The killing of cultured hepatocytes by N-acetyl-p-benzoquinone imine (NAPQI) as a model of the cytotoxicity of acetaminophen
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Cited by (33)
Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways
2014, Hearing ResearchCitation Excerpt :These authors presented solid evidence that killing of hepatocytes by APAP was dependent on a cellular source of ferric iron, potentiated by 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU, an inhibitor of glutathione reductase), and very sensitive to antioxidants. By contrast, NAPQI hepatotoxicity was not prevented by chelation of ferric iron, was unaffected by BCNU, and was insensitive to antioxidants (Harman et al., 1991). Moreover, the killing of cultured hepatocytes by NAPQI was preceded by a collapse of the mitochondrial membrane potential and a depletion of ATP, suggesting that mitochondrial de-energization by a mechanism unrelated to oxidative stress was likely the mechanism of hepatocytes killing by NAPQI (Harman et al., 1991).
Acetaminophen ototoxicity after acetaminophen/hydrocodone abuse: Evidence from two parallel in vitro mouse models
2010, Otolaryngology - Head and Neck SurgeryCitation Excerpt :Although only a small fraction (5%-10%) of acetaminophen is converted by CYP2E1 into NAPQI (90% is excreted as conjugates of glucuronide and sulfate16), acute overdose may overwhelm glutathione stores that normally inactivate NAPQI, resulting in the reported toxic effects to the liver.17 A later study, however, provided plausible evidence that while acetaminophen-mediated hepatotoxicity may be from oxidative injury, NAPQI may kill hepatocytes by a different mechanism.18 Although acetaminophen hepatotoxicity was sensitive to antioxidants and was potentiated by BCNU (carmustine; Bristol Meyers Squibb Oncology/Immunology Division, Princeton, NJ)—an inhibitor of glutathione reductase—NAPQI liver cytotoxicity was insensitive to antioxidants and was unaffected by BCNU.
Elevated hepatic iron: A confounding factor in chronic hepatitis C
2009, Biochimica et Biophysica Acta - General SubjectsAcetaminophen Hepatotoxicity
2007, Clinics in Liver DiseaseCitation Excerpt :Glutathione depletion further contributes to cellular oxidant stress [27,64]. With NAPQI binding to critical cellular targets, such as mitochondrial proteins, mitochondrial dysfunction and loss of cellular ATP occurs [65,66]. The hepatocytes subsequently experience overall energy failure [67–70].
Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice
2005, Journal of HepatologyCar inhibitors: New line of treatment for APAP poisoning?
2003, Journal of Hepatology
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This work was performed during the tenure of a sabbatical leave from the Department of Pharmacology, University of Western Australia, Nedlands, Western Australia.