Oxidative stress in cultured hepatocytes exposed to acetaminophen

Adamson, Gregory M.; Harman, Andrew W.

doi:10.1016/0006-2952(93)90201-7

Cited by 86 publications

(50 citation statements)

References 20 publications

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“…28 APAP toxicity involves a major oxidant component generating reactive oxygen species. 10,11 Furthermore, the generation of reactive oxygen species is associated with mitochondrial damage in murine hepatocytes incubated with APAP. 29 Our data indicate that AMAs are found in sera in almost 35% of APAP poisoning subjects, suggesting that the 2-OADC E2 lipoyl domain is a likely target of APAP-induced reactive oxygen and nitrogen species.…”

Section: Discussionmentioning

confidence: 99%

“…9 Hepatic insult secondary to acetaminophen (APAP) (paracetamol, N-acetyl-p-aminophenol) consumption has a major oxidant component; toxic doses of APAP produce reactive oxygen and nitrogen species and reactive metabolites in experimental animals or cultured cells. 10,11 Importantly, AMA induction and perpetuation appears sensitive to the oxidative state of the tissues involved. [12][13][14] We hypothesized that in patients with ALF, AMA may be induced by the combination of oxidative stress and liver cell death, resulting in exposure of the immune system to both native and modified intracellular proteins.…”

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confidence: 99%

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Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

et al. 2007

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In our previous work, including analysis of more than 10,000 sera from control patients and patients with a variety of liver diseases, we have demonstrated that with the use of recombinant autoantigens, antimitochondrial autoantibodies (AMAs) are only found in primary biliary cirrhosis (PBC) and that a positive AMA is virtually pathognomonic of either PBC or future development of PBC. Although the mechanisms leading to the generation of AMA are enigmatic, we have postulated that xenobiotic-induced and/or oxidative modification of mitochondrial autoantigens is a critical step leading to loss of tolerance. This thesis suggests that a severe liver oxidant injury would lead to AMA production. We analyzed 217 serum samples from 69 patients with acute liver failure (ALF) collected up to 24 months post-ALF, compared with controls, for titer and reactivity with the E2 subunits of pyruvate dehydrogenase, branched chain 2-oxo-acid dehydrogenase, and 2-oxo-glutarate dehydrogenase. AMAs were detected in 28/69 (40.6%) ALF patients with reactivity found against all of the major mitochondrial autoantigens. In addition, and as further controls, sera were analyzed for autoantibodies to gp210, Sp100, centromere, chromatin, soluble liver antigen, tissue transglutaminase, and deaminated gliadin peptides; the most frequently detected nonmitochondrial autoantibody was against tissue transglutaminase (57.1% of ALF patients). Conclusion: The strikingly high frequency of AMAs in ALF supports the thesis that oxidative stress-induced liver damage may lead to AMA induction. The rapid disappearance of AMAs in these patients provides further support for the contention that PBC pathogenesis requires additional factors, including genetic susceptibility. (HEPATOLOGY 2007;46:1436-1442

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

et al. 2007

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“…The major role of oxidative stress in APAP hepatotoxicity is supported by earlier work. [28][29][30][31][32][33] The effect of antioxidants on the TNF-␣-induced apoptosis in these experiments is of particular interest. Although the antioxidants prevented the APAP-and DEMinduced necrosis but not GSH depletion, they did not inhibit the apoptosis induced by TNF-␣ in the APAP-or DEM-sensitized cells.…”

Section: Discussionmentioning

confidence: 99%

Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

et al. 2002

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The effect of reduced glutathione (GSH) depletion by acetaminophen (APAP), diethylmaleate (DEM), or phorone on the mode of cell death and susceptibility to tumor necrosis factor (TNF)-induced cell death was studied in cultured mouse hepatocytes. Dose-dependent necrosis was the exclusive mode of cell death with APAP alone, but the addition of TNF-␣ induced a switch to about half apoptosis without changing total loss of viability. This effect was seen at 1

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“…Paracetamol/NAPQI is able to deplete cellular GSH levels (Adamson and Harman, 1993;Pumford et al, 1997), bind to proteins and DNA (Pumford et al, 1997), increase intracellular calcium concentrations (Tsokos-Kuhn, 1989), cause lipid peroxidation, increase reactive oxygen species (Manov et al, 2002), and has been shown to affect cell cycle progression and DNA synthesis (Djordjevic et al, 1986;Richard et al, 1991). There is some controversy over which mechanism is most important, and its, likely that all play a role, with different mechanisms predominating under differing conditions.…”

Section: Discussionmentioning

confidence: 99%

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

2004

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Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5 -10 mM paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy.

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Oxidative stress in cultured hepatocytes exposed to acetaminophen

Cited by 86 publications

References 20 publications

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis

Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

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