RESUMO
Cholestasis is defined as a reduction of bile secretion caused by a dysfunction of bile formation. Insufficient bile secretion into the intestine undermines the formation of micelles, which may result in the reduced absorption of lipids and fat-soluble vitamins. Here, we investigated the retinol homeostasis and the alterations of retinol metabolism-related genes, including ß-carotene 15,15' monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), cytochrome P450 26A1 (CYP26A1), and retinoic acid receptors (RAR) ß, in a α-naphthyl isothiocyanate (ANIT)-induced cholestasis rat model. Moreover, we examined the expression of the farnesoid X receptor (FXR) target genes. Our results showed that plasma retinol levels were decreased in ANIT rats compared to control rats. On the contrary, hepatic retinol levels were not different between the two groups. The expression of FXR target genes in the liver and intestine of cholestasis model rats was repressed. The BCMO expression was decreased in the liver and increased in the intestine of ANIT rats compared to control rats. Finally, the hepatic expression of LRAT, RARß, and ALDH1A1 in cholestatic rats was decreased compared to the control rats, while the CYP26A1 expression of the liver was not altered. The increased expression of intestinal BCMO in cholestasis model rats might compensate for decreased circulatory retinol levels. The BCMO expression might be regulated in a tissue-specific manner to maintain the homeostasis of retinol.
Assuntos
1-Naftilisotiocianato , Colestase/induzido quimicamente , Colestase/metabolismo , Regulação da Expressão Gênica , Vitamina A/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Animais , Colestase/genética , Colestase/patologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , Vitamina A/genética , beta-Caroteno 15,15'-Mono-Oxigenase/genética , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismoRESUMO
In humans, dehydroepiandrosterone and its sulfate ester metabolite DHEA-S are secreted predominantly from the adrenal cortex, and dehydroepiandrosterone is converted to steroid hormones, including androgens and estrogens, and neurosteroid. Dehydroepiandrosterone exerts protective effects against several pathological conditions. Although there are reports on the association between dehydroepiandrosterone and vitamins, the exact relationship between dehydroepiandrosterone and vitamin E remains to be determined. Therefore, we attempted to elucidate the effect of dehydroepiandrosterone on vitamin E status and the expression of various vitamin E-related proteins, including binding proteins, transporters, and cytochrome P450, in vitamin E-deficient rats. Plasma α-tocopherol levels in vitamin E-deficient rats increased in response to dehydroepiandrosterone administration. The expression of hepatic α-tocopherol transfer protein was repressed in vitamin E-deficient rats compared to that in control rats; however, dehydroepiandrosterone administration significantly upregulated this expression. Hepatic expression of CYP4F2, an α-tocopherol metabolizing enzyme, in vitamin E-deficient rats was decreased by dehydroepiandrosterone administration, whereas hepatic expression of ATP-binding cassette transporter A1, an α-tocopherol transporter, was not altered following dehydroepiandrosterone administration. Dehydroepiandrosterone repressed lipid peroxidation in the liver of vitamin E-deficient rats. Therefore, adequate dehydroepiandrosterone supplementation may improve lipid peroxidation under several pathological conditions, and dehydroepiandrosterone may modulate α-tocopherol levels through altered expression of vitamin E-related proteins.
RESUMO
Dehydroepiandrosterone (DHEA) and its sulfate ester DHEA-sulfate (DHEA-S) are the most abundant adrenal steroids in humans. DHEA has a critical role as a steroidal precursor of androgens and/or estrogens, and in human studies and animal experiments, both DHEA and DHEA-S have multiple beneficial effects. However, there are few reports regarding the relationship between DHEA and nutrient status, especially for vitamins. Therefore, we elucidated the effect of DHEA administration on retinol status. Wistar rats were fed with a standard diet containing 0.4% (wt/wt) DHEA for 2 wk. We assessed retinol status and the expression of retinol-related proteins, including metabolic enzymes, binding proteins, cytochrome P450 (CYP) enzymes, and antioxidant enzymes. Retinol levels in the plasma and the liver of DHEA-fed rats were lower than those of controls. Expression of ß-carotene 15,15'-monooxygenase (BCMO) in the liver and intestine of DHEA-fed rats was lower, whereas BCMO expression in the testes of DHEA-fed rats was higher than that of controls. Expression of the retinol-metabolizing aldehyde dehydrogenase (ALDH) enzyme ALDH1A2 was repressed in the liver of DHEA rats, whereas ALDH1A1 expression was unaltered. Hepatic expression of lecithin:retinol acyltransferase (LRAT) and CYP26A1 was lower in DHEA-fed rats than in controls. Retinol status in DHEA-fed rats might be affected by altered BCMO expression in the liver and intestine and hepatic LRAT expression, whereas BCMO expression in peripheral tissues may be regulated in a tissue-specific manner. We have shown that DHEA administration may influence retinol status and the expression of retinol-related proteins.
Assuntos
Aciltransferases/genética , Desidroepiandrosterona/farmacologia , Vitamina A/análise , Vitamina A/sangue , beta-Caroteno 15,15'-Mono-Oxigenase/genética , Família Aldeído Desidrogenase 1 , Animais , Desidroepiandrosterona/sangue , Dieta , Expressão Gênica/efeitos dos fármacos , Intestinos/enzimologia , Isoenzimas/genética , Fígado/química , Fígado/enzimologia , Masculino , RNA Mensageiro/análise , Ratos , Ratos Wistar , Retinal Desidrogenase/genéticaRESUMO
Diabetes is a metabolic disorder characterized by chronic hyperglycemia. Advanced diabetes is associated with severe complications and impaired nutritional status. Here, we assessed the expression of retinol-associated proteins, including ß-carotene 15,15'-monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), and cytochrome P450 26A1 (CYP26A1), and measured retinol levels in the plasma and liver of streptozotocin (STZ)-induced type 1 diabetic model rats. Compared to the levels in the control rats, retinol levels in the plasma and liver of STZ rats were decreased and increased, respectively. Hepatic expression of the LRAT gene in STZ rats was lower than that in the controls. In the liver of STZ rats, the expression of ALDH1A1, a retinal metabolizing enzyme was higher, whereas ALDH1A2 expression was lower than in the controls. Hepatic CYP26A1 expression in STZ rats was significantly higher than in the control rats. BCMO expression levels in the liver and intestine of STZ rats were much lower than those of the controls. Altered BCMO expression might affect retinol status. It is considered that the metabolic availability of retinol was lessened despite the accelerated catabolism of retinol; therefore, retinol mobilization may be unbalanced in the liver of rats in the type 1 diabetic state.
RESUMO
Retinol and its derivative, retinoic acid, have pleiotropic functions including vision, immunity, hematopoiesis, reproduction, cell differentiation/growth, and development. Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in developed countries and encompasses a broad spectrum of forms, ranging from steatosis to steatohepatitis, which develops further to cirrhosis. Retinol status has an important role in liver homeostasis. The purpose of this study was to evaluate the retinol status and expression of retinol-related proteins, including enzymes and binding proteins, in methionine-choline deficient (MCD) rats as a model of NAFLD. We examined retinol levels in the plasma and liver and gene expression for ß-carotene 15,15'-monooxygenase (BCMO), lecithIn: retinol acyltransferase (LRAT), aldehyde dehydrogenase 1A1 (ALDH1A1), ALDH1A2, and cellular retinol binding protein (CRBP)-I in MCD rats. The plasma retinol levels in MCD rats were lower than those in the controls, whereas hepatic retinol levels in MCD rats were higher. BCMO expression in the intestine and liver in MCD rats was lower, whereas that in the testes and the kidneys was higher than in control rats. Expression of LRAT, CRBP-I, ALDH1A1, and ALDH1A2 in the liver of MCD rats was also higher. Altered expression of retinol-related proteins may affect retinol status in NAFLD.
Assuntos
Aciltransferases/metabolismo , Aldeído Desidrogenase/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Celulares de Ligação ao Retinol/metabolismo , Vitamina A/metabolismo , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismo , Animais , Deficiência de Colina/complicações , Mucosa Intestinal/metabolismo , Rim/metabolismo , Masculino , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/etiologia , Ratos Wistar , Testículo/metabolismo , Vitamina A/sangueRESUMO
Non-alcoholic fatty liver disease is the most common liver disorder in developed countries, and its incidence is increasing in all population groups. As an antioxidant, vitamin E is effective in the treatment of non-alcoholic fatty liver disease, although the mechanism is still unclear. Methionine-choline deficient Wistar rats (n = 5) used as an experimental model of non-alcoholic fatty liver disease were fed a vitamin E-enriched diet (500 mg/kg) for 4 weeks. The effects were assessed by measuring lipid peroxidation, α-tocopherol levels, and the expression of α-tocopherol-related proteins in the liver. In vitamin E-treated methionine-choline deficient rats, lipid peroxidation was reduced, but liver histopathological changes were not improved. Hepatic α-tocopherol levels in these rats were significantly elevated compared to normal rats treated with vitamin E. Expression of liver α-tocopherol transfer protein in vitamin E-treated methionine-choline deficient rats was significantly repressed compared to methionine-choline deficient rats. The expression of liver cytochrome P450 4F2 and ATP-binding cassette transporter protein 1, involved in metabolism and transport of α-tocopherol, respectively, was significantly repressed in vitamin E-treated methionine-choline deficient rats. In methionine-choline deficient rats, vitamin E treatment altered the hepatic α-tocopherol-related protein expression, which may affect α-tocopherol status in the liver, leading to reduced lipid peroxidation.
RESUMO
Vitamin E plays a critical role as an antioxidant in several pathological conditions, including diabetes, cancer, cardiovascular diseases, and neurodegenerative disorders. Diabetes is a metabolic disorder of glucose due to the lack of adequate insulin production (type 1) or peripheral insulin resistance (type 2). Oxidative stress plays a major role in the pathogenesis of diabetes and its complications. The purpose of the present study was to determine α-tocopherol status and the expression of α-tocopherol-related proteins, including binding proteins and metabolizing enzymes, under streptozotocin (STZ)-induced type 1 diabetes in rat models. In STZ rats, plasma α-tocopherol levels decreased compared to the control rats, whereas hepatic α-tocopherol levels in the STZ rats were significantly increased. CuZn-superoxide dismutase (SOD) gene expression in the liver of STZ rats was markedly decreased, whereas Mn-SOD gene expression remained unaltered. Accelerated lipid peroxidation in the liver of STZ rats was observed and the hepatic expression of α-tocopherol transfer protein (α-TTP) in STZ rats decreased compared to that in the controls. The hepatic expression of cytochrome P450 4F2 (CYP4F2) and CYP3A2 genes in STZ rats also decreased. The reduced expression of hepatic α-TTP and CYP4F2 genes probably leads to decreased plasma α-tocopherol levels and elevated α-tocopherol levels in the liver of STZ rats. The altered expression of hepatic α-tocopherol-related proteins might regulate α-tocopherol status in type 1 diabetes. Determining the mechanism of modulating α-tocopherol status may be helpful in promoting antioxidant therapy in diabetes.
Assuntos
Antioxidantes/farmacologia , Proteínas de Transporte/metabolismo , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 1/sangue , alfa-Tocoferol/sangue , Animais , Proteínas de Transporte/genética , Citocromo P-450 CYP3A/genética , Sistema Enzimático do Citocromo P-450/genética , Família 4 do Citocromo P450 , Diabetes Mellitus Tipo 1/induzido quimicamente , Modelos Animais de Doenças , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , EstreptozocinaRESUMO
Fat-soluble vitamin E (α-tocopherol) has antioxidant activity. α-Tocopherol transfer protein (α-TTP), a hepatic cytosolic protein, selectively binds α-tocopherol and has an important role regulating circulatory α-tocopherol levels. However, only a few studies have shown the transcriptional regulation of the α-TTP gene. Here, we demonstrate that liver X receptor (LXR) regulates α-TTP expression through direct interaction with the α-TTP gene promoter, and it modulates circulating α-tocopherol levels. LXR belongs to the nuclear receptor superfamily, acts as a ligand-dependent transcription factor for oxysterols and plays an important role in cholesterol metabolism and lipogenesis. We identified an LXR response element (LXRE; DR4, a direct repeat with four-nucleotides spacing) of the human α-TTP gene promoter by using luciferase and electrophoretic mobility shift assays. Mutations in this element abolished activation of this promoter. Moreover, treatment of vitamin E-deficient rats with T0901317, a synthetic LXR ligand, increased α-TTP expression in the liver and cerebrum and increased the plasma α-tocopherol levels. These results indicate that the LXR signaling pathway modulates α-TTP gene expression and plasma α-tocopherol levels. Our observations imply that the LXR signaling pathway might be a useful target for antioxidant properties by controlling the vitamin E status.
Assuntos
Proteínas de Transporte/metabolismo , Receptores Nucleares Órfãos/metabolismo , Regulação para Cima , alfa-Tocoferol/sangue , Animais , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Humanos , Hidrocarbonetos Fluorados/farmacologia , Lipogênese , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Masculino , Receptores Nucleares Órfãos/genética , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Elementos de Resposta/efeitos dos fármacos , Transdução de Sinais , Sulfonamidas/farmacologia , Deficiência de Vitamina E/tratamento farmacológicoRESUMO
We herein report a case of a pregnant Chinese woman who suffered an acute exacerbation of hepatitis B. The patient's liver enzymes became elevated toward the end of the first trimester. She was treated with lamivudine, interferon (IFN)-ß and steroids early in the second trimester. After this treatment regimen was initiated, aminotransferase levels rapidly normalized within 4 weeks. IFN-ß and steroids were administrated for 2 weeks in the second trimester, while the administration of lamivudine continued until delivery. The spontaneous delivery of a female baby weighing 2984 g occurred at 37 weeks of gestation. A neonatal examination revealed no congenital anomalies, and fetal growth was found to be within normal reference ranges. The infant received simultaneous active and passive hepatitis B virus immunization within 12 h of delivery and completed the hepatitis B vaccine schedule at 2, 3 and 5 months of age. The infant was successfully prevented from contracting hepatitis B virus. This case suggests that combination therapy with lamivudine, IFN-ß and steroids may be safely used during the second trimester to treat acute exacerbations of hepatitis B.
RESUMO
Vitamin E, a critical fat-soluble vitamin antioxidant, is expressed on cell membranes and prevents propagation of lipid peroxidation. α-Tocopherol transfer protein (α-TTP) is a cytosolic protein located in the hepatocytes that acts as the principal regulator of the circulating α-tocopherol levels. Type 2 diabetes is a metabolic disorder characterized by hyperglycemia, caused by insulin resistance. Lipid peroxidation promotes the clinical progression and development of complications in type 2 diabetes. Results of animal and human experiments on the vitamin E status in diabetes are conflicting. The present study was conducted with the objective of investigating the vitamin E status and α-TTP expression in Goto-Kakizaki (GK) rats, a model of type 2 diabetes. In diabetic GK rats, increases of the α-tocopherol levels in the plasma and liver were observed as compared with the levels in the controls. No alternation in the CuZn-superoxide dismutase (SOD) or Mn-SOD gene expression was found in the liver of GK rats as compared with that in the controls. The GK rats showed an increase of the hepatic expression of the α-TTP gene as compared with the level in the controls. It can be suggested that the increased hepatic α-TTP gene expression levels may influence plasma α-tocopherol levels in the diabetic animals. Hence, investigation of the regulatory factors of α-TTP expression may provide important clues to highlighting the antioxidant mechanisms of vitamin E.
Assuntos
Antioxidantes/metabolismo , Proteínas de Transporte/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Peroxidação de Lipídeos , Fígado/metabolismo , Superóxido Dismutase/metabolismo , alfa-Tocoferol/sangue , Animais , Proteínas de Transporte/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Masculino , Estado Nutricional , Ratos , Ratos Endogâmicos , Ratos WistarRESUMO
Tocotrienols (Toc3) have been suggested to possess anticancer effects besides antioxidant and antiinflammatory effects. Previous studies have demonstrated that Toc3 induce apoptosis in epithelial carcinoma. However, the effects of Toc3 on malignant hematopoietic cells have not yet been thoroughly investigated. We investigated Toc3-induced apoptosis in human hematological cancer cell lines. α-, δ-, and γ-Toc3 induced concentration-dependent apoptosis, and γ-Toc3 demonstrated more effective induction than the other Toc3 derivatives in HL-60 cells. γ-Toc3 may have induced apoptosis by activation of the caspase cascade, cytochrome c (Cyt.c) release, Bid cleavage, and mitochondorial membrane depolarization in HL-60, NB-4, Raji, and SY-5Y cells. Furthermore, 10-30 µM γ-Toc3 showed cytotoxicity for leukemic cells from various patients regardless of lymphoblastic, myeloblastic, or relapsed leukemia, but the cytotoxic effect was weak in normal mononuclear cells, interestingly. γ-Toc3 may have a role in cancer prevention and potential for treating hematological malignancies.
Assuntos
Antineoplásicos Fitogênicos/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Cromanos/metabolismo , Neoplasias Hematológicas/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Vitamina E/análogos & derivados , Adolescente , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/patologia , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Citocromos c/metabolismo , Fragmentação do DNA , Feminino , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/prevenção & controle , Humanos , Lactente , Leucemia/patologia , Leucemia/prevenção & controle , Masculino , Potencial da Membrana Mitocondrial , Mitocôndrias/patologia , Proteínas de Neoplasias/metabolismo , Vitamina E/metabolismoAssuntos
Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Neutropenia/genética , Fenótipo , Proteínas Tirosina Quinases/genética , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/sangue , Agamaglobulinemia/terapia , Criança , Pré-Escolar , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Masculino , Neutropenia/sangue , Neutropenia/terapia , IrmãosAssuntos
Envelhecimento/metabolismo , Antineoplásicos/farmacocinética , Leucemia Promielocítica Aguda/metabolismo , Tretinoína/farmacocinética , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Sistema Nervoso Central/efeitos dos fármacos , Criança , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Indução de Remissão , Tretinoína/efeitos adversos , Tretinoína/uso terapêuticoAssuntos
Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Sangue Fetal/metabolismo , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Tretinoína/sangue , Tretinoína/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Complexos Atriais Prematuros , Permeabilidade do Canal Arterial/etiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Leucemia Promielocítica Aguda/sangue , Masculino , Troca Materno-Fetal , Gravidez , Complicações Neoplásicas na Gravidez/sangue , Resultado da Gravidez , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Resultado do Tratamento , Tretinoína/efeitos adversosRESUMO
All-trans retinoic acid (ATRA) is used as differentiation therapy for acute promyelocytic leukemia (APL). The two major adverse effects of ATRA therapy are hyperleukocytosis and retinoic acid syndrome. In order to prevent these adverse effects, low-dose ATRA therapy (25 mg/m2/d) has been tried in adults. Accordingly we assessed the pharmacokinetics of low-dose ATRA in children with cancer. Four children (one with APL and three with other advanced cancer) were administered ATRA and its pharmacokinetics were evaluated. In three patients, the pharmacokinetic parameters of ATRA were similar to those previously determined for APL patients in remission, but the values were lower in one patient. Low-dose ATRA was effective for APL, but not for the solid tumors. This therapy did not cause any severe toxicity. Further studies are needed to determine the optimum ATRA regimen and to evaluate low-dose ATRA combined with chemotherapy in children with APL.