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A novel model of acetaminophen-induced acute hepatic failure in rabbits

Rahman, TM; Selden, AC; Hodgson, HJF; (2002) A novel model of acetaminophen-induced acute hepatic failure in rabbits. J SURG RES , 106 (2) 264 - 272. 10.1006/jsre.2002.6476.

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Abstract

Background. Few reliable and reproducible animal models of acute hepatic failure exist or conform to the criteria proposed by Terblanche and Hickman (Dig. Dis. Sci. 36: 770, 1991). In this prospective randomized study we describe the selective induction of CYP450 enzymes, depletion of glutathione, and hepatotoxic insult using acetaminophen in the development and characterization of a novel rabbit model of acute hepatic failure.Materials and methods. Male New Zealand white rabbits weighing 3-5 kg were used. After preliminary dose ranging experiments, two groups of New Zealand white (n = 8 in each group) rabbits had CYP450 induction with phenobarbitone (40 mg/kg ip, for 5 days) or with 20-methylcholanthrene (80 mg/kg ip). The glutathione synthetase inhibitor buthionine sulfoxime (2 mmol/kg iv) was then administered prior to acetaminophen administration (500 mg/kg sc). Clinical observations were recorded and arterial blood was sampled over 72 h.Results. Grade I-III encephalopathy occurred at 5-12, 12-25, and 28-56 h, respectively, in animals pretreated with 20-methylcholanthrene, but not in the phenobarbitone pretreated group. Mortality was 75% in the 20-methylcholanthrene group compared to 0% in the phenobarbitone group. Blood lactate (P < 0.05), prothrombin time (P < 0.005), aspartate transaminase (P < 0.005), and creatinine (P < 0.05) were higher in the 20-methylcholanthrene group compared to the phenobarbitone group. Histological changes were marked in the 20-methylcholanthrene group with massive coagulative hepatic necrosis compared to minimal histological damage in the phenobarbitone group.Conclusion. The induction with 20-methylcholanthrene, glutathione depletion with buthionine sulfoxime, and subcutaneous administration of acetaminophen have led to the development of an animal model that parallels clinical, biochemical, and histological features of human hepatic failure. (C) 2002 Elsevier Science (USA).

Type: Article
Title: A novel model of acetaminophen-induced acute hepatic failure in rabbits
DOI: 10.1006/jsre.2002.6476
Keywords: liver, hepatic, fulminant, acetaminophen, methylcholanthrene, phenobarbitone, PROSTAGLANDIN ENDOPEROXIDE SYNTHETASE, 3-METHYLCHOLANTHRENE PRETREATMENT, CYTOCHROME-P-450 ISOZYMES, SPECIES VARIATION, YOUNG-RATS, DOG-MODEL, HEPATOTOXICITY, PARACETAMOL, HEPATOCYTES, NECROSIS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: http://discovery.ucl.ac.uk/id/eprint/156090
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