Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the human granulomatous disease sarcoidosis hypercalcemia and/or hypercalciuria result from the endogenous overproduction of 1,25-dihydroxyvitamin D [1,25-(OH)2D] by the disease-activated macrophage. Unlike the renal 25-hydroxy-vitamin D (25OHD)-1-hydroxylase, normally the sole synthetic source of the hormone in man, the 25OHD3-1-hydroxylation reaction in cultured pulmonary alveolar macrophages (PAM) from patients with sarcoidosis is subject to stimulation by the immune cytokine interferon-gamma (IFN gamma) and inhibition by the antiinflammatory glucocorticoid dexamethasone. The data presented here suggest that IFN gamma and calcium ionophore A23187 promote enhanced expression of the sarcoid PAM 25OHD3-1-hydroxylation reaction by increasing endogenous arachidonic acid metabolism through the 5-lipoxygenase pathway. Dexamethasone, an inhibitor of the cellular phospholipase-A2-arachidonic acid-generating system, and BW755C, a lipoxygenase pathway inhibitor, inhibited PAM 1,25-(OH)2D3 synthesis by 64% and 54%, respectively. Conversely, leukotriene C4, a distal metabolite in the arachidonic acid 5-lipoxygenase pathway, increased the hydroxylation reaction by 234% and restored dexamethasone-inhibited PAM 1,25-(OH)2D3 synthetic activity. The results of this study provide presumptive evidence for an important role of agonist (IFN gamma)-calcium-modulated eicosanoid metabolism in the regulated synthesis of 1,25-(OH)2D by PAM in sarcoidosis.
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PMID:A role for endogenous arachidonate metabolites in the regulated expression of the 25-hydroxyvitamin D-1-hydroxylation reaction in cultured alveolar macrophages from patients with sarcoidosis. 210 25

The endogenous overproduction of active vitamin D sterols plays a central causative role in the hypercalcemic/hypercalciuric state associated with granuloma-forming diseases, most notably sarcoidosis, as well as with some human lymphomas. In sarcoidosis, the offending metabolite is most likely 1,25-(OH)2-D and the synthetic source is the disease-activated macrophage. About 50% of hypercalcemic patients with lymphoma harbor frankly elevated or inappropriately high serum 1,25-(OH)2-D concentrations. The source of the hormone in patients with lymphoma is not yet known. The endogenous synthesis of 1,25-(OH)2-D in patients with active sarcoidosis and lymphoma is not subject to regulation by those factors that normally control the production of 1,25-(OH)2-D by the renal 25-OH-D-1-hydroxylase. Treatment and prevention of vitamin D metabolite-mediated hypercalcemia/hypercalciuria consist of pharmacologic inhibition of the abnormal 1-hydroxylation reaction and limitation of substrates for the reaction. The former is best accomplished by the administration of anti-inflammatory concentrations of glucocorticoids and the latter by controlling vitamin D intake and sunlight exposure in susceptible hosts.
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PMID:Vitamin D metabolite-mediated hypercalcemia. 267 72

Production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] by human T-lymphotropic virus-I (HTLV-I)-infected lymphocytes may be the cause of the hypercalcemia frequently found in HTLV-I-associated adult T-cell lymphoma/leukemia. We examined three HTLV-I-transformed lymphocyte cell lines, two HTLV-II-transformed lymphocyte cell lines, and six HTLV-negative B and T-lymphocyte leukemia cell lines for metabolism of 25-hydroxyvitamin D3 (25OHD3). One HTLV-I-positive cell line, designated S-LB1, converted the substrate 25OH-[3H]D3 to several more polar metabolites, which were identified by high performance liquid chromatographic analysis as putative 1,25-(OH)2D3, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], and 1,24,25-trihydroxyvitamin D3 [1,24,25-(OH)3D3]. The other cell lines gave no evidence of 25OH-[3H]D3 metabolism. Likewise, phytohemagglutinin-stimulated normal human lymphocytes did not metabolize 25OH-[3H]D3. The characteristics of 25OHD3 metabolism by S-LB1 cells were investigated in more detail. Kinetic studies revealed average Km values of 92 and 383 nM for 25OHD3 1-hydroxylase and 24-hydroxylase, respectively. Time-course studies showed that both 1,25-(OH)2-[3H]D3 and 24,25-(OH)2-[3H]D3 were further metabolized by S-LB1 cells to more polar compounds [primarily 1,24,25-(OH)3D3] and to compounds from which part of the side-chain had been cleaved. Exogenous 1,25-(OH)2D3 (1) inhibited endogenous 1,25-(OH)2D3 production, (2) stimulated 24,25-(OH)2D3 production, and (3) stimulated production of compounds more polar than 1,25-(OH)2D3. Bovine PTH-(1-34) had no effect on 25OH-[3H]D3 metabolism by S-LB1 cells. Our results indicate that the 25OH-[3H]D3-metabolizing system of cultured HTLV-I-transformed S-LB1 lymphocytes is similar but not identical to that of kidney cell culture systems. It appears, however, that infection of lymphocytes with HTLV does not uniformly result in acquisition of the competence to metabolize 25OHD3.
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PMID:25-Hydroxyvitamin D3 metabolism by human T-lymphotropic virus-transformed lymphocytes. 288 83

The present study was undertaken to evaluate the response of Hyp mice to regulators known to inhibit renal 25-hydroxyvitamin D3-1-hydroxylase (1-hydroxylase) and stimulate renal 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase). Renal mitochondrial metabolism of 25-hydroxyvitamin D3 (25OHD3) was initially examined in vitamin D- and calcium-deprived normal and mutant mice (with no detectable 24-hydroxylase) treated with either calcium, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], or both calcium + 1,25-(OH)2D3. In normal mice, 1,25-(OH)2D3 treatment was more effective than calcium in turning off 1-hydroxylase and turning on 24-hydroxylase activity; serum calcium, however, was similarly increased by both treatments. Although calcium + 1,25-(OH)2D3 did not result in a further change in 25OHD3 metabolism in normal mice, a further elevation in serum calcium was apparent. In Hyp mice, treatment with calcium + 1,25-(OH)2D3 resulted in a greater decrease in 1-hydroxylase and a greater increase in 24-hydroxylase and in serum calcium than treatment with either agent alone. In spite of similar serum calcium levels in both genotypes, 24-hydroxylase was 20-fold, 3-fold, and 8-fold greater in Hyp mice relative to normals treated with calcium, 1,25-(OH)2D3, and calcium + 1,25-(OH)2D3, respectively. Kinetic studies revealed that the maximum velocity (Vmax) for induced 24-hydroxylase was 6-fold greater than normal in Hyp mice whereas the apparent Michaelis-Menten constant (Km) was not different in the two groups of calcium + 1,25-(OH)2D3-treated mice. The effect of 1,25-(OH)2D3 treatment on the above serum and renal parameters was also examined in vitamin D replete normal and Hyp mice. A sharp rise in serum phosphate was observed in 1,25-(OH)2D3-treated Hyp mice whereas normal littermates experienced marked hypercalcemia in response to treatment. Renal 24-hydroxylase was significantly stimulated by 1,25-(OH)2D3 treatment in both normal and Hyp mice and genotype differences were not apparent. The present study demonstrates that vitamin D- and calcium-deprived Hyp mice are more responsive to signals which induce 24-hydroxylase than normal littermates; Vmax for induced 24-hydroxylase is 6-fold greater in Hyp mice than in normal littermates whereas apparent Km is unchanged; the inhibitory control of 1-hydroxylase appears to be intact in the mutant strain; induced 24-hydroxylase is similar in vitamin D replete normal and Hyp mice; and vitamin D status can thus modify the response of both genotypes to treatment with 1,25-(OH)2D3.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of the X-linked Hyp mutation and vitamin D status on induction of renal 25-hydroxyvitamin D3-24-hydroxylase. 380 93

Hypercalcemia in human granuloma-forming diseases like sarcoidosis results from the endogenous overproduction of 1,25-dihydroxyvitamin D [1,25-(OH)2D] by disease-activated tissue macrophages. The recent identification of an immortalized chick myelomonocytic cell line, HD-11, that constitutively expresses a 25-hydroxyvitamin D (25-OHD) 1-hydroxylation reaction has alleviated dependence on studying primary macrophage cultures with no replicative potential in vitro. In these experiments we established conditions for the maximal expression of the HD-11 cell 25-OHD3-1-hydroxylation reaction and localized this activity to the mitochondrial fraction. On a per cell basis, the activity of HD-11 cell 25-OHD3 1-hydroxylation reaction was comparable to that in primary cultures of chick renal tubular epithelial cells, which express the authentic renal 25-OHD3 1-hydroxylase. Maximal product yield was achieved after incubation of HD-11 cells with 200 nM 25-OHD3 for 3 h. Although adherent monolayers possessed 3- to 4-fold more capacity for hormone production than cells in suspension, suspended cells exhibited easily detectable 25-OHD3 catalytic activity (0.58 +/- 0.08 pmol per 10(6) cells per h; +/- SEM), 50% of which remained solubilized in a sonicate of suspended cells cleared of nuclei and plasma membrane. Subcellular localization disclosed 91% of the residual activity to be concentrated in the mitochondrial subfraction. A detergent-solubilized extract of this mitochondrial subfraction contained 1.9 +/- 0.3 pmol 1,25-(OH)2D3 synthetic capacity per mg protein. The catalytic activity (1-hydroxylase activity) was concentrated 20.2-fold after chromatography on octyl-amino agarose and was associated with 0.054 nmol cytochrome P450 per mg protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subcellular localization and partial purification of the 25-hydroxyvitamin D3 1-hydroxylation reaction in the chick myelomonocytic cell line HD-11. 838 98

Tissue macrophages from patients with granuloma-forming disease, most notably sarcoidosis, express a 25-hydroxyvitamin D-1-hydroxylase which can produce in vivo sufficient quantities of the active vitamin D metabolite 1,25-dihydroxyvitamin D to cause hypercalcemia. In contrast to the NADPH-dependent cytochrome P450-linked mixed function oxidase which is normally only expressed in significant quantity in proximal renal tubular cells and regulated in an endocrine fashion, the mitochondrial-based 1-hydroxylase in the macrophage [1] is stimulated in a paracrine mode by cytokines (i.e., IFN-gamma) and lipopolysaccharide (LPS) [2] requires an extracellular source of L-arginine for full basal expression and [3] can be regulated in an intracrine fashion by nitric oxide (NO). In these experiments we employed inducible nitric oxide synthase (iNOS)-free, intact mitochondria preparations from the avain macrophage-like cell line HD-11, which constitutively express the 1-hydroxylase, and nonenzymatically-generated NO to investigate NO-mediated autoregulation of the macrophage 1-hydroxylase. Sodium nitroprusside (SNP)- or S-nitroso-N-acetyl-penicillamine (SNAP)-induced up-regulation of the 1-hydroxylase required the presence of either NADPH or NADP in the reaction mixture, while NO-induced inhibition of mitochondrial 1,25-(OH)2D3 synthesis was NO-dependent and NADP/NADPH-independent. These data suggest NO has bifunctional effects on the macrophage 1-hydroxylase. At relatively high concentrations NO competes with O2 for enzyme binding, inhibiting hormone synthesis. At lower production levels, NO serves as a source of reducing equivalents for the enzyme by providing for the reduction of NADP to NADPH.
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PMID:Autoregulation of 1,25-dihydroxyvitamin D synthesis in macrophage mitochondria by nitric oxide. 882 16

The 4-aminoquinolines, including chloroquine and hydroxychloroquine, have been successfully employed to treat patients with granuloma-forming disease-associated, vitamin D metabolite-mediated hypercalcemia. The calcium-lowering efficacy of these drugs has not been prospectively evaluated in patients with lymphoma and elevated 1,25-(OH)2D levels. Four such hypercalcemic patients with stage IV B-cell lymphoma were treated, two each, with either 400 mg daily oral hydroxychloroquine or a single course of prednisone-containing antitumor chemotherapy (CHOP). Antitumor therapy normalized the serum calcium and 1,25-(OH)2D concentration within 5 days. Over a 15-day period, hydroxychloroquine failed to reduce either the serum calcium or 1,25-(OH)2D level in lymphoma patients. In contrast, within 5 days 400 mg of hydroxychloroquine daily lowered elevated levels of calcium and 1,25-(OH)2D by 37% and 72%, respectively, in a hypercalcemic patient with sarcoidosis. These data suggest that regulation of the vitamin D-1-hydroxylase in lymphoma cells, the putative source of hormone in lymphoma patients, is refractory to the inhibitory actions of the aminoquinolines and that glucocorticoid-containing antitumor regimens are the antihypercalcemic therapies of choice in lymphoma patients with high 1,25-(OH)2D levels.
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PMID:Inability of short-term, low-dose hydroxychloroquine to resolve vitamin D-mediated hypercalcemia in patients with B-cell lymphoma. 1002 56

Chronic uremia is characterized by decreased levels of plasma 1,25(OH)2D3 due to decreased renal 1-hydroxylase activity and by decreased renal phosphate excretion. The consequence is an increased synthesis and secretion of parathyroid hormone--secondary hyperparathyroidism--due to the low levels of plasma calcium, low levels of plasma 1,25(OH)2D3 and high levels of phosphate. The association between renal bone disease and chronic renal failure is well described. Epidemiological studies have indicated that an association also exists between secondary hyperparathyroidism and increased mortality and cardiovascular calcifications in chronic uremic patients. Treatment of secondary hyperparathyroidism in chronic uremia focuses on avoiding hyperphosphatemia by the use of oral phosphate binders, which bind phosphate in the intestine and a concomitant substitution by a 1 alpha-hydroxylated vitamin D analog in order to compensate for the reduced renal hydroxylation. Additional treatment with aluminum containing phosphate binders to overcome phosphate absorption and retention was initiated already in the 1960s and used extensively until aluminum toxicity was disclosed in the mid-1980s. Instead calcium carbonate and calcium acetate were used as phosphate binders. Until recently, the most commonly used active vitamin D drug was either the natural 1,25(OH)2D3, or the 1 alpha-hydroxylated analog, 1alpha(OH)D3 which after 25-hydroxylation in the liver is converted to 1,25(OH)2D3. 1alpha(OH)D3 was produced by LEO Pharma in 1973. The two vitamin D analogs were used in different geographical areas: In Europe 1alpha(OH)D3 was mainly used, while 1,25(OH)2D3 was mainly used in the USA. 1,25(OH)2D3 increases the intestinal absorption of calcium and improves skeletal abnormalities. The combined treatment with calcium containing phosphate binders and active vitamin D induces an increase in plasma Ca 2+ and hypercalcemia became a clinical problem. Subsequently therefore, dialysis fluid with a reduced calcium concentration ("low-calcium") was introduced. In 1981 Madsen et al. [148] demonstrated for the first time a direct suppressive effect of intravenous 1,25(OH)2D3 on plasma PTH in acutely uremic patients. In 1984, Slatopolsky et al. [74] demonstrated that intravenous 1,25(OH)2D3 induces a marked suppression of plasma PTH with no increase in plasma Ca 2+ in chronic uremic patients. In the middle of the 1980s, 1alpha(OH)D3 became available not only as an oral, but also as an intravenous formulation. The main purpose of the present studies was to increase the knowledge of the action and effects of different treatment regimes with 1alpha(OH)D3, and thereby to improve the prophylaxis and treatment of secondary hyperparathyroidism in uremic patients on chronic dialysis. 168 patients on chronic dialysis treatment and six healthy volunteers were included in the seven studies included in this thesis. The first part of the studies, focused on short- (12 weeks) and long-term (103 weeks) effects of intravenous 1alpha(OH)D3 on plasma PTH and plasma Ca 2+ in relation to the doses of 1alpha(OH)D3 given. Further, it was examined whether the marked suppression of plasma PTH induced by 300 days of intermittent intravenous treatment with 1alpha(OH)D3, could be maintained when the administration was changed from intravenous to the oral route for 16 further weeks and then shifted back to intravenous administration for another 16 weeks. The second part focused on long-term effects (88 weeks in hemodialysis patients and 52 weeks in CAPD patients) of a treatment modality combining 1alpha(OH)D3, and CaCO3 as phosphate binders instead of aluminum containing compounds and a decreased calcium concentration in the dialysis fluid to 1.25 mmol/l in an attempt to avoid development of hypercalcemia. The third part focused upon the pharmacokinetic differences between intravenous and oral administration of 1,25(OH)2D3 and 1alpha(OH)D3 and upon the acute effects of different doses of the two compounds on the plasma levels of PTH, Ca 2+ and phosphate. Plasma PTH is a biochemical parameter most often used for the diagnosis and monitoring of bone disease in patients with chronic uremia. The level of plasma PTH measures depends on the assay used. More specific assays measuring only whole PTH 1-84 without co-measuring large C-terminal fragments have been developed. In this thesis, five different assays were used - one "N-terminal", one "C-terminal", two "Intact" and one "Whole" PTH assay. Each sample was analyzed by 1-3 different assays. Based on the results of my studies [1-7], it is concluded that: 1a. Intravenous administration of 1alpha(OH)D3 induces a marked suppression of plasma PTH without causing serious side-effects in patients on chronic hemodialysis. It is possible to prevent hypercalcemia by closely monitoring plasma Ca 2+ levels and by adjusting the dose of 1alpha(OH)D3 accordingly. 1b. Long-term intermittent intravenous treatment with 1alpha(OH)D3 was effective in suppressing plasma levels of Intact PTH. 1c. When plasma intact PTH was suppressed to a stable level by intravenous 1alpha(OH)D3 the suppression could be maintained by intermittent oral 1alpha(OH)D3 therapy. It was not examined whether a similar degree of suppression of severe secondary hyperparathyroidism could be induced by intermittent oral 1alpha(OH)D3 treatment alone. The responses following chronic intravenous or oral administration of 1alpha(OH)D3 on circulating levels of intact PTH and N- and C-terminal PTH fragments did not reveal any significant differences between the two routes of administration on the actions on the parathyroid glands. 2a. The combination of "low-calcium" hemodialysis fluid (1.25 mmol/l), CaCO3 as a phosphate binder, and intermittent intravenous 1alpha(OH)D3 prevented development of secondary hyperparathyroidism in uremic patients with normal PTH at the initiation of the study and induced a long-term suppression of PTH in patients with secondary hyperparathyroidism. No clinical or biochemical indications of development of adynamic bone disease were observed. Intravenous administration of 1alpha(OH)D3 prevented a decrease of BMC in the lumbar spine and femoral neck of hemodialysis patients both with normal and with elevated PTH levels. It was possible to use larger doses of CaCO3 and to reduce, but not exclude, the use of aluminum-containing phosphate binders in combination with intravenous administration of 1alpha(OH)D3. A decrease of plasma Ca 2+ was induced during dialysis, and special care had to be taken on the compliance of the patients as to the use of CaCO3 binders in order not to aggravate secondary hyperparathyroidism. 2b. In patients on CAPD, the use of low-calcium dialysis (1.25 mmol/l) made it possible to use larger doses of CaCO3 phosphate binders and to reduce, but not exclude, the use of aluminium containing phosphate binder in combination with oral pulses of 1alpha(OH)D3. A negative calcium balance was induced, and it is therefore recommended that a reduction of the calcium concentration in the dialysis fluid is only used in patients under strict control. 3a. The metabolic clearance rate of 1,25(OH)2D3 was 57% lower in uremic patients than in normal subjects (p < 0.03). The bioavailability of 1,25(OH)2D3 in both normal subjects and uremic patients was markedly lower following administration of 1alpha(OH)D3 both intravenously and orally than after administration of oral 1,25(OH)2D3. Despite lower plasma 1,25(OH)2D3 levels after administration of 1alpha(OH)D3 than after 1,25(OH)2D3, no significant difference was observed in the PTH suppressive effect in uremic patients of 4 mug intravenously of either of the two vitamin D analogs. 3b. A single intravenous high dose of 10 mug of 1alpha(OH)D3 or 1,25(OH)2D3 significantly suppressed plasma PTH. The acute suppressive effect of 1,25(OH)2D3 was three times greater than that of 1alpha(OH)D3.The increase in plasma Ca 2+ after intravenous administration of 10 mug 1,25(OH)2D3 was significantly higher than that of 1alpha(OH)D3. Due to the simultaneous effect on plasma Ca 2+ observed it was not possible to decide whether 1alpha(OH)D3 has a direct effect per se on the parathyroid glands or not. The study further did not give any further knowledge about the possible therapeutic equivalence of long-term treatment with 1alpha(OH)D3 or 1,25(OH)2D3. The PTH responses to acute administration of the 1alpha(OH)D3 and 1,25(OH)2D3 analogs were in principle the same when measured by one "whole" PTH and two "intact" PTH assays, namely mainly in a parallel shift of the PTH response curve. In this study on chronic uremic patients circulating levels of large C-terminal PTH fragments were not affected by differences in plasma Ca 2+ concentration or by the intravenous administration of 1alpha(OH)D3 or 1,25(OH)2D3. There is now a general agreement on the importance of carefully controlling plasma phosphate, normalize and avoid increases of plasma Ca 2+, and not to oversuppress PTH during treatment. Focus today is on the potential deleterious role of calcium overloading in the development of vascular calcifications in uremic patients. There is an urgent need for a development of an algorithm for the use of phosphate binders and vitamin D supplementation in combination with calcimimetics focusing upon long term morbidity and mortality in uremic patients.
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PMID:1alpha(OH)D3 One-alpha-hydroxy-cholecalciferol--an active vitamin D analog. Clinical studies on prophylaxis and treatment of secondary hyperparathyroidism in uremic patients on chronic dialysis. 1923 59

Hypercalcemia 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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PMID:Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment. 2758 37