Bacterial lipopolysaccharide exposure alters aflatoxin B(1) hepatotoxicity: benchmark dose analysis for markers of liver injury

Aflatoxin B(1) (AFB(1)) is a fungal toxin that causes both acute hepatotoxicity and hepatocellular carcinoma in humans and experimental animals. Previous studies demonstrated that a small, noninjurious dose of bacterial lipopolysaccharide (LPS) augments the hepatotoxicity of AFB(1) through activation of inflammatory cells and production of soluble inflammatory mediators (Barton et al., 2000b, 2001). This study was conducted to examine the effect of LPS on the dose-response relationship for AFB(1)-induced liver injury. Male Sprague-Dawley rats (250-350g) were treated with AFB(1) (0.1 mg/kg-6.3 mg/kg, ip) and 4 h later with a noninjurious dose of E. coli LPS (7.4 x 10(6) EU/kg, iv). Twenty-four h after AFB(1) administration, hepatic parenchymal cell injury was estimated from elevations in serum alanine aminotransferase and aspartate aminotransferase activities. Injury to intrahepatic bile ducts was evaluated from increased serum gamma-glutamyl transferase and alkaline phosphatase activities. Based on benchmark dose (BMD) analysis, the AFB(1) BMD for parenchymal cell injury was decreased 10-fold by LPS cotreatment, whereas AFB(1) BMDs for bile duct injury were decreased nearly 20-fold. The data suggest that concurrent inflammation renders the liver considerably more sensitive to the hepatotoxic effects of AFB(1).