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Arch Toxicol ; 87(6): 1001-12, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23052196

RESUMEN

Inorganic arsenic (i-As) is a naturally occurring toxic metalloid affecting millions of people worldwide. It is known to be carcinogen, liver being a potential target, and related to the prevalence of diabetes in arseniasis-endemic areas. Hepatocyte nuclear factor 1 and 4 alpha (HNF1α and HNF4α) are key members of a transcriptional network essential for normal liver architecture. Changes in HNF1α and HNF4α expression are clearly associated with the development of liver malignancies and diabetes in humans. In this work, hepatic HepG2 cells and golden Syrian hamsters were exposed to sub-toxic, environmentally relevant doses of sodium arsenite (SA; up to 10 µM in vitro, 15 mg/L in vivo) in order to evaluate whether arsenic is able to compromise the expression of hepatocyte nuclear factors. Also, liver histopathological examination was carried out, and several markers of hepatocyte differentiation and glucose metabolism status were determined as a measure of i-As-induced effects. Results show a consistent down-regulation of HNF1α and HNF4α under a scenario of exposure where HepG2 cells (1) gained resistance to arsenic-induced toxicity/apoptosis, (2) attained loss of tissue-specific features (as shown by the observed down-regulation of ALDOB, PEPCK and CYP1A2, triggering of the epithelial-to-mesenchymal transition program and the hypersecretion of matrix metalloproteinase-2 and 9), (3) failed to maintain balanced expression of the "stemness" genes C-MYC, OCT3/4, LIN28 and NOTCH2 and (4) showed glucose metabolism impairment. We conclude that the i-As-induced down-regulation of HNF1α and HNF4α under chronic settings may play a central role in the features of disease and cancer observed both in vivo and in vitro.


Asunto(s)
Arsenitos/toxicidad , Carcinógenos Ambientales/toxicidad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Compuestos de Sodio/toxicidad , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cricetinae , Citocromo P-450 CYP1A1/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Fructosa-Bifosfato Aldolasa/metabolismo , Glucosa/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hígado/metabolismo , Hígado/patología , Mesocricetus , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas de Unión al ARN/metabolismo , Receptor Notch2/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
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