Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice

Masubuchi, Yuji; Suda, Chieko; Horie, Toshiharu

doi:10.1016/j.jhep.2004.09.015

Cited by 282 publications

(181 citation statements)

References 43 publications

(52 reference statements)

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“…When large doses of acetaminophen are consumed, the detoxification pathways become saturated and result in depletion of hepatocellular GSH. Once GSH is consumed, any persisting NAPQI will covalently attach to cellular proteins and provoke oxidative stress, lipid peroxidation, DNA fragmentation and mitochondrial dysfunction finally leads to massive hepatocyte necrosis, liver damage or death [32,33]. In agreement with the results of other studies [33,34] acetaminophen overdose treatment in this study showed significantly increase in serum transaminase, hepatic malondialdehyde (MDA), and decrease in hepatic GSH and SOD.…”

Section: Discussionsupporting

confidence: 91%

Protective Effect of Curcumin versus N-acetylcystein on Acetaminophen Induced Hepatotoxicity in Adult Albino Rats

AB¹,

HE²

2015

J Cytol Histol

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Curcumin exerted hepatoprotective influences on various animal models of liver injury such as carbon tetrachloride, endotoxin and thioacetamide. This Study aimed to investigate the protective effects of curcumin as compared to N-acetylcysteine in the rat model of acetaminophen induced hepatotoxicity. 55 albino rats were divided into four groups: group (control group). Group II received acetaminophen. Group III received both acetaminophen and N-acetylcysteine and Group IV received both acetaminophen and curcumin. At the end of the experiment, liver specimens were processed for histological study by light microscope and stained immunohistochemically for detection of apoptosis in hepatic cells by using anti p53 and the oxidative damage by anti-inducible nitric oxide synthase (anti iNOS). Serum levels of liver injury markers were assessed as well as the levels of malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) activity were determined in all dissected tissues. Histological examination of liver sections of acetaminophen treated group revealed degeneration, cytoplasmic vacuolation and hydropic necrosis of hepatocytes. The central and the portal veins were dilated and congested and invading infiltrative inflammatory cells were appeared in association with significant increase in p53 and iNOS positive cells. Significant rise in serum levels of liver injury markers and MDA in liver tissues were recorded. However, levels of GSH and SOD were significantly decreased. Both curcumin and N-acetylcysteine resolved most of these morphological, immunohistochemical and biochemical alterations. Curcumin has protective effect similar to N-acetylcysteine against liver damage induced by acetaminophen in rats by reducing oxidative stress and apoptosis.

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Section: Discussionsupporting

confidence: 91%

Protective Effect of Curcumin versus N-acetylcystein on Acetaminophen Induced Hepatotoxicity in Adult Albino Rats

AB¹,

HE²

2015

J Cytol Histol

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“…Mitochondria have been documented to play an important role in the AAP-induced liver injury (Vendemiale et al 1996;Burcham and Harman 1991;Masubuchi et al 2005). Oxidative stress promotes MPT (Reid et al 2005) characterised by a decrease of mitochondrial membrane potential (MMP).…”

Section: Discussionmentioning

confidence: 99%

Effect of S-adenosylmethionine on Acetaminophen-induced Toxic Injury of Rat Hepatocytes in vitro

et al. 2009

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Acetaminophen (AAP) overdose causes severe liver injury and is the leading cause of acute liver injury in humans. The mechanisms participating in its toxic effect are glutathione depletion, oxidative stress and mitochondrial dysfunction. S-adenosylmethionine (SAMe) is the principal biological methyl donor and is also a precursor of glutathione. In our previous studies we have documented a protective action of SAMe against various toxic injuries of rat hepatocytes in primary cultures. The aim of this study was to evaluate a possible protective effect of SAMe against AAP-induced toxic injury of primary rat hepatocytes. Hepatocytes were exposed to AAP (2.5 mM) or AAP together with SAMe at the final concentrations of 5, 25 or 50 mg/l for 24 h. Incubation of hepatocytes with AAP caused a significant increase of the leakage of lactate dehydrogenase (LDH) (p < 0.001) and decline of the activity of cellular dehydrogenases (WST-1) (p < 0.001). Co-incubation of hepatocytes with SAMe at any dose did not improve these markers of cellular integrity. The functional indicators improved in hepatocytes co-cultured with SAMe -urea production was significantly increased when using the highest dose of SAMe (p < 0.05); albumin synthesis was higher in all cultured hepatocytes exposed to SAMe (p < 0.05). SAMe did not influence AAP-induced decrease of cellular content of glutathione. Mitochondrial respiration of harvested digitonin-permeabilized hepatocytes was measured; Complex II was more sensitive to toxic action of AAP, respiration was decreased by 20%. This decrease was completely abolished by SAMe. Hepatotoxicity, hepatoprotective effect, mitochondrial membrane potential, urea, albumin, glutathione, LDHAcetaminophen (AAP) is a widely used, relatively safe analgesic/antipyretic drug. Nevertheless, AAP overdose causes centrilobular necrosis of the liver and is the leading cause of acute liver injury in humans in the United States and most of Europe (Lee 2007). The primary metabolic pathway for AAP is glucuronidation and sulphation in the liver; this yields relative non-toxic metabolites, which are excreted into bile (Mitchell et al. 1973). AAP hepatotoxicity is dependent on another metabolic pathway. The remaining part of AAP dose, which is not directly conjugated with the hydrophylic group, is biotransformed by the cytochrome P450 family to an electrophilic, highly reactive metabolite N-acetylp-benzoquinone imine (NAPQI), which is detoxified by glutathione (Jaeschke and Bajt 2006). However, if the formation of NAPQI exceeds the capacity of liver glutathione (GSH), this reactive metabolite forms covalent adducts primarily with cysteine residues on various cellular proteins (Nelson and Bruschi 2003; Allameh and Alikhani 2006). The most important mechanism of AAP-induced cell death seems to be a change in the function of critical cellular proteins due to covalent bindings. Numerous cytosolic, mitochondrial, ribosomal, microsomal, and nuclear proteins bound to AAP have been identified. Nevertheless, the primary cellular targe...

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“…NAPQI reacts rapidly with GSH, a phenomenon that exacerbates oxidative stress in conjunction with mitochondrial dysfunction. The GSH depletion, occurring in acute hepatotoxicity, gives free way to the highly reactive intermediates, whose actions on structural and functional molecules affects the liver functions and leads to massive hepatocyte necrosis, liver failure or death [58][59][60]. Since oxidative stress and GSH depletion contributes to the acetaminophen induced liver injury, the agents with antioxidant properties and/or GSH preserving ability may provide a preventive action against hepatocellular injury [61].…”

Section: Main Hepatotoxic Agents Used In Hepatoprotective Studiesmentioning

confidence: 99%

Hepatoprotective Effects of Mushrooms

et al. 2013

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Abstract:The particular characteristics of growth and development of mushrooms in nature result in the accumulation of a variety of secondary metabolites such as phenolic compounds, terpenes and steroids and essential cell wall components such as polysaccharides, β-glucans and proteins, several of them with biological activities. The present article outlines and discusses the available information about the protective effects of mushroom extracts against liver damage induced by exogenous compounds. Among mushrooms, Ganoderma lucidum is indubitably the most widely studied species. In this review, however, emphasis was given to studies using other mushrooms, especially those presenting efforts of attributing hepatoprotective activities to specific chemical components usually present in the mushroom extracts.

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Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice

Cited by 282 publications

References 43 publications

Protective Effect of Curcumin versus N-acetylcystein on Acetaminophen Induced Hepatotoxicity in Adult Albino Rats

Protective Effect of Curcumin versus N-acetylcystein on Acetaminophen Induced Hepatotoxicity in Adult Albino Rats

Effect of S-adenosylmethionine on Acetaminophen-induced Toxic Injury of Rat Hepatocytes in vitro

Hepatoprotective Effects of Mushrooms

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