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


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.


CONCLUSIONS
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.
Rahman
Tony Manibur
TM
Department of Intensive Care Medicine, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom.
Selden
Angela Clare
AC
Hodgson
Humphrey Julian Francis
HJ
D000082:Acetaminophen / Q000008:administration & dosage; D000208:Acute Disease; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005978:Glutathione / Q000037:antagonists & inhibitors; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000401:mortality / Q000473:pathology; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology; D008297:Male; D008748:Methylcholanthrene; D010634:Phenobarbital; D011817:Rabbits
D000963:Antimetabolites; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D008748:Methylcholanthrene; D005978:Glutathione; D010634:Phenobarbital