Abstract
BackgroundAcetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects.MethodsNinety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal.ResultsAPAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues.ConclusionsWe report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress accompanying APAP over-dose, with subsequent clinically beneficial effects on liver and kidney tissues.
Highlights
Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure
APAP is metabolized by cytochrome P450 (CYP) to form the highly reactive species, N-acetyl-p-benzoquinone imine (NAPQI), which under normal conditions is readily detoxified by conjugation with glutathione (GSH)
We aimed to evaluate the protective effects of Pleurotus ostreatus on APAP-induced hepatorenal toxicity in mice, with emphasis on mitochondrial dysfunction trying to elucidate the mechanism(s) by which Pleurotus ostreatus may execute its protective effect
Summary
Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. We evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. In the presence of hepatic, renal or cardiopulmonary insufficiency, even therapeutic doses of APAP may cause hepato-renal damage [6,7]. High doses of APAP saturate the detoxification pathways [8]; depletion of GSH leaves NAPQI free to bind to possibly critical cellular proteins and cause cell necrosis. APAP toxicity is determined by the amount of NAPQI produced and the insufficient availability of GSH for APAP detoxification [9,10,11]
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