PubMed · 11935887
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A Dines. 2001. Antidotes.. https://doi.org/10.7748/en2001.11.9.7.23.c1374
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Acetaminophen (AAP) overdose can cause severe hepatotoxicity and even liver failure in experimental animals and humans. Despite substantial efforts over the last 30 years, the mechanism of AAP-induced liver cell injury is still not completely understood. It is widely accepted that the injury process is initiated by the metabolism of AAP to a reactive metabolite, which first depletes glutathione and then binds to cellular proteins including a number of mitochondrial proteins. One consequence of this process may be the observed inhibition of mitochondrial respiration, ATP depletion and mitochondrial oxidant stress. In the presence of sufficient vitamin E, reactive oxygen formation does not induce severe lipid peroxidation but the superoxide reacts with nitric oxide to form peroxynitrite, a powerful oxidant and nitrating agent. Peroxynitrite can modify cellular macromolecules and may aggravate mitochondrial dysfunction and ATP depletion leading to cellular oncotic necrosis in hepatocytes and sinusoidal endothelial cells. Thus, we hypothesize that reactive metabolite formation and protein binding initiate the injury process, which may be then propagated and amplified by mitochondrial dysfunction and peroxynitrite formation. This concept also reconciles many of the controversial findings of the past and provides a viable hypothesis for the mechanism of hepatocellular injury after AAP overdose.
To determine the importance of IL-6 in acetaminophen (APAP) toxicity, wild type (WT) and IL-6 knock out (KO) mice were dosed with APAP (300 mg/kg i.p.) and sacrificed at 4 and 24h. No differences were found between the two groups by analysis of serum AST levels or histopathology. Also, the relative amounts of APAP protein binding and nitrotyrosine formation were equal. Subsequently, WT and KO mice were dosed with APAP (300 mg/kg i.p.) and sacrificed at 24, 48, and 72 h. AST normalized by 48 h in the WT mice, but not until 72 h in the KO mice. The severity of the histopathological alterations was comparable in the two groups of mice; however, fewer regenerating hepatocytes were present in the KO mice. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed reduced staining in the KO mice. Pretreatment of KO mice with IL-6 lowered AST and normalized PCNA staining in the IL-6 KO mice. These data suggest that IL-6 is important in hepatocyte regeneration following APAP toxicity in the mouse.
Acetaminophen, a safe analgesic when dosed properly but hepatotoxic at overdoses, has been reported to induce DNA strand breaks but it is unclear whether this event preceeds hepatocyte toxicity or is only obvious in case of overt cytotoxicity. Moreover, it is not known whether the formation of reactive oxygen species (ROS) is involved in the formation of the DNA strand breaks. In the present study, the dose-response curves for cytotoxicity and DNA strand breaks and the response to antioxidant protection have been compared. In primary hepatocytes from untreated male rats, cytotoxicity as measured by the MTT test and by Neutral Red accumulation was obvious at 10 mM acetaminophen but DNA strand breaks as measured by the comet assay were only found at 25-30 mM acetaminophen. Non-cytotoxic concentrations of three compounds with antioxidant activity, the glutathione precursor N-acetylcysteine (100 micro M), the plant polyphenol silibin (25 micro M) and the antioxidant vitamin alpha-tocopherol (50 micro M), were not able to inhibit acetaminophen toxicity at any acetaminophen concentration, while they completely prevented the formation of DNA strand breaks at 25-30 mM acetaminophen. The occurrence of oxidative stress in our experiments was indicated by a slight increase of malondialdehyde formation at 40 mM acetaminophen and by an adaptive increase in catalase mRNA concentration. We conclude that in acetaminophen-treated hepatocytes ROS-independent cell death and ROS-dependent DNA strand breaks occur which appear not to be causally related as judged from their dose dependency and their response to antioxidants.