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Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer

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Title: Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer
Authors: Kyriakides, M
Maitre, L
Stamper, B
Mohar, I
Kavanagh, T
Foster, J
Wilson, I
Holmes, E
Nelson, S
Coen, M
Item Type: Journal Article
Abstract: The leading cause of drug-induced liver injury in the developed world is overdose with N-acetyl-p-aminophenol (APAP). A comparative metabonomic approach was applied to the study of both xenobiotic and endogenous metabolic profiles reflective of in-vivo exposure to APAP (300 mg/kg) and its structural isomer N-acetyl-m-aminophenol (AMAP; 300 mg/kg) in C57BL/6J mice, which was anchored with histopathology. Liver and urine samples were collected at 1, 3 and 6 hours post-treatment and analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (liver only). Histopathology revealed the presence of centrilobular necrosis from 3 hours post-APAP treatment, while an AMAP-mediated necrotic end-point was not observed within the time-scale of this study, yet two of five treated mice showed minimal centrilobular eosinophilia. The 1H-NMR spectroscopic xenobiotic metabolic profile of APAP-treated animals comprised of mercapturate (urine and liver) and glutathionyl (liver) conjugates detected at 1 hour post-treatment. This finding corroborated the hepatic endogenous metabolic profile which showed depletion of glutathione from 1 hour onwards. In contrast, AMAP glutathionyl conjugates were not detected, nor was AMAP-induced depletion of hepatic glutathione observed. APAP administration induced significant endogenous hepatic metabolic perturbations, primarily linked to oxidative and energetic stress, and perturbation of amino acid metabolism. Early depletion of glutathione was followed by depletion of additional sulphur containing metabolites, while altered levels of mitochondrial and glycolytic metabolites indicated a disruption of energy homeostasis. In contrast, AMAP administration caused minimal, transient, distinct metabolic perturbations and by 6 hours the metabolic profiles of AMAP-treated mice were indistinguishable from those of controls.
Issue Date: 9-Jan-2016
Date of Acceptance: 22-Nov-2015
URI: http://hdl.handle.net/10044/1/28057
DOI: 10.1007/s00204-015-1655-x
ISSN: 1432-0738
Publisher: Springer Verlag (Germany)
Start Page: 3073
End Page: 3085
Journal / Book Title: Archives of Toxicology
Volume: 90
Issue: 12
Copyright Statement: © The Author(s) 2016. This article is published with open access at Springerlink.com
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: DSMB_P22283
Keywords: Hepatotoxicity
Metabonomics/Metabolic Phenotyping
N-acetyl-m-aminophenol (AMAP)
N-acetyl-p-aminophenol (APAP)
Nuclear magnetic resonance spectroscopy
1115 Pharmacology And Pharmaceutical Sciences
Publication Status: Published
Appears in Collections:Department of Surgery and Cancer