Mechanisms of Acetaminophen- Induced Liver Disease

Nelson, Sidney D.; Bruschi, Sam A.

doi:10.1201/9780203909126.pt3

Cited by 33 publications

(47 citation statements)

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“…Acute injury to hepatocytes alters their transport function and membrane permeability, leading to leakage of marker enzymes from the cells (Yang et al, 2008). The intracellular mechanisms of injury due to APAP in hepatocytes are the formation of reactive metabolites, depletion of glutathione and alkylation of proteins, especially the mitochondrial proteins (Nelson & Bruschi, 2003). These initiating events trigger mitochondrial membrane permeability transition.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential ofMoringa oleiferaextracts against acetaminophen-induced hepatotoxicity in rats

Sharifudin

Fakurazi²,

Hidayat

et al. 2012

Pharmaceutical Biology

100

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Section: Discussionmentioning

confidence: 99%

Therapeutic potential ofMoringa oleiferaextracts against acetaminophen-induced hepatotoxicity in rats

Sharifudin

Fakurazi²,

Hidayat

et al. 2012

Pharmaceutical Biology

100

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“…Approximately 90% of a therapeutic dose of APAP is conjugated with glucuronic acid or sulfate within the hepatocytes and excreted into bile or plasma. The remaining ∼5-10% of the APAP dose is metabolized by cytochrome P450 (CYP), particularly CYP2E1 (Nelson and Bruschi, 2003). The product of this reaction is a reactive metabolite, N-acetyl-para-benzoquinone imine (NAPQI) (Nelson and Bruschi, 2003), which is detoxified by glutathione (GSH).…”

Section: Acetaminophen Liver Toxicitymentioning

confidence: 99%

“…The remaining ∼5-10% of the APAP dose is metabolized by cytochrome P450 (CYP), particularly CYP2E1 (Nelson and Bruschi, 2003). The product of this reaction is a reactive metabolite, N-acetyl-para-benzoquinone imine (NAPQI) (Nelson and Bruschi, 2003), which is detoxified by glutathione (GSH). Once hepatocellular GSH levels are depleted, NAPQI reacts with sulfhydryl groups of proteins leading to formation of APAP protein adducts (Jollow et al, 1973).…”

Section: Acetaminophen Liver Toxicitymentioning

confidence: 99%

Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury

2007

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Polymorphonuclear leukocytes (neutrophils) are essential in the defense against invading microorganisms, tissue trauma or any inciting inflammatory signals. Hepatic infiltration of neutrophils is an acute response to recent or ongoing liver injury, hepatic stress or unknown systemic inflammatory signals. Once neutrophils reach the liver, they can cause mild-to-severe tissue damage and consequent liver failure. For neutrophils to appear in the liver, neutrophils have to undergo systemic activation (priming) by inflammatory mediators such as cytokines, chemokines, complement factors, immune complexes, opsonized particles and other biologically active molecules, e.g., platelet activating factor. Neutrophils accumulated in the hepatic microvasculature (sinusoids and postsinusoidal venules) can extravasate (transmigrate) into the hepatic parenchyma if they receive a signal from distressed cells. Transmigration can be mediated by a chemokine gradient established towards the hepatic parenchyma and generally involves orchestration by adhesion molecules on neutrophils (β 2 integrins) and on endothelial cells (intracellular adhesion molecules, ICAM-1). After transmigration, neutrophils adhere to distressed hepatocytes through their β 2 integrins and ICAM-1 expressed on hepatocytes. Neutrophil contact with hepatocytes mediate oxidative killing of hepatocytes by initiation of respiratory burst and neutrophil degranulation leading to hepatocellular oncotic necrosis. Neutrophil-mediated liver injury has been demonstrated in a variety of diseases and chemical/drug toxicities. Relevant examples are discussed in this review.

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“…4,6,9 Activated phagocytes undergo respiratory burst to generate superoxide and hydrogen peroxide, which are important in killing invading organisms, and are also capable of inflicting damage to surrounding tissues. Respiratory burst was measured in isolated hepatic leukocytes stimulated by PMA to examine whether neutrophils contribute to oxidative stress in the liver.…”

Section: Respiratory Burst In Hepatic Leukocytesmentioning

confidence: 99%

“…The toxic response to APAP is thought to be initiated by a highly electrophilic intermediate, N-acetyl-p-benzoquinone-imine (NAPQI), generated by hepatic CYP2E1. [2][3][4] Excessive NAPQI depletes hepatic glutathione (GSH) and covalently binds to cellular macromolecules, resulting in oxidative stress reactions, dysfunction of mitochondria, and DNA damage. 4 These initiation events ultimately may result in direct damage to hepatocytes, leading to cell death of hepatocytes.…”

mentioning

confidence: 99%

Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

et al. 2006

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We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-␥) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1 ؉ Gr-1 ؉ ). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1-deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1-deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1-deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Mechanisms of Acetaminophen- Induced Liver Disease

Cited by 33 publications

References 0 publications

Therapeutic potential ofMoringa oleiferaextracts against acetaminophen-induced hepatotoxicity in rats

Therapeutic potential ofMoringa oleiferaextracts against acetaminophen-induced hepatotoxicity in rats

Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury

Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

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