The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity

Jaeschke, Hartmut; Knight, Tamara R.; Bajt, Mary Lynn

doi:10.1016/s0378-4274(03)00239-x

Cited by 397 publications

(262 citation statements)

References 70 publications

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“…NAPQI, the toxic metabolite of acetaminophen, binds to GSH covalently and causes GSH depletion. 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.…”

Section: Resultsmentioning

confidence: 99%

“…2 Cytochrome P-450 oxidation of acetaminophen forms a chemically reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which reacts with glutathione (GSH) to form an acetaminophen-GSH conjugate. Once GSH is exhausted, NAPQI binds to cellular proteins, including a number of mitochondrial proteins, 3,4 which leads to hepatocellular death. In mouse hepatocytes, acetaminophen inhibits mitochondrial oxidative phosphorylation, resulting in depletion of adenosine triphosphate (ATP).…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

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confidence: 99%

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

et al. 2004

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“…This results in ROS formation that promotes functional loss of membranal integrity, alters enzyme activities, and consequently results in hepatic injury or necrosis (Rajib et al, 2009). When these happen, cytosolic AST, ALT and ALP are released into systemic circulation and their measurement can be used to assess the extent of drug-induced hepatotoxicity (Jaeschke et al, 2003). In this study, the elevated activities of these marker enzymes in the CCl 4 -intoxicated rats may be indicative of liver damage and cell necrosis resulting from formation of CCl 3 * in excess of GSH detoxification capacity.…”

Section: Discussionmentioning

confidence: 94%

Mechanism of hepatoprotective potential of aqueous leaves extract of Eucalyptus obliqua (Myrtaceae) in carbon tetrachloride intoxicated Wistar rats

2017

J App Pharm Sci

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This study investigated the protective mechanism of aqueous leaves extract of Eucalyptus obliqua (EOAE) in CCl4-mediated liver damage in Wistar rats. The animals were orally pretreated with either the extract (200 and 400 mg/kg) or vitamin C (200 mg/kg) for 10 days prior to the intraperitoneal administration of 3 mL/kg CCl4 (30% in olive oil). Subsequently, hepatic function, antioxidant and histological analyses were evaluated. The results showed that the CCl4-induced increases in the activities of ALT, ALP, AST and the concentrations of bilirubin, oxidized glutathione and malondialdehyde were significantly and dose-dependently reduced in the extract-treated rats. The extract also significantly improved the attenuated activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase as well as total protein, albumin and glutathione concentrations in the hepatotoxic animals. These improvements could be attributed to the phytoconstituents revealed by the GCMS analysis of the extract. The observed activities compared with that of vitamin C and are suggestive of hepatoprotective and antioxidant properties of EOAE and were also supported by the histological results. Overall, these data indicate that EOAE has a significant protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its capability to fortify the antioxidant defense systems.

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“…Interestingly, mice with a genetic deficiency of glutathione peroxidase did not demonstrate any exacerbation of liver injury after APAP [16], indicating that these modifications are most likely a consequence, rather than a cause of mitochondrial dysfunction. However, while individual protein modifications are unlikely to influence downstream events, mitochondrial adduct formation as a whole is important for subsequent steps in toxicity, since NAPQI binding to mitochondrial proteins correlates with toxicity [17]. Taken together, the current data indicate that formation of mitochondrial protein adducts on a number of different proteins, probably beyond a certain threshold, is critical for initiating mitochondrial dysfunction and subsequent cell signaling ultimately resulting in hepatocyte necrosis.…”

Section: Acetaminophen Hepatotoxicitymentioning

confidence: 87%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity

Cited by 397 publications

References 70 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

Mechanism of hepatoprotective potential of aqueous leaves extract of Eucalyptus obliqua (Myrtaceae) in carbon tetrachloride intoxicated Wistar rats

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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