Calcium-dependent DNA damage and adenosine 3′,5′-cyclic monophosphate- independent glycogen phosphorylase activation in an in vitro model of acetaminophen-induced liver injury

Salas, Virginia M.; Corcoran, George B.

doi:10.1002/hep.510250621

Cited by 39 publications

(17 citation statements)

References 34 publications

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“…DNA fragmentation is another mechanism that has been implicated in acetaminophen-induced hepatotoxicity (Salas and Corcoran 1997). Genomic DNA fragmentation in liver (TUNEL assay and DNA laddering) following hepatotoxic doses of acetaminophen in the mouse was originally reported by Corcoran’s laboratory (Ray et al 1990, 1993).…”

Section: Intracellular Signaling Mechanisms In Acetaminophen Toxicitmentioning

confidence: 99%

Mechanisms of Acetaminophen-Induced Liver Necrosis

Hinson

Roberts²,

James³

2009

Handbook of Experimental Pharmacology

849

681

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Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.

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Section: Intracellular Signaling Mechanisms In Acetaminophen Toxicitmentioning

confidence: 99%

Mechanisms of Acetaminophen-Induced Liver Necrosis

Hinson

Roberts²,

James³

2009

Handbook of Experimental Pharmacology

849

681

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“…Loss of mitochondrial or nuclear ion balance has also been suggested to be a toxic mechanism involved in acetaminophen-mediated cell death since either of these losses can lead to increases in cytosolic (Nelson, 1990;Ray et al, 1993;Salas and Corcoran, 1997). The effect of the addition of NAPQI on isolated mitochondria has been reported (Weis et al, 1992) and inhibition of mitochondrial respiration has been investigated as an important mechanism in acetaminophen toxicity (Donnelly et al, 1994).…”

Section: Biochemical Mechanisms Of Toxicitymentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity

James¹,

Mayeux²,

Hinson³

2003

Drug Metab Dispos

890

683

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1␤ is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.

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“…It continues to be a significant cause of liver injury and lethality in humans (2). Studies have suggested that APAP-induced liver injury may be related to protein arylation (3), oxidative stress (4 -6), disruption of calcium (7,8) and mitochondrial homeostasis (9), alteration of transcription pathways (10 -12), proinflammatory signaling (13)(14)(15), and the induction of cell death pathways (2). However, the precise molecular events occurring within the liver following APAP insult have still not been deciphered, and only a limited number of pathways involved in controlling toxicity progression have been identified (6,16).…”

mentioning

confidence: 99%