci112478

Cited by 98 publications

(32 citation statements)

References 27 publications

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“…Increases in cytoplasmic-free calcium have been implicated in both initial T cell activation (37,38) as well as IL-1 production by monocytes (39). Recent work has demonstrated that calcitriol can induce rapid increases in cytoplasmic-free calcium (40), which suggests a mechanism that could account for either of these activities. Since induction of TfR expression on T cells is dependent on an interaction of IL-2 with its receptor (27), the augmentation in TfR mRNA observed with calcitriol at 6 and 12 h may be a consequence of increased IL-2 message and subsequent IL-2 production.…”

Section: Resultsmentioning

confidence: 99%

Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA.

Rigby¹,

Denome²,

Fanger³

1987

J. Clin. Invest.

348

176

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The steroid hormone, la,25-dihydroxyvitamin D3 (calcitriol), has been shown to inhibit T cell proliferation, primarily through inhibition of interleukin 2 (IL-2) production. In these experiments, we show that calcitriol also markedly inhibited production of the lymphokine, gamma interferon (IFN-y), by activated human T lymphocytes. Regulation of both IL-2 and IFN-y production as well as transferrin receptor (TfR) expression by calcitriol was apparent at the messenger RNA (mRNA) level as determined by Northern blotting. The decrease in IL-2 and IFN-'y mRNA that occurred with calcitriol treatment was coordinate and not apparent up to 12 h after phytohemagglutinin stimulation, whereas decreased accumulation of TfR mRNA was not present before 24-36 h. Furthermore, the effects of calcitriol on IL-2, IFN-'y, and TfR mRNA accumulation were specific; actin mRNA accumulation was comparable between control and treated cells. These data indicate that calcitriol regulated proteins associated with T cell activation at the transcriptional level and that these effects were mediated in a specific, coordinate fashion.

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Section: Resultsmentioning

confidence: 99%

Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA.

Rigby¹,

Denome²,

Fanger³

1987

J. Clin. Invest.

348

176

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“…Recent studies have demonstrated that hepatic tissue has several physiological responses to 1,25(OH)2D3 (16)(17)(18)(19)(20)(21)(22)(23)(24)46) and appears to contain high-affinity receptors for this potent hormone (47). General vitamin D deficiency in the rat has been shown to alter hepatic function as manifested by delayed bromosulfthalein clearance and elevated plasma transaminases (16).…”

Section: Identificationmentioning

confidence: 99%

“…In addition to these generalized symptoms of vitamin D deficiency, 1,25(OH)2D3 is known to specifically increase hydroxymethylglutaryl CoA reductase activity (18), decrease liver regeneration time independent of calcium (17), regulate the synthesis of hepatic DNA polymerase a (19,20), increase [3H]thymidine incorporation into hepatic DNA (17), and enable regenerating liver cells to make functional ribonucleotide reductase subunits (21). 1,25(OH)2D3 also increases hepatocyte cytosolic calcium levers (22) through its potential action on phospholipase A activity (23). Given the vast array of known actions of 1,25(OH)2D3 on hepatic function, it is not surprising that in situ production of the hormone exists in the liver.…”

Section: Identificationmentioning

confidence: 99%

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25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

Proc. Natl. Acad. Sci. U.S.A.

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In vitro studies were performed to assess the ability of hepatic homogenates, mitochondria, and microsomes to la-hydroxylate 25-hydroxyvitamin D3 (25(OH)D3]. Addition of 25(OH)D3 to either hepatic mitochondria or microsomes caused a concentration-dependent increase in the production of 1,25-dihydroxyvitamin D3 [1,25(OH) Because of its inability to achieve substrate saturation, meaningful kinetic parameters could not be calculated for the hepatic microsomal la-hydroxylase. These data demonstrate the liver to be an even more dynamic organ than was previously believed with respect to vitamin D metabolism in that the liver has the potential to produce 1,25(OH)2D3 in situ by at least two separate mechanisms.It is well established that various side chain and/or A-ring hydroxylation reactions are essential for the metabolic activation of vitamin D3 (1, 2). Circulating vitamin D3 first undergoes a hepatic conversion to 25-hydroxyvitamin D3 [25(OH)D3] (3). The hydroxylase enzymes responsible for this conversion are known to be cytochrome P-450 mixed-function oxidases that are NADPH dependent and are located in both hepatic mitochondria (4-6) and microsomes (7,8). Final activation of 25(OH)D3 into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] takes place primarily in the kidney (9). The renal enzyme responsible for this activation, 25(OH)D3 lahydroxylase, is also known to be a cytochrome P450 mixedfunction oxidase that is located solely in the inner mitochondrial membrane (10, 11). In recent years, other tissues have also been shown to be capable of synthesizing 1,25(OH)2D3, including placenta (12), bone cells (13), lymphatic tissue (14), and keratinocytes (15). Compared with the renal 25(OH)D3 la-hydroxylase, very little information is known with respect to the metabolic control of these extrarenal 25(OH)D3 lahydroxylases and essentially no information is available concerning their subcellular distribution.Because of the important role of 1,25(OH)2D3 in various aspects of hepatic function (16-24), the possibility that the liver could synthesize in situ this hormonal form of vitamin D3 was investigated. It is reported here that both hepatic mitochondria and microsomes possess a 25(OH)D3 lahydroxylase in significant amounts. These enzymes differ in some characteristics, but both appear to behave as cytochrome P-450 mixed-function oxidases. MN). Coomassie blue protein assay reagent was purchased from Pierce. Nicotinamide adenine dinucleotide phosphate, isocitrate, N,N'-diphenylethylenediamine (DPED), dithiothreitol, and ethylenediaminetetraacetic acid were purchased from Sigma. All solvents were of HPLC grade and were obtained from Fisher. MATERIALS AND METHODS ReagentsLivers. Livers from 3-month-old castrated male pigs, maintained on stock diet, were obtained at the time of slaughter. The livers were perfused with ice-cold 0.15 M NaCl, minced, and placed in an appropriate volume of ice-cold 50 mM Na2HPO4 (pH 7.4) buffer containing 0.25 M sucrose and 0.5 mM EDTA to provide a 20% (wt/vol) 6009The publication costs of th...

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“…The most widely accepted explanation is that the rapid actions of steroids are receptor independent; direct action on the cell membrane modulates its lipid composition, changes ion fluxes, and activates ion-dependent metabolic processes (2)(3)(4). However, recent data indicate that rapid actions of la,25-(OH)2D3 can occur at very low concentrations (5)(6)(7)(8)(9)(10)(11)(12) and with high cholecalciferol analog specificity (6,7,(9)(10)(11)(12)(13)(14)(15), suggesting to us that the la,25-(OH)2D3 receptor could mediate rapid actions.…”

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confidence: 99%

Receptor-mediated rapid action of 1 alpha,25-dihydroxycholecalciferol: increase of intracellular cGMP in human skin fibroblasts.

Bársony

Marx

1988

Proc. Natl. Acad. Sci. U.S.A.

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The intracellular cGMP concentration in normal human cultured fibroblasts was increased 2-to 3-fold by la,25-dihydroxycholecalciferol [la,2D3] in a dosedependent manner between 0.01 nM and 1 FM. The response was detectable within 1 min, reached a maximum (225% ± 8% of baseline) at 6-8 min, and was no longer detectable at 30 min. The half-maximal effect of la,25-(OH)2D3 was at 1.8 nM, and 24,25-dihydroxycholecalciferol showed an estimated ECso 100-fold higher. 113,25-Dihydroxycholecalciferol, 25-hydroxycholecalciferol, and cholecalciferol had no detectable effect. Human skin fibroblasts with three different types of la,25-(OH)2D3 receptor defect did not respond to la,25-(OH)2D3 exposure with cGMP increase; however, the same cells (like normal cells) responded to testosterone or sodium nitroprusside with a rapid rise of cGMP. We conclude that the rapid rise of cGMP in response to calciferols shows an ECse for la,25-(OH)2D3, a cholecalciferol analog specificity, and a cell line dependency that are all suggestive of mediation through a specific la,25-(OH)2D3 receptor.Over the past 15 years, studies from a number of laboratories have provided evidence that la,25-dihydroxycholecalciferol [la,25-(OH)2D3 or calcitriol] acts like a steroid hormone through receptor-mediated regulation of nuclear events. However, rapid, presumably nongenomic, actions of la,25-(OH)2D3 (similar to those of other steroid hormones) have been documented in several systems (1). The most widely accepted explanation is that the rapid actions of steroids are receptor independent; direct action on the cell membrane modulates its lipid composition, changes ion fluxes, and activates ion-dependent metabolic processes (2-4). However, recent data indicate that rapid actions of la,25-(OH)2D3 can occur at very low concentrations (5-12) and with high cholecalciferol analog specificity (6, 7, 9-15), suggesting to us that the la,25-(OH)2D3 receptor could mediate rapid actions.Rapid stimulation of cGMP by steroids (16-19) including la,25-(OH)2D3 (20) cinyl-cGMP-tyrosine methyl ester (specific activity, >2000 ,Ci/1 ,umol; 1 Ci = 37 GBq) was from Meloy Laboratories (Springfield, VA). Antiserum against cGMP (no. 33:5-6-81) was provided by Kevin Catt. All cholecalciferol analogs were tested for purity on reverse-phase high-performance liquid chromatography within a week before use (21).Cell Culture. All studies were performed on human cultured skin fibroblasts. Three cell lines from patients with hereditary resistance to la,25-(OH)2D3 had been tested previously for la,25-(OH)2D3 receptor binding, for la,25-(OH)2D3 nuclear uptake, and for la,25-(OH)2D3 receptor elution from DNA-cellulose to characterize their defects in la,25-(OH)2D3 action (21-23) ( and maintained for 24 hr in serum-free medium. Cell cultures from passages 12-30 were used at 75% confluency. Cells were tested for mycoplasma (American Type Culture Collection) with negative results.Perturbation of Intracellular cGMP. Immediately before exposure to hormones cells were washed three times wit...

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1,25 Dihydroxyvitamin D increases hepatocyte cytosolic calcium levels. A potential regulator of vitamin D-25-hydroxylase.

Cited by 98 publications

References 27 publications

Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA.

Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA.

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Receptor-mediated rapid action of 1 alpha,25-dihydroxycholecalciferol: increase of intracellular cGMP in human skin fibroblasts.

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