Molecular Aspects of Paracetamol-Induced Hepatotoxicity and its Mechanism-Based Prevention

Vermeulen, Nico; Bessems, Jos; Straat, R. van de

doi:10.3109/03602539208996298

Cited by 286 publications

(196 citation statements)

References 106 publications

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“…Despite considerable research, the mechanisms responsible for acetaminophen (APAP) hepatotoxicity in humans and experimental animals are not yet fully understood (for reviews see Nelson, 1 Vermeulen et al, 2 Hinson et al, 3 and Cohen et al 4 ). Metabolic activation 5 of APAP and subsequent binding of its electrophilic metabolite N-acetyl-p-benzoquinone imine (NAPQI) to glutathione (GSH) and, after GSH depletion, to nucleophilic protein targets 6 seems to be necessary but is not sufficient for toxicity.…”

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confidence: 99%

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

et al. 1998

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Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-␣ (LT-␣). Male TNF/LT-␣ knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-␣-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-␣ were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-␣, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity. (HEPATOLOGY 1998;27:1021-1029.)

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confidence: 99%

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

et al. 1998

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“…The hepatotoxicity of Paracetamol ® is as a result of formation of toxic metabolites when part of it is activated by hepatic . cytochrome p-450 to a highly reactive metabolite-N-acetyl-pbenzoquinonimine (NAPQI) [3,4]. Liver disorders are global problem.…”

Section: Introductionmentioning

confidence: 99%

Effect of Quail Egg Pretreatment on the Lipid Profile and Histomorphology of the Liver of Acetaminophen-Induced Hepatotoxicity in Rats

Emeka¹,

Eneasato²,

Onah³

2016

J App Biol Biotech

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Quail eggs contain lots of vitamins and minerals that help fight some diseases in the body. Overdose of paracetamol ® (acetaminophen) is considered one of the major causes of damages to liver cells. This study was conducted to assess the effect of graded doses of quail egg pretreatment on lipid profile and liver histomorphology of acetaminophen-induced hepatotoxicity in rats. Thirty (30) albino rats were assigned into 5 groups of 6 rats per group. Rats in groups 2-4 were pretreated with 30 mg/kg, 15 mg/kg, 7.5 mg/kg respectively of quail egg solution for 7 days before intoxication with 2000 mg/kg paracetamol® orally. Rats in group 5 were intoxicated but pretreated with distilled water (DW) at 10 ml/kg to serve as negative control while rats in group 1 were not intoxicated but pretreated with DW (10 ml/kg) (positive control). Fourty eight (48 h) hours post intoxication, blood was collected for lipid profile analysis. Thereafter, 2 rats per group were humanely sacrificed and the liver collected for histomorphological examination. The results obtained showed that 30 mg/kg quail eggpretreated rats (Group 2 rats) had significantly (P<0.05) lower levels of total cholesterol, low density lipoproten, triglyceride and very low density lipoprotein when compared with that of the negative control. Hepatic histomorphometric results indicate that the vacuolar degeneration observed in all the acetaminophen-induced liver damaged rats were less severe in the liver of group 2 rats. It was concluded that the quail egg pretreatment at the dose of 30 mg/kg was hypolipidemic and posses hepatoprotective properties.

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“…When consumed in large doses, it is known to cause severe centrilobular hepatic toxicity [1][2][3]. But at therapeutic doses is rapidly metabolized in the liver principally through glucuronidation and sulfation, and only a small portion is oxidized by cytochrome P-450 2E1 to generate a highly reactive and cytotoxic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI) [4,5]. This metabolite is efficiently detoxified by being reduced back to APAP or covalently linked to GSH to form a 3-glutathione-S-yl-APAP conjugate [6].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death

Ahmed

Al-Obosi²,

Osman

et al. 2015

Ind J Clin Biochem

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Acetaminophen (APAP) a commonly used drug for decrease the fever and pain but is capable to induced hepatotoxicity at over dose. This study was carried out to investigate the effect of APAP on the expression of antiapoptotic and antioxidative defense genes, and whether aldose reductase over-expressing plasmid capable to protect against APAP-induced oxidative stress and cell death. APAP treatment induced oxidative stress and hepatotoxicity, and significantly increased aldose reductase mRNA and protein expression in mouse hepatocyte (AML-12).Unexpectedly, AML-12 cells over-expressing aldose reductase augmented APAP-induced reduction in cell viability, reactive oxygen species (ROS) production, glutathione (GSH) depletion and glutathione S-transferase A2 expression. Moreover, over-expression of aldose reductase potentiated APAP induced reduction on proliferating cell nuclear antigen, B cell lymphoma-extra large (bcl-x L ), catalase, glutathione peroxidase-1 (GPx-1) and abolished APAP-induced B-cell lymphoma 2 (bcl-2) inductions. Further, over-expression of aldose reductase significantly abolished AMP activated protein kinase (AMPK) activity in APAP-treated cells and induced p53 expression. This results demonstrate that APAP induced toxicity in AML-12, increased aldose reductase expression, and over-expression of aldose reductase render this cell more susceptible to APAP induced oxidative stress and cell death, this probably due to inhibition AMPK or bcl-2 activity, or may due to competition between aldose reductase and glutathione reductase for NADPH.

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Molecular Aspects of Paracetamol-Induced Hepatotoxicity and its Mechanism-Based Prevention

Cited by 286 publications

References 106 publications

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

Effect of Quail Egg Pretreatment on the Lipid Profile and Histomorphology of the Liver of Acetaminophen-Induced Hepatotoxicity in Rats

Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death

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