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Toxicological Sciences 55, 444-452 (2000)
Copyright © 2000 by the Society of Toxicology

Bacterial Lipopolysaccharide Exposure Augments Aflatoxin B1-Induced Liver Injury

C. Charles Barton, Dwayne A. Hill, Steven B. Yee, Eva X. Barton, Patricia E. Ganey and Robert A. Roth1

Department of Pharmacology and Toxicology, National Center for Food Safety and Toxicology and Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824

Bacterial endotoxin (lipopolysaccharide; LPS) given to animals in large doses results in pronounced, midzonal liver injury. Exposure to smaller, non-injurious doses of LPS augments the toxicity of certain hepatotoxicants. This study was conducted to delineate the development of injury in a rat model of augmentation of aflatoxin B1 (AFB1) hepatotoxicity by LPS. At large doses (i.e., > 1 mg/kg, ip), AFB1 administration resulted in pronounced injury to the periportal regions of the liver. Male, Sprague-Dawley rats (250–350 g) were treated with 1 mg AFB1/kg, ip or its vehicle (0.5% DMSO/saline) and 4 h later with either E. coli LPS (7.4 x 106 EU/kg, iv) or its saline vehicle. Liver injury was assessed 6, 12, 24, 48, 72, or 96 h after AFB1 administration. Hepatic parenchymal cell injury was evaluated as increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum and from histologic examination of liver sections. Biliary tract alterations were evaluated as increased concentration of serum bile acids and activities of {gamma}-glutamyltransferase (GGT), alkaline phosphatase (ALP), and 5'-nucleotidase (5'-ND) in serum. At all times and for all markers, injury in rats treated with either AFB1 or LPS alone was absent or modest. In the AFB1/LPS cotreated group, hepatic parenchymal cell injury was pronounced by 24 h and had returned to control values by 72 h. The injury began in the periportal region and spread midzonally with time. Furthermore, changes in serum markers indicative of biliary tract alterations were evident by 12 h and had returned to control values by 72 h. Thus, the nature of the hepatic lesions suggested that LPS potentiated the effects of AFB1 on both parenchymal and bile duct epithelial cells.

Key Words: aflatoxin B1; apoptosis; endotoxin; lipopolysaccharide; LPS; liver injury; necrosis; oncosis; sensitivity to intoxication; sepsis.


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