Acetaminophen‐induced hepatic injury: Protective role of glutathione in man and rationale for therapy

Mitchell, Jerry R.; Thorgeirsson, Snorri S.; Potter, William Z.; Jollow, David J.; Keiser, Harry R.

doi:10.1002/cpt1974164676

Cited by 903 publications

(802 citation statements)

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“…Thus, the rate of GSH depletion parallels the rate of NAPQI formation under these conditions. 7,28,29 Because the time course and extent of GSH depletion in hepatocytes after acetaminophen exposure was nearly identical with and without CsA (see Fig. 1C), we can conclude that CsA likely does not inhibit the bioactivation of acetaminophen.…”

Section: Discussionmentioning

confidence: 75%

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Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

et al. 2004

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Acetaminophen overdose causes massive hepatic failure via mechanisms involving glutathione depletion, oxidative stress, and mitochondrial dysfunction. The ultimate target of acetaminophen causing cell death remains uncertain, and the role of apoptosis in acetaminophen-induced cell killing is still controversial. Our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. After administration of 10 mmol/L acetaminophen, necrotic killing increased to more than 49% and 74%, respectively, after 6 and 16 hours. MPT inhibitors, cyclosporin A (CsA), and NIM811 temporarily decreased necrotic killing after 6 hours to 26%, but cytoprotection was lost after 16 hours. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization approximately 4.5 hours after acetaminophen administration. CsA delayed these changes, indicative of the MPT, to approximately 11 hours after acetaminophen administration. Apoptosis indicated by nuclear changes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase-3 activation also increased after acetaminophen administration. Fructose (20 mmol/L, an adenosine triphosphategenerating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis from 37% to 59% after 16 hours. In the presence of fructose plus glycine, CsA decreased apoptosis and delayed but did not prevent the MPT. In conclusion, after acetaminophen a CsA-sensitive MPT occurred after 3 to 6 hours followed by a CsA-insensitive MPT 9 to 16 hours after acetaminophen. The MPT then induces ATP depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

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Section: Discussionmentioning

confidence: 75%

“…3,4 Thus, after exposure of hepatocytes to acetaminophen the rate of GSH depletion parallels the rate of NAPQI formation. 7,28,29 After acetaminophen, GSH decreased by approximately 50% after 1 hour and 80% after 2 hours (see Fig. 1C).…”

Section: Resultsmentioning

confidence: 85%

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

et al. 2004

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“…Glutathione peroxidase is a key enzyme in the antioxidant defense system, and it acts by catalyzing the transformation of hydrogen peroxide into water, being dependent on selenium and reduced glutathione (18) . This enzyme also plays a major protective role in the hepatic necrosis produced by acetaminophen (23) . It is depleted in the cirrhotic group, in the attempt to stabilize the oxygen reactive species formed by the high lipoperoxidation index observed in this group.…”

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confidence: 99%

Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats

Pereira-Filho

Ferreira

Schwengber

et al. 2008

Arq. Gastroenterol.

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-Background -Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. Aim -To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. Methods -The animals were randomly in three experimentals groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS). Results -The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. Conclusion -N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.

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“…Factors that relate to the detoxification of N-acetyl-p-benzoquinone imine in the liver are implicated in the lesser susceptibility of postnatal mice to paracetamol toxicity. (Pediatr Res 29: [496][497][498][499]1991) to detoxify this metabolite by conjugation to GSH (2)(3)(4), and a number of incompletely understood processes initiated by NAPQI that lead to cell death (5).…”

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confidence: 99%

Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

1991

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ABSTRACT. The hepatotoxicity of paracetamol in mice of 2, 3, 8-10, 24-26, 32-34, and 52-54 wk of age was determined by lethality data, histopathologic examination of the liver, and appearance of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase activities in the plasma over an 8-h exposure period. At a dose of 300 mg/kg, there was evidence of hepatocytic necrosis and transaminase leakage in the 32-to 34-and 52-to 54-wk-old mice, but lethality was only recorded in the oldest age group. At 500 mg/kg, paracetamol produced 30% lethality in 3-wk-old mice and between 50 and 90% lethality in the adult age groups. There was histologic evidence of hepatocytic necrosis at all of these ages and its extent increased with age. Similarly, there were increases in plasma transaminases in each of these age groups. However, in 2-wk-old mice there was no lethality, no hepatocytic necrosis, and no increase in plasma transaminases. The lack of susceptibility of 2-wk-old mice to paracetamol toxicity was not due to immaturity of the cytochrome P-450 enzymes responsible for metabolism of paracetamol to its reactive metabolite (N-acetyl-p-benzoquinone imine). In fact, the activity of this enzyme pathway in 2-wk-old mice was greater than that in adults. The partial clearance of the glutathione-derived metabolites of paracetamol after a nontoxic (50 mg/kg) dose was 80% greater in 2-wk-old mice than in 8-to 10-wk-old mice. Therefore, despite having greater capacity to generate N-acetyl-p-benzoquinone imine, 2-wk-old mice had no hepatotoxic effects from a dose that killed at least 50% of adult mice. Factors that relate to the detoxification of N-acetyl-p-benzoquinone imine in the liver are implicated in the lesser susceptibility of postnatal mice to paracetamol toxicity. (Pediatr Res 29: 496-499,1991) to detoxify this metabolite by conjugation to GSH (2-4), and a number of incompletely understood processes initiated by NAPQI that lead to cell death (5).It is generally accepted that children are less susceptible to paracetamol toxicity than are adults (6). This impression has developed from clinical observations that the incidence of overdose toxicity is less in the young (7). However, the scientific basis for this has yet to be confirmed.Our present study is aimed at examining developmental aspects of the susceptibility of mice to paracetamol toxicity. Previous work in this field has been conflicting, with some research indicating that young mice (8) and rats (9) are more susceptible to high doses of paracetamol. However, the majority of findings indicate that during the postnatal period young rats and mice are less susceptible to toxicity (10, II). These latter observations have been attributed to the immaturity of the cytochrome P-450-linked mixed function oxidase enzymes in the postnatal period and the consequent decrease in the rate of activation of paracetamol to NAPQI (10) or to a lack of susceptibility to hepatotoxins in general (12). We have recently observed that hepatocytes from postnatal mice are less su...

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Acetaminophen‐induced hepatic injury: Protective role of glutathione in man and rationale for therapy

Cited by 903 publications

References 8 publications

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats

Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

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