RESUMEN
VD3 is a crucial vitamin for human health, as it enhances calcium absorption in the intestines and prevent rickets. Calcifediol (25(OH)VD3) and calcitriol (1α,25(OH)2VD3) are two derivatives of vitamin D3 that play an important role in preventing and treating osteoporosis, as well as regulating human physiological functions. Currently, the production of calcifediol, and calcitriol primarily relies on chemical synthesis, which has disadvantages such as low product yield, numerous by-products, and environmental unfriendliness. Therefore, developing a green, safe, and environmentally friendly biocatalytic synthesis pathway is of utmost importance. This article mainly reviews the biocatalytic synthesis pathways of calcifediol, and calcitriol. The P450 enzymes, including P450 monooxygenases (cytochrome P450 monooxygenases, CYPs) and P450 peroxygenases (unspecific peroxygenases, UPOs), are crucial for the production of calcifediol and calcitriol. The catalytic mechanism of the extensively studied P450 monooxygenases, the selection of suitable redox partners, and the key residues involved in the enzyme's catalytic activity are analyzed. In addition, the review explores H2O2-driven UPOs, including their catalytic mechanism, strategies for high heterologous expression, and in situ regeneration of H2O2. UPOs are regarded as highly promising biocatalysts because they can facilitate reactions without the need for expensive cofactors and redox partners. This review offers insights into the engineering of P450 for the efficient production of vitamin D3 derivatives.
Asunto(s)
Calcifediol , Calcitriol , Sistema Enzimático del Citocromo P-450 , Calcitriol/metabolismo , Calcitriol/biosíntesis , Sistema Enzimático del Citocromo P-450/metabolismo , Calcifediol/metabolismo , Calcifediol/biosíntesis , Humanos , BiocatálisisRESUMEN
Hypercalcaemia of malignancy (HCM) is a paraneoplastic syndrome that often portends a poor prognosis. We present an extremely rare (<1%) case of HCM due to extrarenal calcitriol (1,25-(OH)2D) production in a patient with splenic marginal zone lymphoma. A man in his 80s presented with a 3-week history of fatigue, unsteadiness and abdominal pain, and new findings of anaemia, kidney injury and hypercalcaemia. Laboratory evaluation, bone marrow biopsy and positron emission tomography/computed tomography (PET/CT) confirmed the diagnosis of splenic marginal zone lymphoma which produced calcitriol (1,25-(OH)2D3), causing the patient's hypercalcaemia.
Asunto(s)
Hipercalcemia , Síndromes Paraneoplásicos , Vitamina D , Humanos , Masculino , Calcitriol/biosíntesis , Ergocalciferoles , Hipercalcemia/etiología , Hipercalcemia/diagnóstico , Linfoma/complicaciones , Linfoma/diagnóstico , Síndromes Paraneoplásicos/complicaciones , Tomografía Computarizada por Tomografía de Emisión de Positrones , Vitamina D/efectos adversos , Anciano de 80 o más AñosRESUMEN
Friedreich ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here, we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1 (FDX1), a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both FDX1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction in apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.
Asunto(s)
Calcitriol/farmacología , Ferredoxinas/metabolismo , Ataxia de Friedreich/metabolismo , Proteínas de Unión a Hierro/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neuronas/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Apoptosis/efectos de los fármacos , Calcitriol/biosíntesis , Calcitriol/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Humanos , Proteínas de Microfilamentos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Vitamina D/metabolismo , FrataxinaRESUMEN
Hypercalcaemia in malignancy is most commonly caused by paraneoplastic secretion of parathyroid hormone-related protein or osteolytic metastases. Very rarely (<1% of cases), the mechanism behind increased serum calcium is increased production of calcitriol (1,25-dihydroxyvitamin D) and even rarer is the occurrence of this phenomenon in solid malignancies, with few such instances reported in the literature. We present a case of a neuroendocrine malignancy originating in the oesophagus associated with calcitriol-induced hypercalcaemia, a phenomenon that has not been previously described. We review the pathophysiology of calcitriol-induced hypercalcaemia and previously reported cases of solid tumours with this presentation.
Asunto(s)
Calcitriol/biosíntesis , Carcinoma Neuroendocrino/metabolismo , Neoplasias Esofágicas/metabolismo , Hipercalcemia/etiología , Calcitriol/fisiología , Carcinoma Neuroendocrino/secundario , Neoplasias Esofágicas/patología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
This review explores the relationship between vitamin D supplementation and lithogenesis. A causal relationship has been assumed despite myriad studies demonstrating that therapeutic doses of vitamin D do not increase lithogenic risk. Select stone formers may be at increased risk for recurrence with vitamin D supplementation, possibly from CYP24A1 gene mutations. Additionally, the evidence for who is vitamin D deficient, and the benefits of supplementation in those not at risk for rickets, is sparse. Concerns may be avoidable as vitamin D screening appears unnecessary in most patients, and superior pharmacology is available which increases bone density, while decreasing stone formation.
Asunto(s)
Calcio/efectos adversos , Suplementos Dietéticos/efectos adversos , Cálculos Renales/etiología , Vitamina D/efectos adversos , Vitaminas/efectos adversos , Animales , Densidad Ósea/efectos de los fármacos , Calcitriol/biosíntesis , Calcitriol/metabolismo , Calcio/administración & dosificación , Calcio/metabolismo , Estudios de Cohortes , Difosfonatos/uso terapéutico , Femenino , Humanos , Absorción Intestinal , Cálculos Renales/química , Cálculos Renales/prevención & control , Masculino , Mutación , Hormona Paratiroidea/sangre , Ratas , Receptores de Calcitriol/genética , Tiazidas/uso terapéutico , Vitamina D/administración & dosificación , Vitamina D/metabolismo , Deficiencia de Vitamina D/terapia , Vitamina D3 24-Hidroxilasa/genética , Vitamina D3 24-Hidroxilasa/metabolismo , Vitaminas/administración & dosificación , Vitaminas/metabolismoRESUMEN
Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)2D3 synthesis on vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)2D3 synthesis was essential for vitamin D3-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4+ Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D3 reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)2D3 production and CTLA-4 upregulation in CNS-infiltrating CD4+ T cells. We suggest that CTLA-4 serves as a vitamin D3-regulated immunological checkpoint in multiple sclerosis prevention.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4/análisis , Calcitriol/biosíntesis , Colecalciferol/farmacología , Encefalomielitis Autoinmune Experimental/prevención & control , Macrófagos/metabolismo , Microglía/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Animales , Antígeno B7-2/análisis , Antígeno CTLA-4/fisiología , Modelos Animales de Enfermedad , Femenino , Ratones , Esclerosis Múltiple/prevención & control , Elemento de Respuesta a la Vitamina D/fisiologíaRESUMEN
We have reported that 25-hydroxyvitamin D3 [25(OH)D3] binds to vitamin D receptor and exhibits several biological functions directly in vitro. To evaluate the direct effect of 25(OH)D3 in vivo, we used Cyp27b1 knockout (KO) mice, which had no detectable plasma 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] when fed a diet containing normal Ca and vitamin D. Daily treatment with 25(OH)D3 at 250 µg kg-1 day-1 rescued rachitic phenotypes in the Cyp27b1 KO mice. Bone mineral density, female sexual cycles, and plasma levels of Ca, P, and PTH were all normalized following 25(OH)D3 administration. An elevated Cyp24a1 mRNA expression was observed in the kidneys, and plasma concentrations of Cyp24a1-dependent metabolites of 25(OH)D3 were increased. To our surprise, 1,25(OH)2D3 was detected at a normal level in the plasma of Cyp27b1 KO mice. The F1 to F4 generations of Cyp27b1 KO mice fed 25(OH)D3 showed normal growth, normal plasma levels of Ca, P, and parathyroid hormone, and normal bone mineral density. The curative effect of 25(OH)D3 was considered to depend on the de novo synthesis of 1,25(OH)2D3 in the Cyp27b1 KO mice. This suggests that another enzyme than Cyp27b1 is present for the 1,25(OH)2D3 synthesis. Interestingly, the liver mitochondrial fraction prepared from Cyp27b1 KO mice converted 25(OH)D3 to 1,25(OH)2D3. The most probable candidate is Cyp27a1. Our findings suggest that 25(OH)D3 may be useful for the treatment and prevention of osteoporosis for patients with chronic kidney disease.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Conservadores de la Densidad Ósea/farmacología , Calcifediol/farmacología , Calcitriol/biosíntesis , Calcitriol/sangre , Raquitismo/tratamiento farmacológico , Animales , Densidad Ósea/efectos de los fármacos , Calcitriol/genética , Calcio/sangre , Colestanotriol 26-Monooxigenasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoporosis/tratamiento farmacológico , Hormona Paratiroidea/sangre , Fósforo/sangre , Vitamina D3 24-Hidroxilasa/biosíntesis , Vitamina D3 24-Hidroxilasa/genéticaRESUMEN
Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORSKC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL. Concomitantly, specific inhibitors were applied to analyze the inhibition of the VD3 processing cytochrome P450 isoenzyme family by TKIs. In vitro, IMA and NIL significantly impaired the production of calcitriol in HaCaT and cultured ORSKC cells from hair follicles of IMA treated children. For NIL, this inhibitory effect demonstrated a 4fold increase. In HaCaT and ORSKC, application of specific CYP450 inhibitors revealed that CYP27B1 was impaired by IMA and NIL leading to an intracellular accumulation of calcidiol. However, during TKI treatment, KC of IMA treated children revealed no differences in calcidiol and calcitriol levels. In conclusion, IMA and NIL interfere with the vitamin D3 cascade due to their metabolism by CYP27B1.
Asunto(s)
Colecalciferol/metabolismo , Mesilato de Imatinib/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Calcitriol/biosíntesis , Línea Celular , HumanosRESUMEN
The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)2D3 (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA-specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1 Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell-specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/fisiología , Calcitriol/inmunología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/sangre , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/deficiencia , Animales , Linfocitos B/inmunología , Médula Ósea/inmunología , Calcitriol/biosíntesis , Calcitriol/deficiencia , Femenino , Helmintiasis Animal/inmunología , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Parasitosis Intestinales/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nematospiroides dubius/inmunología , Especificidad de Órganos , Ovalbúmina/inmunología , Receptores de Calcitriol/fisiología , Bazo/inmunología , Linfocitos T/inmunología , Deficiencia de Vitamina D/inmunologíaRESUMEN
BACKGROUND: Effects of vitamin D deficiency in pregnancy have been associated with some adverse pregnancy outcomes. The 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1) is integral to the vitamin D metabolic pathway. The enzyme catalyzes localized conversion of pro-hormone 25-hydroxyvitamin D3 to active 1,25-dihydroxyvitamin D3. Our aim was to investigate the expression of CYP27B1 at the fetal-maternal interface in the first trimester pregnancy and to determine whether CYP27B1 was associated with recurrent miscarriage (RM). METHODS: Expressions of CYP27B1 mRNA and protein in villi and decidua from 20 women undergoing primary miscarriage, 20 women with RM and 20 women with normal pregnancy were evaluated by western blot, and quantitative real-time PCR. The co-localization of CYP27B1 and certain cytokines including IL-10, IFN-γ, TNF-α, and IL-2 expression were examined using immunohistochemistry and confocal microscopy. RESULTS: Women with RM had a significantly lower expression of CYP27B1 mRNA and protein in villous and decidual tissues compared with the normal pregnant women (P = 0.000 in villus, P = 0.002 in decidua for mRNA; P = 0.036 in villus, P = 0.007 in decidua for protein.). Compared with the normal pregnancy, immunostaining for CYP27B1 was significantly decreased in villous trophoblasts and decidual glandular epithelial cells in RM women. No significant differences in the localization of CYP27B1, IL-10, IFN-γ, TNF-α, and IL-2 expression were identified between the normal pregnant and RM women. CONCLUSIONS: Women with RM have a lower level of CYP27B1 expression in chorionic villi and decidua compared with normal pregnant women, suggesting that reduced CYP27B1 expression may be associated with RM. The consistent localization of CYP27B1 and IL-10, IFN-γ, TNF-α, and IL-2 expression in villous and decidual tissues suggests the importance of the local production of 1,25(OH)2D3 at the fetal-maternal interface to regulate cytokine responses.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Aborto Habitual/patología , Vellosidades Coriónicas/metabolismo , Decidua/metabolismo , Hemorragia Uterina/patología , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/biosíntesis , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Adulto , Calcitriol/biosíntesis , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Embarazo , ARN Mensajero/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo , Deficiencia de Vitamina D/patologíaRESUMEN
Calcitroic acid was isolated and characterized almost four decades ago, but little is known about this important vitamin D metabolite. Four reported synthetic strategies to generate calcitroic acid are presented that highlight the scientific progress in the field of chemistry directed to vitamin D analog synthesis. The most recent synthesis described the generation of calcitroic acid with an overall yield of 12.8% in 13 steps. The endogenous formation of calcitroic acid has been demonstrated in perfused rat kidney using 24,25,26,27-tetranor-1,23(OH)2D3. Although, the majority of vitamin D metabolism is mediated by 24-hydoxylase (CYP24A1), it is not clear why the formation of calcitroic acid was not observed in the presence of recombinant CYP24A1 enzyme. Furthermore, it is not known if enzyme 1α-hydroxylase (CYP27B1) can convert calcioic acid into calcitroic acid. In addition to the lack of research investigating the endogenous formation of calcitroic acid, the physiological role of calcitroic acid remains unknown. Only a few reports mentioned the biological activity of calcitroic acid in connection with the vitamin D receptor (VDR). When administered subcutaneously, calcitroic acid has anthracitic properties and elevates calcium blood levels when administered intravenously. In vitro, calcitroic acid at higher concentrations has been shown to bind VDR and induce gene transcription. However, these studies were not carried out in cells derived from target organs of calcitroic acid such as kidney, liver, and intestine. We can conclude that our current knowledge of calcitroic acid is limited, and more studies are needed to identify its physiological role.
Asunto(s)
Calcitriol/análogos & derivados , Animales , Calcitriol/biosíntesis , Calcitriol/química , HumanosRESUMEN
Biologically active vitamin D (1,25-dihydroxycholecalciferol or 1,25(OH)2D) is synthetized from inactive prohormone 25-hydroxycholecalciferol (25(OH)D) by the enzyme CYP27B1 1-α-hydroxylase in kidney and several extrarenal tissues including breast. Although the development of breast cancer has been linked to inadequate vitamin D status, the importance of bioactive vitamin D production within tumors themselves is not fully understood. To investigate the role of tumoral vitamin D production in mammary epithelial cell progression to breast cancer, we conducted a Cre-loxP-mediated Cyp27b1 gene ablation in the mammary epithelium of the polyoma middle T antigen-mouse mammary tumor virus (PyMT-MMTV) mouse breast cancer model. Targeted ablation of Cyp27b1 was accompanied by significant acceleration in initiation of spontaneous mammary tumorigenesis. In vivo, cell proliferation, angiogenesis, cell cycle progression, and survival markers were up-regulated in tumors by Cyp27b1 ablation, and apoptosis was decreased. AK thymoma (AKT) phosphorylation and expression of several components of nuclear factor κB (NF-κB), integrin, and signal transducer and activator of transcription 3 (STAT3) signaling pathways were increased in Cyp27b1-ablated tumors compared with nonablated controls. In vitro, 1,25(OH)2D treatment induced a strong antiproliferative action on tumor cells from both ablated and nonablated mice, accompanied by rapid disappearance of NF-κB p65 from the nucleus and segregation in the cytoplasm. In contrast, treatment with the metabolic precursor 25(OH)D was only effective against cells from nonablated mice. 25(OH)D did not inhibit growth of Cyp27b1-ablated cells, and their nuclear NF-κB p65 remained abundant. Our findings demonstrate that in-tumor CYP27B1 1-α-hydroxylase activity plays a crucial role in controlling early oncogene-mediated mammary carcinogenesis events, at least in part by modulating tumoral cell NF-κB p65 nuclear translocation.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , FN-kappa B/metabolismo , Vitamina D/biosíntesis , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Animales , Apoptosis/genética , Apoptosis/fisiología , Calcifediol/biosíntesis , Calcifediol/sangre , Calcitriol/biosíntesis , Calcitriol/sangre , Calcio/sangre , Proliferación Celular/genética , Proliferación Celular/fisiología , Progresión de la Enfermedad , Femenino , Inmunohistoquímica , Técnicas In Vitro , Masculino , Neoplasias Mamarias Animales/sangre , Neoplasias Mamarias Animales/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Transducción de Señal/genética , Transducción de Señal/fisiología , Células Tumorales Cultivadas , Vitamina D/sangreRESUMEN
Autosomal dominant hypophosphatemic rickets(ADHR)is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage. Fibroblast growth factor 23(FGF23)is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. Low iron status plays a role in the pathophysiology of ADHR. Iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. It was reported that FGF23 elevation in patients with CKD, who are often iron deficient. In patients with nondialysis-dependent CKD, treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and FGF23.
Asunto(s)
Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/fisiología , Deficiencias de Hierro , Hierro/fisiología , Fosfatos/metabolismo , Biomarcadores/sangre , Calcitriol/biosíntesis , Raquitismo Hipofosfatémico Familiar/diagnóstico , Raquitismo Hipofosfatémico Familiar/genética , Raquitismo Hipofosfatémico Familiar/metabolismo , Compuestos Férricos/farmacología , Compuestos Férricos/uso terapéutico , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Riñón/metabolismo , Mutación , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismoRESUMEN
Vitamin D has garnered a great deal of attention in recent years due to a global prevalence of vitamin D deficiency associated with an increased risk of a variety of human diseases. Specifically, hypovitaminosis D in pregnant women is highly common and has important implications for the mother and lifelong health of the child, since it has been linked to maternal and child infections, small-for-gestational age, preterm delivery, preeclampsia, gestational diabetes, as well as imprinting on the infant for life chronic diseases. Therefore, factors that regulate vitamin D metabolism are of main importance, especially during pregnancy. The hormonal form and most active metabolite of vitamin D is calcitriol. This hormone mediates its biological effects through a specific nuclear receptor, which is found in many tissues including the placenta. Calcitriol synthesis and degradation depend on the expression and activity of CYP27B1 and CYP24A1 cytochromes, respectively, for which regulation is tissue specific. Among the factors that modify these cytochromes expression and/or activity are calcitriol itself, parathyroid hormone, fibroblast growth factor 23, cytokines, calcium and phosphate. This review provides a current overview on the regulation of vitamin D metabolism, focusing on vitamin D deficiency during gestation and its impact on pregnancy outcomes.
Asunto(s)
Calcitriol/biosíntesis , Fenómenos Fisiologicos Nutricionales Maternos , Resultado del Embarazo , Deficiencia de Vitamina D/sangre , Calcio/sangre , Citocinas/sangre , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Metaanálisis como Asunto , Estudios Observacionales como Asunto , Hormona Paratiroidea/sangre , Fosfatos/sangre , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of the BCRABL1 fusion gene, a constitutively active, oncogenic tyrosine kinase that is responsible for the clinical features of CML. Tyrosine kinase inhibitors, such as imatinib, have markedly altered the treatment of CML. However, tyrosine kinase inhibitors are associated with side effects on bone metabolism, in adult and pediatric patients. Vitamin D3 is involved in the complex cycle of bone remodeling, therefore the present study aimed to investigate the influence of imatinib on vitamin D3 metabolism in the HaCaT human keratinocyte cell line, using commercially available enzyme assays. Imatinib was shown to significantly reduce the production of calcidiol and calcitriol. Based on interaction studies of imatinib with the cytochrome P450 (CYP450) inhibitors VID400 and ketoconazole, it is proposed that imatinib may interfere with the vitamin D3 cascade due to its metabolism by CYP27B1, which is involved in vitamin D3 metabolism.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Colecalciferol/biosíntesis , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Calcitriol/biosíntesis , Línea Celular , Humanos , Mesilato de Imatinib , Redes y Vías Metabólicas/efectos de los fármacosRESUMEN
Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1α-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild-type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1α-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by µCT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1α-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression thereby impacting on calcium and phosphate metabolism.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Densidad Ósea/fisiología , Calcitriol/biosíntesis , Quinasa de Punto de Control 2/metabolismo , Riñón/metabolismo , Animales , Western Blotting , Calcio/metabolismo , Ensayo de Inmunoadsorción Enzimática , Factor-23 de Crecimiento de Fibroblastos , Regulación de la Expresión Génica/fisiología , Glucuronidasa/metabolismo , Células HEK293 , Humanos , Proteínas Klotho , Ratones , Ratones Noqueados , Fosfatos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Microtomografía por Rayos XRESUMEN
Calcitriol, a powerful regulator of phosphate metabolism and immune response, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney and macrophages. Renal 1α-hydroxylase expression is suppressed by Klotho and FGF23, the expression of which is stimulated by calcitriol. Interferon γ (INFγ) regulates 1α-hydroxylase expression in macrophages through transcription factor interferon regulatory factor-1. INFγ-signaling includes Janus kinase 3 (JAK3) but a role of JAK3 in the regulation of 1α-hydroxylase expression and mineral metabolism has not been shown. Thus, the impact of JAK3 deficiency on calcitriol formation and phosphate metabolism was measured. Renal interferon regulatory factor-1 and 1α-hydroxylase transcript levels, serum calcitriol and FGF23 levels, intestinal phosphate absorption as well as absolute and fractional renal phosphate excretion were significantly higher in jak3 knockout than in wild-type mice. Coexpression of JAK3 increased the phosphate-induced current in renal sodium-phosphate cotransporter-expressing Xenopus oocytes. Thus, JAK3 is a powerful regulator of 1α-hydroxylase expression and phosphate transport. Its deficiency leads to marked derangement of phosphate metabolism.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Calcitriol/sangre , Janus Quinasa 3/metabolismo , Riñón/enzimología , Fosfatos/metabolismo , ARN Mensajero/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/análisis , Animales , Calbindinas/genética , Calcitriol/biosíntesis , Heces/química , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Factor 1 Regulador del Interferón/análisis , Factor 1 Regulador del Interferón/genética , Mucosa Intestinal/metabolismo , Janus Quinasa 3/deficiencia , Janus Quinasa 3/genética , Riñón/química , Masculino , Ratones , Ratones Noqueados , Oocitos/enzimología , Fosfatos/análisis , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Regulación hacia Arriba , XenopusRESUMEN
One century after its discovery, vitamin D has been shown to be, in fact, a pleiotropic steroid hormone, which, besides regulation of calcium homeostasis and bone turnover, has antiproliferative, prodifferentiation, antibacterial, immunomodulatory, and anti-inflammatory properties in various cells and tissues. D hormone (1α,25(OH)2 D), regulated in an endocrine, autocrine, and paracrine manner, must be bound to the specific nuclear vitamin D receptor (VDR) to exert epigenetic and genetic effects, acting as a connection between extracellular stimuli and genomic responses of the cells. Since only high doses of hormone, provoking hypercalcemia, can achieve immunomodulatory effects, more than 3000 VDR agonists have been synthesized. Numerous experimental trials have been performed in animal models, evidencing the preventive and therapeutic potential of VDR agonists for chronic inflammatory diseases and cancer. Considering the selective anti-inflammatory effects of VDR agonists compared to glucocorticoids, sparing microbicidal functions, the fear of hypercalcemia as their only frequent side effect becomes a questionable reason for the lack of clinical studies.
Asunto(s)
Antiinflamatorios/farmacología , Receptores de Calcitriol/agonistas , Animales , Antiinflamatorios/uso terapéutico , Calcitriol/biosíntesis , Epigénesis Genética , Humanos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/metabolismoRESUMEN
Abnormalities in chronic kidney disease-related bone and mineral metabolism (CKD-MBD) have emerged as novel risk factors in excess cardiovascular mortality in patients with CKD and end-stage renal disease (ESRD). The pathophysiological links between CKD-MBD and adverse cardiovascular events in this patient population are unclear. Hyperphosphatemia through induction of vascular calcifications and decreased active vitamin D production leading to activation of the renin angiotensin system (RAS) along with defects in innate immunity are purported to be the proximate cause of CKD-MBD-associated mortality in CKD. Recently, this view has been challenged by the observation that fibroblast growth factor-23 (FGF23), a newly discovered hormone produced in the bone that regulates phosphate and vitamin D metabolism by the kidney, is a strong predictor of adverse cardiovascular outcomes in patients with CKD and ESRD. Whether these associations between elevated circulating FGF23 levels and cardiovascular outcomes are causative, and if so, the mechanisms mediating the effects of FGF23 on the cardiovascular system are not clear. The principal physiological functions of FGF23 are mediated by activation of FGF receptor/α-klotho coreceptor complexes in target tissues. Elevated FGF23 has been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 may induce myocardial hypertrophy through a direct effect on cardiac myocytes. A direct 'off target' effect of FGF23 on LVH is controversial, however, since α-klotho (which is believed to be indispensable for the physiologic actions of FGF23) is not expressed in the myocardium. Another possibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' regulation of hormonal pathways in the kidney, which include suppression of angiotensin-converting enzyme 2, Cyp27b1and α-klotho, which would be predicted to act on circulating factors known to regulate RAS, 1,25(OH)2D production and ion transport in the myocardium. Understanding of FGF23's pathophysiology and mechanisms of action responsible for its negative effects will be necessary to develop therapeutic strategies to treat CKD-MBD.
Asunto(s)
Síndrome Cardiorrenal/etiología , Factores de Crecimiento de Fibroblastos/fisiología , Calcitriol/biosíntesis , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hipertrofia Ventricular Izquierda/etiología , Insuficiencia Renal Crónica/complicaciones , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Traditionally regarded as a typical vitamin regulating calcium and phosphorus homeostasis, vitamin D is now discovered as a highly versatile molecule with emerging roles in immunity, cancer, infectious diseases, fibrosis, fatty liver diseases, and alcoholic liver diseases. A large body of clinical evidence has demonstrated the prevalence and risks of vitamin D deficiency in various chronic diseases. Biologically active vitamin D, 1,25-dihydroxylvitamin D3, is synthesized in two distinct systems. In addition to the classic two-step hydroxylation in the liver and kidneys, 1,25-dihydroxylvitamin D3 can also be produced locally by immune cells in response to infection. The bioactive vitamin D generated in these two pools apparently functions differently: while the former facilitates calcium adsorption and homeostasis, the latter confers immune regulation. The immune regulatory functions of vitamin D are demonstrated by induction of antimicrobial peptides, suppression of innate immune response, induction of Th2 cytokines, and stimulation of T-regulatory T cells. Vitamin D deficiency or insufficiency is overwhelmingly associated with viral hepatitis, cirrhosis, and fatty liver diseases. Recent clinical trials have shown that vitamin D supplements significantly enhance the efficacy of interferon plus ribavirin therapy through sustained virological response. A recent study showed that 25-dihydroxyvitamin D rather than 1,25-dihydroxyvitamin D could directly suppress hepatitis C virus assembly. Moreover, clinical evidence has shown that vitamin D deficiency is associated with alcoholic and non-alcoholic fatty liver diseases. In this review, we highlight some recent advances in vitamin D researches and clinical trails.