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1.
Dig Dis Sci ; 64(2): 324-344, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30370494

RESUMO

Vitamin D has immunomodulatory, anti-inflammatory, antioxidant, and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease. The goals of this review are to describe the nature of these expanded roles, examine the implications of vitamin D deficiency in autoimmune hepatitis, and identify opportunities for future investigation. Abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses. Macrophages and dendritic cells can produce 1,25-dihydroxyvitamin D within the microenvironment. This active form of vitamin D can inhibit immune cell proliferation, promote an anti-inflammatory cytokine profile, expand regulatory T cells, enhance glucocorticoid actions, increase glutathione production, and inhibit hepatic stellate cells. Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases, and it has been associated with histological severity, advanced hepatic fibrosis, and non-response to conventional glucocorticoid therapy in autoimmune hepatitis. Vitamin D analogues with high potency, low calcemic effects, and independence from hepatic hydroxylation are possible interventions. In conclusion, vitamin D has properties that could ameliorate immune-mediated disease, and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases, including autoimmune hepatitis. Loss of vitamin D-dependent homeostatic mechanisms may promote disease progression. Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis.


Assuntos
Hepatite Autoimune/imunologia , Deficiência de Vitamina D/imunologia , Vitamina D/imunologia , Imunidade Adaptativa/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade/imunologia , Citocinas , Células Dendríticas/imunologia , Di-Hidroxicolecalciferóis/metabolismo , Fibrose , Glucocorticoides/metabolismo , Glutationa/metabolismo , Células Estreladas do Fígado/metabolismo , Hepatite Autoimune/metabolismo , Humanos , Imunidade Inata/imunologia , Inflamação , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Macrófagos/imunologia , Linfócitos T , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismo
2.
J Clin Invest ; 116(8): 2062-72, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16886050

RESUMO

The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sun exposure and the fortification of milk with vitamin D resulted in almost complete eradication of the disease. Vitamin D (where D represents D2 or D3) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorus, and bone metabolism. Vitamin D deficiency has again become an epidemic in children, and rickets has become a global health issue. In addition to vitamin D deficiency, calcium deficiency and acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolism cause rickets. This review summarizes the role of vitamin D in the prevention of rickets and its importance in the overall health and welfare of infants and children.


Assuntos
Raquitismo/epidemiologia , Deficiência de Vitamina D/epidemiologia , Cálcio/metabolismo , Criança , Pré-Escolar , Di-Hidroxicolecalciferóis/metabolismo , Feminino , Humanos , Hidroxicolecalciferóis/metabolismo , Masculino , Fósforo/metabolismo , Prevalência , Raquitismo/etiologia , Raquitismo/genética , Raquitismo/radioterapia , Raios Ultravioleta , Vitamina D/efeitos da radiação , Deficiência de Vitamina D/radioterapia
3.
J Anim Sci ; 81(6): 1568-80, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12817506

RESUMO

Growing giant-breed dogs are more susceptible to developing skeletal disorders than small-breed dogs when raised on diets with deficient or excessive Ca content. Differential hormonal regulation of Ca homeostasis in dogs with different growth rates was investigated in Great Danes (GD, n = 9) and Miniature Poodles (MP, n = 8). All animals were raised on the same balanced diet and under identical conditions. Calciotropic and growth-regulating hormones were measured. Production and clearance of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) were investigated with the aid of [3H]-1,25(OH)2D3 and renal messenger RNA abundance of 1 alpha-hydroxylase and 24-hydroxylase. Intestinal, renal, and skeletal Ca handling were evaluated with the aid of 45Ca balance studies. Skeletal development was evaluated by radiology and histomorphometry. Great Danes had greater (P < 0.001) growth rates than MP, as indicated by the 17-fold greater body weight gain, by increased longitudinal growth reflected in the increased (P < 0.05) gain in length of the radius and ulna, and by increased (P < 0.001) growth plate thickness. These findings were accompanied in GD by greater (P < 0.05) plasma GH and IGF-I concentrations. Effects were observed for vitamin D3 metabolism, such as greater (P < 0.01) plasma 1,25(OH)2D3 concentrations due to decreased (P < 0.01) clearance rather than increased production of 1,25(OH)2D3, and decreased (P < 0.01) plasma 24,25-dihydroxycholecalciferol (24,25[OH]2D3) concentrations likely due to competitive inhibition of the production of 24,25(OH)2D3. These findings were accompanied in both breeds by a limited hormonal regulation of Ca and P absorption at the intestinal level, and in GD by increased (P < 0.05) renal reabsorption of inorganic P (Pi) compared with MP, resulting in greater (P < 0.01) Pi retention and greater (P < 0.01) plasma Pi concentrations. Bone turnover, resorption, and formation were greater (P < 0.01) in GD than in MP. In addition, GD had more irregular (P < 0.01) growth plates than MP, accompanied by disorders of endochondral ossification. It is suggested that in GD, increased calcitonin levels and/or a relative deficiency in 24,25(OH)2D3 at the growth-plate level may both be responsible for the retarded maturation of chondrocytes, resulting in retained cartilage cones and osteochondrosis, and this may be a pathophysiological factor for the increased susceptibility of large breed dogs to developing skeletal disorders.


Assuntos
Osso e Ossos/metabolismo , Cálcio da Dieta/administração & dosagem , Cálcio/metabolismo , Cães/fisiologia , Homeostase/fisiologia , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Cálcio/farmacocinética , Di-Hidroxicolecalciferóis/metabolismo , Cães/genética , Cães/crescimento & desenvolvimento , Cães/metabolismo , Hormônio do Crescimento/sangue , Homeostase/genética , Fator de Crescimento Insulin-Like I , Absorção Intestinal , Taxa de Depuração Metabólica , Fósforo/metabolismo , Fósforo/farmacocinética , Radiografia
4.
Biochim Biophys Acta ; 1346(2): 147-57, 1997 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-9219897

RESUMO

In vivo metabolism of 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3) in female dogs has been studied thoroughly, and its major bile metabolite identified. After single oral administration of 24,25-(OH)2 [6,19,19-3H]D3 the plasma concentrations of radioactive metabolites were monitored for 504 h, and the metabolites in the bile collected and analyzed. The concentration of 24,25-(OH)2D3 in plasma reached a maximum after 6 h and decayed in two distinct phases; a fast-phase with a half-life of 17 h, followed by a slow-phase with a 17-day half-life. The area under the concentration/time curve (AUC) was 78-84% (0-504 h). The only detectable metabolite in the plasma was 25-hydroxy-24-oxovitamin D3 whose AUC was less than 5%. At 504 h, about 50% of administered radioactivity has been excreted, of which about 90% was found in the feces, indicating most of the administered 24,25-(OH)2D3 to be excreted in bile. A major metabolite, which constituted 23% of the total bile radioactivity at 504 h, was found in the bile. This metabolite was efficiently deconjugated by beta-glucuronidase to afford an aglycone which was identified as 23S,25-dihydroxy-24-oxovitamin D3 (23S,25-(OH)2-24-oxo-D3), by co-chromatography on HPLC with synthetic standards. The glucuronide was isolated from the bile of dogs given large doses of 24,25-(OH)2D3, and the structure determined being 23-(beta-glucuronide) of 23S,25-(OH)2-24-oxo-D3, by analyzing its negative ion mass spectrum and the positive ion mass spectrum of its derivatives. Thus it was concluded that, in dogs, 24,25-(OH)2D3 is a long lasting vitamin D metabolite, is mainly excreted in bile when metabolized to 23S,25-(OH)2-24-oxo-D3 and is conjugated at 23-OH as glucuronide.


Assuntos
24,25-Di-Hidroxivitamina D 3/metabolismo , Bile/química , Di-Hidroxicolecalciferóis/metabolismo , 24,25-Di-Hidroxivitamina D 3/farmacocinética , Animais , Arilsulfatases/metabolismo , Cromatografia Líquida de Alta Pressão , Di-Hidroxicolecalciferóis/química , Di-Hidroxicolecalciferóis/isolamento & purificação , Cães , Ergocalciferóis/química , Ergocalciferóis/metabolismo , Feminino , Glucuronatos/química , Glucuronatos/metabolismo , Glucuronidase/metabolismo , Espectrometria de Massas , Estrutura Molecular
5.
J Bone Miner Res ; 10(7): 1116-21, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7484288

RESUMO

Whether a radiographic and histologic cure of osteopetrosis includes normalization of mineral homeostasis remains unknown. Thus, we explored the extent of defective mineral metabolism in the microphthalmic (mi/mi) mouse before and after cure. Under basal conditions mi mutants exhibit normocalcemia, hypophosphatemia, and elevated renal 25-hydroxyvitamin D-1-hydroxylase activity. However, administration of PTHrP (3 micrograms/h x 24 h) further stimulated enzyme activity in mi mutants with active disease, to a level no different than that in treated normals. Serum phosphorus levels also declined in mi/mi mice following PTHrP, suggesting a normal renal response to this hormone. In contrast, failure to suppress enzyme function in mi/mi mice following prolonged calcitriol infusion indicates that the observed enhancement of 1,25-dihydroxyvitamin D production occurred secondary to autonomous parathyroid function and/or nonparathyroid hormone-related stimuli. Although an increased fractional excretion and decreased tubular reabsorption of phosphate were demonstrated in mi/mi mice, serum PTH levels were no different in mi mutants compared with normal littermates. Following skeletal cure, the mi/mi mice surprisingly display normal serum phosphorus levels and renal enzyme activity. Moreover, treatment restored normal responsiveness to calcitriol suppression and maintained normal PTHrP responsiveness of enzyme activity. These data indicate that the cure of osteopetrosis in the mi mutant is universal and includes normalization of serum phosphorus and renal 25-hydroxyvitamin D-1-hydroxylase. Furthermore, these data suggest that phosphate depletion of unknown origin is the likely cause of elevated enzyme activity in this murine osteopetrotic mutant.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Densidade Óssea/fisiologia , Cálcio/sangue , Osteopetrose/terapia , Fósforo/sangue , Proteínas/uso terapêutico , Animais , Calcitriol/administração & dosagem , Calcitriol/farmacologia , Calcitriol/uso terapêutico , Terapia Combinada , Di-Hidroxicolecalciferóis/metabolismo , Modelos Animais de Doenças , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Microftalmia/genética , Mutação/genética , Osteopetrose/genética , Hormônio Paratireóideo/sangue , Proteína Relacionada ao Hormônio Paratireóideo , Proteínas/administração & dosagem , Proteínas/farmacologia , Vitamina D/metabolismo
6.
J Endocrinol Invest ; 15(10): 771-5, 1992 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1491127

RESUMO

We describe an elderly man who presented with hypercalcemia associated with suppressed intact parathyroid hormone (PTH) levels. Despite renal insufficiency the circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) was in the upper part of the normal range. Known causes of hypercalcemia were absent and mild hypercalcemia with suppression of intact PTH persisted until after bilateral hip replacement for severe arthritis (1 year after presentation). After hip replacement the ionized calcium normalized, intact PTH normalized, and 1,25(OH)2D decreased markedly. We believe the abnormalities in mineral homeostasis were related to production of 1,25(OH)2D by inflammatory mononuclear cells associated with arthritis.


Assuntos
Artrite/metabolismo , Di-Hidroxicolecalciferóis/metabolismo , Hipercalcemia/metabolismo , Idoso , Artrite/complicações , Prótese de Quadril , Humanos , Hipercalcemia/complicações , Masculino , Monócitos/metabolismo , Hormônio Paratireóideo/sangue
7.
Nihon Sanka Fujinka Gakkai Zasshi ; 44(11): 1443-9, 1992 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-1460364

RESUMO

The effects of intravenous magnesium sulfate tocolysis on calcium metabolism were studied in 10 patients with preterm labor. A loading dose of magnesium sulfate (4g) was administered intravenously maintenance intravenous infusion of magnesium sulfate (1g per hour). All patients simultaneously received 50 micrograms ritodrin per minutes by intravenous infusion. Serum magnesium increased from 1.91 +/- 0.06mg/dl to 4.6 +/- 0.71mg/dl at 30 minutes (p < 0.01) and it remained relatively high. The fall in serum calcium corrected by serum total protein was most rapid during the first 30 minutes, from 9.04 +/- 0.47mg/dl to 8.3 +/- 0.27mg/dl (p < 0.01). Urinary excretion of magnesium, represented as the calcium/creatinine ratio, rose markedly from 0.05 +/- 0.01 to 3.18 +/- 0.8 at an hour (p < 0.01) and thereafter remained higher than the baseline level. Changes in urinary excretion of calcium paralleled those of urinary evcretion of magnesium. Serum parathyroid hormone rose from 118 +/- 42.2pg/ml to 294 +/- 121pg/ml at 6 hours (p < 0.05). Serum 1 alpha,25-(OH)2D3-rose from 89.3 +/- 44.2pg/ml to 126 +/- 38.7pg/ml (p < 0.05). Serum calcitonin showed no significant change. These findings indicate that correction of hypocalcemia mainly depends on secretion of parathyroid hormone in the early stage, and thereafter depends on the cooperative action of parathyroid hormone and 1 alpha,25-(OH)2D3.


Assuntos
Cálcio/metabolismo , Sulfato de Magnésio/farmacologia , Trabalho de Parto Prematuro/metabolismo , Adulto , Nitrogênio da Ureia Sanguínea , Creatinina/urina , Di-Hidroxicolecalciferóis/metabolismo , Feminino , Humanos , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/farmacocinética , Hormônio Paratireóideo/metabolismo , Fósforo/sangue , Gravidez
8.
J Clin Endocrinol Metab ; 70(5): 1334-40, 1990 May.
Artigo em Inglês | MEDLINE | ID: mdl-2335575

RESUMO

In an earlier 8-day study, we showed increased immunoreactive PTH (iPTH) levels in young adults fed high phosphorus (P), low calcium (Ca) diets assembled from common grocery foods, a dietary pattern characteristic of teens and young adults. Because animals fed high P, low Ca diets developed secondary hyperparathyroidism and, ultimately, osteopenia, perhaps the typical teen diet may reduce peak bone mass and contribute to osteoporotic fracture later in life. To determine if the elevation in iPTH levels and action persists with chronic intake of this typical diet, we studied the 24-h mineral and hormone responses of 15 young women (18-25 yr of age) to either high P, low Ca or control diets. Each subject served as her own control, first consuming a basal diet (800 mg Ca, 900 mg P) for 28 days; 10 women were then switched to the high P, low Ca test diet (400 mg Ca, 1700 mg P) for 28 days, while the remaining 5 women in the control group continued eating the basal diet. On days 28 and 56, all subjects were studied as inpatients for 24 h, with blood drawn every 4 h and collection of fasting and 24-h urine. Serum iPTH (midregion) and serum intact PTH (2-site immunoradiometric assay) increased significantly [maximal increases of 26% (P less than 0.002) and 36% (P less than 0.004), respectively] after 4 weeks of consuming the test diet, and there was no change in the control group. In contrast to our 8-day study, plasma levels of 1,25-dihydroxyvitamin D did not change in either group. Our findings suggest that this common dietary pattern in young adult women causes persistent alterations in calcium-regulating hormones that could be unfavorable to achieving maximal positive bone balance.


Assuntos
Cálcio da Dieta/administração & dosagem , Dieta , Hormônio Paratireóideo/metabolismo , Fósforo/administração & dosagem , Adulto , Osso e Ossos/metabolismo , Cálcio/metabolismo , Cálcio da Dieta/metabolismo , Di-Hidroxicolecalciferóis/metabolismo , Feminino , Humanos , Minerais/metabolismo , Osteocalcina/metabolismo , Osteoporose/metabolismo , Osteoporose/prevenção & controle , Fósforo/metabolismo
9.
J Clin Invest ; 81(6): 1768-73, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2838521

RESUMO

The prevention of neonatal rickets by oral supplementation with vitamin D2 (ergocalciferol) has tended to obscure our ignorance of the natural mechanism by which young mammals receive an adequate supply of vitamin D. To investigate the possibility of specific intrauterine transfer and storage of vitamin D in fetal tissues, vitamin D-deficient female rats were given depot injections of 3H- or 14C-labeled vitamin D3 (cholecalciferol) before mating and the 3H-labeled animals were killed at stages during the last third of gestation. Analysis of lipid extracts from whole fetuses revealed a linear increase in the concentration of 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and D3 itself between days 14 and 19 of gestation. During this period the elimination half-time of 3H-labeled molecules in maternal plasma fell from 27.1 to 4.4 d, suggesting that a specific mechanism was transferring vitamin D molecules into the fetuses. The vitamin was stored predominantly as 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3, with the highest concentrations in fetal muscle. Immediately after birth, pups from 3H- and 14C-labeled mothers were exchanged and later killed after 1-3 wk of suckling. Analysis of total lipid extracts for 3H and 14C content determined the relative contributions of vitamin D supplied before birth via the placenta and after birth in the maternal milk. The vitamin D content of the rat milk was relatively high, between 1.0 and 3.5 micrograms/liter. Nevertheless, the supply of vitamin D in utero, rather than from milk, was the main determinant of vitamin D status in early neonatal life. This is the first indication in a mammal of a specific transfer mechanism that allows the fetus to accumulate vitamin D from the mother during the last third of gestation.


Assuntos
Colecalciferol/metabolismo , Feto/metabolismo , Troca Materno-Fetal , Leite/análise , Vitamina D/metabolismo , 24,25-Di-Hidroxivitamina D 3 , Animais , Animais Recém-Nascidos , Calcifediol/análise , Calcifediol/sangue , Calcifediol/metabolismo , Colecalciferol/administração & dosagem , Colecalciferol/análise , Colecalciferol/sangue , Di-Hidroxicolecalciferóis/análise , Di-Hidroxicolecalciferóis/sangue , Di-Hidroxicolecalciferóis/metabolismo , Desenvolvimento Embrionário e Fetal , Feminino , Feto/análise , Gravidez , Ratos , Vitamina D/análise , Vitamina D/sangue
10.
Jpn J Psychiatry Neurol ; 40(1): 57-60, 1986 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-3773353

RESUMO

Plasma 25-hydroxyvitamin D (25-OH D), 1,25-dihydroxyvitamin D (1,25-(OH)2 D) and parathyroid hormone (PTH) concentrations were determined in 30 outpatients receiving various antiepileptic drugs (AED). None of the patients exhibited high plasma PTH levels. The plasma 1,25-(OH)2 D levels were normal or high, although in a third of the patients the 25-OH D levels were reduced. There was a correlation between the 25-OH D and serum calcium levels. These findings suggest that the low plasma concentrations of 25-OH D, not 1,25-(OH)2 D, might play an important part in the occurrence of AED-induced disturbances of bone metabolism.


Assuntos
Anticonvulsivantes/administração & dosagem , Di-Hidroxicolecalciferóis/sangue , Epilepsia/tratamento farmacológico , Adolescente , Adulto , Idoso , Fosfatase Alcalina/sangue , Cálcio/sangue , Di-Hidroxicolecalciferóis/metabolismo , Combinação de Medicamentos , Epilepsia/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue
12.
Bone ; 7(5): 331-6, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3539155

RESUMO

Vitamin D metabolism is altered in the pregnant animal, presumably in response to fetal demands for calcium. Circulating levels of 1,25-dihydroxyvitamin D are elevated in the pregnant animal. The stimulus of this increase and the hydroxylase(s) (placental or renal) responsible are unknown. Maternal plasma 25-hydroxyvitamin D levels have been reported to be both unchanged and decreased during pregnancy but very much dependent upon exposure to ultraviolet light and vitamin D supplementation. The major vitamin D metabolites (25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D) circulate in fetal plasma but generally at lower concentrations than in the mother (exception is the sheep). All of these metabolites are able to cross the placenta. The fetal kidney and placenta both have 25-hydroxyvitamin D1 alpha- and 24-hydroxylase activity. However, the relative contribution of mother, fetus, and placenta to fetal vitamin D metabolism has yet to be fully determined.


Assuntos
Prenhez/metabolismo , Gravidez/metabolismo , Vitamina D/metabolismo , Animais , Calcifediol/metabolismo , Calcitriol/metabolismo , Di-Hidroxicolecalciferóis/metabolismo , Feminino , Feto/metabolismo , Humanos , Recém-Nascido
13.
Am J Cardiol ; 56(16): 68H-74H, 1985 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-2866707

RESUMO

The renin-angiotensin-aldosterone system regulates blood pressure and volume homeostasis in addition to sodium and potassium metabolism, and may be linked to divalent cation metabolism as well as hypertensive disease. In essential hypertension, circulating serum magnesium and Ca++, and the calcium regulating hormones, parathyroid hormone, calcitonin and 1,25 dihydroxyvitamin (1,25D) are different in the various renin subgroups. Elevated blood pressure induced by such maneuvers as dietary salt loading is associated with exacerbations of these calcium metabolic deviations, and appears related to salt-induced changes in serum Ca++ or 1,25D levels. Short- or longer-term lowering of blood pressure with the calcium-channel blocker, nifedipine, or with calcium or magnesium supplementation is associated with a shift of renin system activity and calcium metabolic indexes back to average normotensive values in those subjects most susceptible to these hypotensive agents. These observations suggest that deviations in calcium metabolism in essential hypertension may be related to the pathophysiology of the hypertensive process. Further, renin system activity and calcium metabolic indexes such as serum Ca++ levels may help target specific subgroups of hypertensive populations most susceptible to various dietary or drug maneuvers, and thus may provide a basis to better understand and treat clinical hypertension.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Cálcio/metabolismo , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina , Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina , Animais , Pressão Sanguínea , Calcitonina/metabolismo , Dieta Hipossódica , Di-Hidroxicolecalciferóis/metabolismo , Diuréticos/uso terapêutico , Humanos , Hipertensão/dietoterapia , Hipertensão/metabolismo , Magnésio/metabolismo , Hormônio Paratireóideo/metabolismo , Cloreto de Sódio/administração & dosagem
14.
J Clin Invest ; 76(1): 370-3, 1985 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2991340

RESUMO

Serum immunoreactive parathyroid hormone (PTH) is increased in obese as compared with nonobese subjects and declines with weight loss. To determine whether alteration of the vitamin D-endocrine system occurs in obesity and whether ensuing secondary hyperparathyroidism is associated with a reduction in urinary calcium, a study was performed in 12 obese white individuals, five men and seven women, and 14 nonobese white subjects, eight men and six women, ranging in age from 20 to 35 yr. Body weight averaged 106 +/- 6 kg in the obese and 68 +/- 2 kg in the nonobese subjects (P less than 0.01). Each of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium and 900 mg of phosphorus. Whereas mean serum calcium, serum ionized calcium, and serum phosphorus were the same in the two groups, mean serum immunoreactive PTH (518 +/- 48 vs. 243 +/- 33 pg/ml, P less than 0.001), mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] (37 +/- 2 vs. 29 +/- 2, P less than 0.01), and mean serum Gla protein (33 +/- 2 vs. 24 +/- 2 ng/ml, P less than 0.02) were significantly higher, and mean serum 25-hydroxyvitamin D (25-OHD) (8 +/- 1 vs. 20 +/- 2 ng/ml, P less than 0.001) was significantly lower in the obese than in the nonobese men and women. Mean urinary phosphorus was the same in the two groups, whereas mean urinary calcium (115 +/- 10 vs. 166 +/- 13 mg/d, P less than 0.01) was significantly lower, and mean urinary cyclic AMP (3.18 +/- 0.43 vs. 1.84 +/- 0.25 nM/dl GF, P less than 0.01) and creatinine clearance (216 +/- 13 vs. 173 +/- 6 liter/d, P less than 0.01) were significantly higher in the obese than in the nonobese individuals. There was a significant positive correlation between percentage of ideal body weight and urinary cyclic AMP (r = 0.524, P less than 0.01) and between percentage of ideal body weight and serum immunoreactive PTH (r = 0.717, P less than 0.01) in the two groups. The results provide evidence that alteration of the vitamin D-endocrine system in obese subjects is characterized by secondary hyperparathyroidism which is associated with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D. The reduction of serum 25-OHD in them is attributed to feedback inhibition of hepatic synthesis of the precursor by the increased serum 1,25(OH)2D.


Assuntos
Obesidade/metabolismo , Hormônio Paratireóideo/sangue , Vitamina D/metabolismo , Adulto , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/sangue , AMP Cíclico/urina , Di-Hidroxicolecalciferóis/metabolismo , Feminino , Humanos , Magnésio/metabolismo , Masculino , Osteocalcina , Fósforo/metabolismo , Potássio/metabolismo , Sódio/metabolismo
15.
Arch Biochem Biophys ; 234(1): 97-104, 1984 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-6091567

RESUMO

Tritium-labeled 24,25-dihydroxyvitamin D3 was prepared both in vitro, by using chick kidney homogenates, and in vivo in rats from [26,27-methyl-3H]25-hydroxyvitamin D3. These compounds were mixed with synthetic 24(R),25- and 24(S),25-dihydroxyvitamin D3, converted to the corresponding trimethylsilyl ether derivatives, and analyzed by a high-pressure liquid chromatography procedure that separates the derivatized isomers. The tritium-labeled 24,25-dihydroxyvitamin D3 derivatives were found to be a mixture of both the 24(R) and 24(S) epimers; the ratio was found to be 96.4:3.6 in chick kidney homogenates and 96.8:3.2 in the serum of rats under physiological conditions. In addition, nonradioactive 24,25-dihydroxyvitamin D3 isolated from the serum of rats given large doses of vitamin D3 was shown to be an 89.5:10.5 mixture of the 24(R) and 24(S) isomers. When 25-hydroxy-24-oxo-vitamin D3 was utilized as a substrate, it was found to be more selectively reduced to 24(S),25-dihydroxyvitamin D3 than 24(R),25-dihydroxyvitamin D3 by the renal enzyme. The 24(S),25-dihydroxyvitamin D3 has been identified by ultraviolet absorption spectrophotometry, cochromatography with an authentic standard, and mass spectrometry. The reduced metabolites of 25-hydroxy-24-oxo-vitamin D3 were a 1:50 mixture of the 24(R) and 24(S) epimers. There are two known metabolic pathways leading to 24,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3; one is 24(R)-hydroxylation of 25-hydroxyvitamin D3 and the other is reduction of 25-hydroxy-24-oxo-vitamin D3. In contrast, 24(S),25-dihydroxyvitamin D3 is produced only by reduction of 25-hydroxy-24-oxo-vitamin D3 in the kidney. Therefore, naturally occurring 24,25-dihydroxyvitamin D3 is a mixture of the 24(R) and 24(S) isomers, and not just the 24(R) isomer as reported previously.


Assuntos
Di-Hidroxicolecalciferóis , 24,25-Di-Hidroxivitamina D 3 , Animais , Galinhas , Colecalciferol/metabolismo , Cromatografia Líquida de Alta Pressão , Di-Hidroxicolecalciferóis/sangue , Di-Hidroxicolecalciferóis/isolamento & purificação , Di-Hidroxicolecalciferóis/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Espectrometria de Massas , Ratos , Ratos Endogâmicos , Análise Espectral , Estereoisomerismo , Compostos de Trimetilsilil/análise
16.
Biochemistry ; 23(16): 3749-54, 1984 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-6332645

RESUMO

By cochromatography, mass spectrometry, and chemical derivatization, we have shown that a metabolite isolated from the perfused rat kidney incubated with 24-(R),25-dihydroxyvitamin D3 is indistinguishable from chemically synthesized 24,25,26,27-tetranor-23-hydroxyvitamin D3. The new metabolite is also produced from 24-oxo-25-hydroxyvitamin D3 but not from 23(S),25-dihydroxyvitamin D3. Enzymes required for the synthesis of the new metabolite are absent in the vitamin D deplete animal but are induced along with the 25-hydroxyvitamin-D3 24-hydroxylase by vitamin D repletion. The pathway of 24,25-dihydroxyvitamin D3 metabolism in the perfused kidney is stimulated by pre-treatment of the rat with large doses of vitamin D3, suggesting that the pathway is a degradative one.


Assuntos
Di-Hidroxicolecalciferóis/metabolismo , Hidroxicolecalciferóis/isolamento & purificação , Rim/metabolismo , 24,25-Di-Hidroxivitamina D 3 , Animais , Cromatografia Líquida de Alta Pressão , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Perfusão , Ratos , Ratos Endogâmicos , Espectrofotometria
17.
Cell Calcium ; 5(1): 43-55, 1984 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-6608994

RESUMO

The effect of the X-linked Hyp mutation on 25-hydroxyvitamin D3 (25-OH-D3) metabolism in mouse renal cortical slices was investigated. Vitamin D replete normal mice and Hyp littermates fed the control diet synthesized primarily 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3); only minimal synthesis of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was detected in both genotypes and 1,25-(OH)2D3 formation was not significantly greater in Hyp mice relative to normal littermates, despite hypophosphatemia and hypocalcemia in the mutants. Calcium-deficient diet fed to normal mice reduced serum calcium (p less than 0.01), increased renal 25-hydroxyvitamin D3-1-hydroxylase (1-OHase) activity (p less than 0.05), and decreased 25-hydroxyvitamin D3-24-hydroxylase (24-OHase) activity (p less than 0.05). In contrast, Hyp littermates on the calcium-deficient diet had decreased serum calcium (p less than 0.01), without significant changes in the renal metabolism of 25-OH-D3. Both normal and Hyp mice responded to the vitamin D-deficient diet with a fall in serum calcium (p less than 0.01), significantly increased renal 1-OHase, and significantly decreased renal 24-OHase activities. In Hyp mice, the fall in serum calcium on the vitamin D-deficient diet was significantly greater than that observed on the calcium-deficient diet. Therefore the ability of Hyp mice to increase renal 1-OHase activity when fed the vitamin D-deficient diet and their failure to do so on the calcium-deficient diet may be related to the resulting degree of hypocalcemia. The results suggest that although Hyp mice can respond to a disturbance of calcium homeostasis, the in vivo signal for the stimulation of renal 1-OHase activity may be set at a different threshold in the Hyp mouse; i.e. a lower serum calcium concentration is necessary for Hyp mice to initiate increased synthesis of 1,25(-OH)2D3.


Assuntos
Calcifediol/metabolismo , Cálcio/sangue , Hipofosfatemia Familiar/metabolismo , Rim/metabolismo , 24,25-Di-Hidroxivitamina D 3 , Animais , Calcitriol/metabolismo , Dieta , Di-Hidroxicolecalciferóis/metabolismo , Feminino , Técnicas In Vitro , Córtex Renal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fósforo/sangue , Deficiência de Vitamina D/metabolismo , Cromossomo X
18.
Arch Biochem Biophys ; 228(1): 179-84, 1984 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-6546486

RESUMO

To elucidate the biosynthesis of 25-hydroxyvitamin D3-26,23-lactone, various vitamin D3 derivatives were incubated individually with kidney homogenates prepared from vitamin D3-supplemented chicks, a preparation known to produce the 25-hydroxyvitamin D3-26,23-lactone from 25-hydroxyvitamin D3. The 25-hydroxyvitamin D3-26, 23-lactone produced in vitro was then separated, purified, identified, and quantitated by consecutive analysis by high-pressure liquid chromatography. The naturally occurring 23(S), 25(R)-25-hydroxyvitamin D3-26,23-lactone was produced from 23(S),25-dihydroxyvitamin D3, 25(R),26-dihydroxyvitamin D3, and 23(S),25(R),26-trihydroxyvitamin D3. 23(S),25 (S)-25-Hydroxyvitamin D3-26,23-lactone was synthesized from 25(S),26-dihydroxyvitamin D3 and 23(S),25(S),26-trihydroxyvitamin D3. The relative amounts of 25-hydroxyvitamin D3-26,23-lactones generated from the following vitamin D3 derivatives used as substrate (23(S),25(S),26-trihydroxyvitamin D3; 23(R),25(R),26-trihydroxyvitamin D3; 23(S),25(R),26-trihydroxyvitamin D3; 23(R),25(S),26-trihydroxyvitamin D3; 23(S), 25-dihydroxyvitamin D3; 23(R),25-dihydroxyvitamin D3; 25(S),26-dihydroxyvitamin D3; and 25(R),26-dihydroxyvitamin D3) are, respectively, 15:1.7:24:3.3:2.5:0:1:1.7. These results indicate that when the lactonization at C-23 and C-26 positions of various vitamin D3 derivatives occurred the stereochemical configuration at their C-23 and/or C-25 positions was not changed and the difference of the stereochemical configurations determined the rate of lactonization.


Assuntos
Calcifediol/análogos & derivados , Calcitriol/farmacologia , Hidroxicolecalciferóis/metabolismo , Rim/metabolismo , Animais , Calcifediol/biossíntese , Galinhas , Cromatografia Líquida de Alta Pressão , Di-Hidroxicolecalciferóis/metabolismo , Masculino , Conformação Molecular , Estereoisomerismo
20.
Horm Metab Res ; 15(8): 399-403, 1983 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6311708

RESUMO

The conversion of 25-hydroxyvitamin D3 (25 OH D3) to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) and 1,24,25-trihydroxyvitamin D3 (1.24,25-(OH)3D3) was studied in renal tubules prepared from chicks raised on a vitamin D deficient diet with or without vitamin D supplementation. As described previously, in tubules from vitamin D deficient chicks, cyclic AMP caused an increase in the net accumulation of 1,25-(OH)2D3, the major metabolite formed under these circumstances. This stimulation was shown to be due to an increased maximum velocity of the hydroxylation reaction. There was also a significant inhibition of the net accumulation of 24,25-(OH)2D3. Cyclic GMP caused a significant inhibition of 1,25-(OH)2D3 formation and stimulation of the net accumulation of 24,25-(OH)2D3. In chicks supplemented with high doses of vitamin D, 24,25-(OH)2D3 was the major metabolite of 25 OH D3 detected and 1-hydroxylase activity was negligible. Under these circumstances, neither cyclic AMP nor cyclic GMP affected net accumulation of 24,25(OH)2D3. This suggested that the apparent effect of the nucleotides on formation of 24,25-(OH)2D3 may have been due to further metabolism of 24,25-(OH)2D3 when 1-hydroxylase activity was high. It is concluded that cyclic AMp and cyclic GMP have reciprocal effects on renal 25 OH D3-1-hydroxylase activity, and both should be considered potential intracellular regulators of 25 OH D3 metabolism.


Assuntos
Calcifediol/metabolismo , AMP Cíclico/farmacologia , GMP Cíclico/farmacologia , Túbulos Renais/metabolismo , 24,25-Di-Hidroxivitamina D 3 , Animais , Calcitriol/metabolismo , Galinhas , Di-Hidroxicolecalciferóis/metabolismo , Hidroxicolecalciferóis/metabolismo , Túbulos Renais/efeitos dos fármacos , Masculino , Deficiência de Vitamina D/metabolismo
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