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1.
J Inorg Biochem ; 191: 119-125, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30500573

RESUMO

Male rats of 80-90 g were overloaded with either Fe(II) or Cu(II) for 42 days by high concentrations of FeCl2 or CuSO4 in the drinking water. The animals were fed with a commercial rodent diet of 2780 kcal/100 g. Both metal treatments led to a liver redox imbalance and dyshomeostasis with oxidative stress and damage and the concomitant enhancement of oxidative processes as indicated by in vivo surface liver chemiluminescence, the sensitive and organ non-invasive assay for oxidative free radical reactions, and by ex vivo determined processes of phospholipid peroxidation and protein oxidation. In parallel, marked decreases in the antioxidant defense were observed. Liver reduced glutathione (GSH) content and the reduced/oxidized glutathione ratio (GSH/GSSG) were early indicators of oxidative metabolic disturbance upon the metal overloads. Thus, GSH plays a central role in the defense reactions involved in the chronic toxicity of Fe and Cu. Chronic overloads of Fe or Cu in rats afford an experimental animal model of hemochromatosis and of Wilson's disease, respectively. These two animal models could be useful in the study and development of the beneficial effects of pharmacological interventions in the two human diseases.


Assuntos
Cobre/metabolismo , Homeostase , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Animais , Doença Crônica , Humanos , Fígado/patologia , Masculino , Oxirredução , Ratos , Ratos Sprague-Dawley
2.
J Inorg Biochem ; 172: 94-99, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28445841

RESUMO

Rat liver mitochondria (1.5-2.1mg protein·mL-1) supplemented with either 25 and 100µM Cu2+ or 100 and 500µM Fe3+ show inhibition of active respiration (O2 consumption in state 3) and increased phospholipid peroxidation . Liver mitochondria were supplemented with the antioxidants reduced glutathione, N-acetylcysteine or butylated hydroxitoluene, to evaluate their effects on the above-mentioned alterations. Although the mitochondrial dysfunction is clearly associated to phospholipid peroxidation, the different responses to antioxidant supplementation indicate that the metal ions have differences in their mechanisms of toxicity. Mitochondrial phospholipid peroxidation through the formation of hydroxyl radical by a Fenton/Haber-Weiss mechanism seems to precede the respiratory inhibition and to be the main fact in Fe-induced mitochondrial dysfunction. In the case of Cu2+, it seems that the ion oxidizes glutathione, and low molecular weight protein thiol groups in a direct reaction, as part of its intracellular redox cycling. The processes involving phospholipid peroxidation, protein oxidation and mitochondrial respiratory inhibition characterize a redox dyshomeostatic situation that ultimately leads to cell death. However, Cu2+ exposure involves an additional, yet unidentified, toxic event as previous reduction of the metal with N-acetylcysteine has only a minor effect in preventing the mitochondrial damage.


Assuntos
Antioxidantes/farmacologia , Respiração Celular/efeitos dos fármacos , Cobre/farmacologia , Ferro/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Cobre/química , Radicais Livres/metabolismo , Íons/farmacologia , Ferro/química , Masculino , Modelos Biológicos , Fosfolipídeos/metabolismo , Ratos
3.
J Inorg Biochem ; 166: 5-11, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27815982

RESUMO

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu2+ and Fe3+ addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu2+ and Fe3+ produced decreases in O2 consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C50) 60µM Cu2+ and 1.25mM Fe3+), and with succinate as complex II substrate: 64-69% with C50 of 50µM Cu2+ and with C50 of 1.25mM of Fe3+. Respiratory control decreased with Cu2+ (C50 50µM) and Fe3+ (C50 1.25-1-75mM) with both substrates. Cu2+ produced a 2-fold increase and Fe3+ a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25µM Cu2+ (C50 40µM) and from 100µM Fe3+ (C50 1.75mM). Supplementations with Cu2+ and Fe3+ ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death.


Assuntos
Cobre/farmacologia , Ferro/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Fosfolipídeos/metabolismo , Animais , Complexo I de Transporte de Elétrons/metabolismo , Masculino , Mitocôndrias Hepáticas/patologia , Proteínas Mitocondriais/metabolismo , Ratos , Ratos Sprague-Dawley
4.
Auton Neurosci ; 180: 43-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24231341

RESUMO

Hyperhomocysteinemia (HHcy) is associated with cardiovascular disease, atherosclerosis and reactive oxygen species generation. Thus, our aim was to investigate whether there was an association between HHcy, blood pressure, autonomic control and liver oxidative stress. Male Wistar rats were divided into 2 groups and treated for 8weeks: one group (control, CO) received tap water, while the other group (methionine, ME) was given a 100mg/kg of methionine in water by gavage. Two catheters were implanted into the femoral artery and vein to record arterial pressure (AP) and heart rate (HR) and drug administration. Signals were recorded by a data acquisition system. Baroreflex sensitivity was evaluated by HR responses to AP changes induced by vasoactive drugs. HR variability and AP variability were performed by spectral analysis in time and frequency domains to evaluate the contribution of the sympathetic and parasympathetic modulation. Lipid peroxidation and antioxidant enzyme activities were evaluated by measuring superoxide dismutase, catalase and glutathione peroxidase in liver homogenates. The ME group presented a significant increase in systolic arterial pressure (118±9 vs 135±6mmHg), diastolic arterial pressure (81±6 vs. 92±4) and mean arterial pressure (95±7 vs. 106±6). In addition, pulse interval variability presented a significant decrease (41%), while the low frequency component of AP was significantly increased (delta P=6.24mmHg(2)) in the ME group. We also found a positive association between lipid peroxidation and cardiac sympathetic modulation, sympathetic and vagal modulation ratio and systolic pressure variability. Collectively, these findings showed that HHcy induced dysfunction of cardiovascular autonomic system and liver oxidative stress.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Hiper-Homocisteinemia/fisiopatologia , Hipertensão/etiologia , Fígado/metabolismo , Estresse Oxidativo , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Catalase/análise , Glutationa Peroxidase/análise , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/metabolismo , Hipertensão/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Metionina/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/análise
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