RESUMEN
Overdose of acetaminophen (APAP) is the main reason for acute liver failure. Oxidative stress is associated with hepatotoxicity caused by APAP. Betaine is a methyl donor and S-adenosylmethionine precursor. The present study investigated the effect of betaine and the role of nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) genes in hepatotoxicity induced by APAP in mice. In this study, male Naval Medical Research Institute (NMRI) mice were treated with 500 mg/kg of betaine for 5 days followed with a single dose of APAP 300 mg/kg on the fifth day. Biochemical, histological, immunohistochemical, Western blot, and real-time polymerase chain reaction (PCR) analyses were then conducted. The results of the present study showed that betaine pretreatment improved hepatotoxicity through the reduction of serum ALT and AST levels and ameliorating histopathological finding. Betaine pretreatment also increased glutathione level and decreased malondialdehyde level. Importantly, the results of immunohistochemical, Western blot and real-time PCR showed that the APAP increased the expression of the genes and proteins of Nrf2 and HO-1. While betaine decreased Nrf2 and HO-1 expression in comparison with the APAP group. The findings of this study demonstrated that the increased expression of Nrf2 and HO-1 genes and proteins by APAP is a compensatory mechanism to combat acute liver toxicity. While the protective effect of betaine against acute liver injury induced by APAP is independent on the Nrf2 and HO-1 genes but occurs via modifying cysteine supply as a precursor of glutathione in the transsulfuration pathway in the liver.
Asunto(s)
Acetaminofén , Analgésicos , Betaína/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hemo-Oxigenasa 1/genética , Proteínas de la Membrana/genética , Factor 2 Relacionado con NF-E2/genética , Sustancias Protectoras/uso terapéutico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Betaína/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Expresión Génica , Glutatión/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Malondialdehído/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Sustancias Protectoras/farmacología , Regulación hacia ArribaRESUMEN
Arsenic trioxide (As2O3) is utilized for treating patients suffering from hematological malignancies particularly acute promyelocytic leukemia. Unfortunately, the extensive application of this chemotherapeutic agent has been limited due to its adverse effects such as cardiotoxicity. Ellagic acid, as a phenolic compound, has shown to exert antioxidant, anti-inflammatory, antifibrotic, and antiatherogenic properties. It is also capable of protecting against drug toxicity. In this study, we evaluated whether ellagic acid can protect against As2O3-induced heart injury in rats. Thirty-two male Wistar rats were randomly divided into four treatment groups, that is, control (0.2 mL of normal saline, intraperitoneally (ip)), As2O3 (5 mg/kg, ip), As2O3 plus ellagic acid, and ellagic acid (30 mg/kg, orally) groups. The drugs were administered daily for 10 days and pretreatment with ellagic acid was performed 1 h prior to As2O3 injection. Cardiotoxicity was characterized by electrocardiological, biochemical, and histopathological evaluations. Our results showed that ellagic acid pretreatment significantly ameliorated As2O3-induced increase in glutathione peroxidase activity and malondialdehyde concentration ( p < 0.05 and p < 0.001, respectively) and also diminished QTc prolongation ( p < 0.0001) and cardiac tissue damages. Pretreatment with ellagic acid also lowered the increased troponin I ( p < 0.0001) and creatine kinase isoenzyme MB ( p < 0.01) levels in response to As2O3. In conclusion, results of this study demonstrated that ellagic acid has beneficial cardioprotective effects against As2O3 toxicity. It is suggested that the protective effects were mediated by antioxidant properties of ellagic acid.
Asunto(s)
Antioxidantes/farmacología , Arritmias Cardíacas/prevención & control , Arsenicales , Cardiomiopatías/prevención & control , Ácido Elágico/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Óxidos , Animales , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Trióxido de Arsénico , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiotoxicidad , Forma BB de la Creatina-Quinasa/sangre , Citoprotección , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Masculino , Malondialdehído/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Troponina I/sangreRESUMEN
Chronic arsenic exposure has been linked to many health problems including diabetes and cancer. In the present study, we assessed the protective effect of ellagic acid (EA) against toxicity induced by arsenic in isolated rat liver mitochondria. Reactive oxygen species (ROS) and mitochondrial membrane potential decline were assayed using dichlorofluorescein diacetate and rhodamine 123, respectively, and dehydrogenase activity obtained by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide conversion assay. Arsenic increased ROS levels and mitochondrial dysfunction, which led to a reduction in mitochondrial total dehydrogenase activity. Mitochondria pretreated with EA exposed to arsenic at various concentrations led to a reversal of ROS production and mitochondrial damage. Our results showed that mitochondria were significantly affected when exposed to arsenic, which resulted in excessive ROS production and mitochondrial membrane disruption. Pretreatment with EA, reduced ROS amounts, mitochondrial damage, and restored total dehydrogenase activity specifically associated with mitochondrial complex II. EA protective characteristics may be accomplished particularly throughout the mitochondrial maintenance either directly by its antioxidant property or indirectly through its maintaining of complex II. These findings also suggest a potential role for EA in treating or preventing mitochondria associated disorders.