Acetaminophen-Induced Hepatic Necrosis V. Correlation of Hepatic Necrosis, Covalent Binding and Glutathione Depletion in Hamsters

Potter, William Z.; Thorgeirsson, SS; Jollow, David J.; Mitchell, Jerry R.

doi:10.1159/000136531

Cited by 296 publications

(127 citation statements)

References 8 publications

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“…Covalent binding was originally proposed as the mechanism for the initiation of APAP-induced toxicity based on the observation that extensive arylation of macromolecules occurs after NAPQI formation (33). However, many subsequent studies have shown that the resistance to APAP can occur without a FEBRUARY 22, 2008 • VOLUME 283 • NUMBER 8…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Toxicity-associated Metabolites by Metabolomics and Mass Isotopomer Analysis of Acetaminophen Metabolism in Wild-type and Cyp2e1-null Mice

Chen

Krausz

Idle

et al. 2008

Journal of Biological Chemistry

135

131

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CYP2E1 is recognized as the most important enzyme for initiation of acetaminophen (APAP)-induced toxicity. In this study, the resistance of Cyp2e1-null mice to APAP treatment was confirmed by comparing serum aminotransferase activities and blood urea nitrogen levels in wild-type and Cyp2e1-null mice. However, unexpectedly, profiling of major known APAP metabolites in urine and serum revealed that the contribution of CYP2E1 to APAP metabolism decreased with increasing APAP doses administered. Measurement of hepatic glutathione and hydrogen peroxide levels exposed the importance of oxidative stress in determining the consequence of APAP overdose. Subsequent metabolomic analysis was capable of constructing a principal components analysis (PCA) model that delineated a relationship between urinary metabolomes and the responses to APAP treatment. Urinary ions high in wild-type mice treated with 400 mg/kg APAP were elucidated as 3-methoxy-APAP glucuronide (VII) and three novel APAP metabolites, including S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid (VI, formed by a Cys-APAP transamination reaction in kidney), 3,3-biacetaminophen (VIII, an APAP dimer), and a benzothiazine compound (IX, originated from deacetylated APAP), through mass isotopomer analysis, accurate mass measurement, tandem mass spectrometry fragmentation, in vitro reactions, and chemical treatments. Dose-, time-, and genotype-dependent appearance of these minor APAP metabolites implied their association with the APAP-induced toxicity and potential biomarker application. Overall, the oxidative stress elicited by CYP2E1-mediated APAP metabolism might significantly contribute to APAPinduced toxicity. The combination of genetically modified animal models, mass isotopomer analysis, and metabolomics provides a powerful and efficient technical platform to characterize APAP-induced toxicity through identifying novel biomarkers and unraveling novel mechanisms. Acetaminophen (APAP)3 overdose causes acute liver and kidney failure (1, 2). Because of its clinical importance, APAPinduced acute toxicity has become an indispensable model for studying drug-induced liver and kidney injury. Over the past 40 years, numerous efforts have been undertaken to understand the molecular mechanism of this toxicological event. Results from those studies indicated that the toxicity is initiated by P450-mediated reactions that convert APAP to the reactive electrophile, N-acetyl-p-benzoquinone imine (NAPQI), causing glutathione depletion and covalent binding (3). Subsequent damage to mitochondria, cell membranes, and nuclei, as well as the disruption of cell death-and survival-related signaling pathways, lead to massive necrosis and apoptosis (4). Besides the P450-catalyzed oxidation reactions, detoxicating reactions including sulfation, glucuronidation, and glutathione conjugation also significantly contribute to the biotransformation of APAP and NAPQI. The balance between these activation and detoxication routes can largely determine the consequences of APAP treatment. Severa...

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Toxicity-associated Metabolites by Metabolomics and Mass Isotopomer Analysis of Acetaminophen Metabolism in Wild-type and Cyp2e1-null Mice

Chen

Krausz

Idle

et al. 2008

Journal of Biological Chemistry

135

131

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“…NAPQI is detoxified by conjugation with GSH (26), which becomes rapidly depleted in the presence of high acetaminophen concentrations. Unconjugated NAPQI is toxic to the liver (27). NAC works in this case by generating more reduced GSH (28).…”

Section: Figurementioning

confidence: 99%

N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice

Chen¹,

Adili²,

Gushiken³

et al. 2011

J. Clin. Invest.

210

187

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Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by systemic microvascular thrombosis caused by adhesion of platelets to ultra-large vWF (ULVWF) multimers. These multimers accumulate because of a deficiency of the processing enzyme ADAMTS13. vWF protein forms long multimers from homodimers that first form through C-terminal disulfide bonds and then join through their N termini by further disulfide bonding. N-acetylcysteine (NAC) is an FDA-approved drug that has long been used to treat chronic obstructive lung disease and acetaminophen toxicity and is known to function in the former disorder by reducing mucin multimers. Here, we examined whether NAC could reduce vWF multimers, which polymerize in a manner similar to mucins. In vitro, NAC reduced soluble plasma-type vWF multimers in a concentration-dependent manner and rapidly degraded ULVWF multimer strings extruded from activated ECs. The effect was preceded by reduction of the intrachain disulfide bond encompassing the platelet-binding A1 domain. NAC also inhibited vWF-dependent platelet aggregation and collagen binding. Injection of NAC into ADAMTS13-deficient mice led to the rapid resolution of thrombi produced by ionophore treatment of the mesenteric venules and reduced plasma vWF multimers. These results suggest that NAC may be a rapid and effective treatment for patients with TTP.

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“…hepatocytes, and lessened the severity of the biochemical and histopathological changes observed after paracetamol-induced acute liver injury Mitchell et al 1973;Potter et al 1973Potter et al ,1974. Therefore, NAPQI has been implicated as the toxic intermediate responsible of paracetamol-induced acute liver injury.…”

Section: Introductionmentioning

confidence: 99%

Novel acetylcysteine regimens for treatment of paracetamol overdose

Waring

2012

Therapeutic Advances in Drug Safety

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Pathophysiology of paracetamol-induced liver injuryAcute paracetamol administration is associated with significant depletion of glutathione (GSH), attributed to covalent binding of an intermediate paracetamol metabolite, N-acetyl-p-benzoquinone imine (NAPQI) to critical proteins and enzymes within hepatocytes. Restoration of intrahepatic glutathione concentrations in animals minimized the extent of NAPQI covalent binding to Novel acetylcysteine regimens for treatment of paracetamol overdose W. Stephen Waring Abstract: Paracetamol (acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose. Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment. The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations. This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury. Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.

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Acetaminophen-Induced Hepatic Necrosis V. Correlation of Hepatic Necrosis, Covalent Binding and Glutathione Depletion in Hamsters

Cited by 296 publications

References 8 publications

Identification of Novel Toxicity-associated Metabolites by Metabolomics and Mass Isotopomer Analysis of Acetaminophen Metabolism in Wild-type and Cyp2e1-null Mice

Identification of Novel Toxicity-associated Metabolites by Metabolomics and Mass Isotopomer Analysis of Acetaminophen Metabolism in Wild-type and Cyp2e1-null Mice

N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice

Novel acetylcysteine regimens for treatment of paracetamol overdose

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