Bacterial lipopolysaccharide exposure augments aflatoxin B-1-induced liverinjury

Bacterial endotoxin (lipopolysaccharide; LPS) given to animals in large dos es results in pronounced, midzonal liver injury. Exposure to smaller, non-i njurious doses of LPS augments the toxicity of certain hepatotoxicants. Thi s study was conducted to delineate the development of injury in a rat model of augmentation of aflatoxin B-1 (AFB(1)) hepatotoxicity by LPS. At large doses (i.e., > 1 mg/kg, ip), AFB(1) administration resulted in pronounced i njury to the periportal regions of the liver. Male, Sprague-Dawley rats (25 0-350 g) were treated with 1 mg AFB(1)/kg, ip or its vehicle (0.5% DMSO/sal ine) and 4 h later with either E. coli LPS (7.4 x 10(6) EU/kg, iv) or its s aline vehicle. Liver injury was assessed 6, 12, 24, 48, 72, or 96 h after A FB(1) administration. Hepatic parenchymal cell injury was evaluated as incr eased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) a ctivities in serum and from histologic examination of liver sections. Bilia ry tract alterations were evaluated as increased concentration of serum bil e acids and activities of gamma-glutamyltransferase (GGT), alkaline phospha tase (ALP), and 5'-nucleotidase (5'-ND) in serum. At all times and for all markers, injury in rats treated with either AFB(1) or LPS alone was absent or modest. In the AFB(1)/LPS cotreated group, hepatic parenchymal cell inju ry was pronounced by 24 h and had returned to control values by 72 h. The i njury began in the periportal region and spread midzonally with time. Furth ermore, changes in serum markers indicative of biliary tract alterations we re evident by 12 h and had returned to control values by 72 h. Thus, the na ture of the hepatic lesions suggested that LPS potentiated the effects of A FB(1) on both parenchymal and bile duct epithelial cells.