Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline

Individuals are commonly exposed to bacterial endotoxin (lipopolysaccharide [LPS]) through gram-negative bacterial infection and from its translocatio n from the gastrointestinal lumen into the circulation. Inasmuch as noninju rious doses of LPS augment the hepatotoxicity of certain xenobiotic agents, exposure to small amounts of LPS may be an important determinant of suscep tibility to chemical intoxication. Monocrotaline (MCT) is a pyrrolizidine a lkaloid phytotoxin that at large doses produces centrilobular liver lesions in rats. In the present study, MCT was coadministered with LPS to determin e whether LPS would enhance its hepatotoxicity. Doses of MCT (100 mg/kg, ip ) and LPS (7.4 x 10(6) EU/kg, iv), which were nonhepatotoxic when administe red separately, produced significant liver injury in male, Sprague-Dawley r ats when given in combination. Within 18 h after MCT administration, this c otreatment resulted in enhanced plasma alanine aminotransferase and asparta te aminotransferase activities, two markers of liver injury. Histologically , overt hemorrhage and necrosis appeared between 12 and 18 h. The lesions w ere centrilobular and midzonal and exhibited characteristics similar to les ions associated with larger doses of MCT and LPS, respectively. In the pres ence of LPS, the threshold for MCT toxicity was reduced to 13-33% of the do se required for toxicity with MCT alone. A study in isolated, hepatic paren chymal cells revealed no interaction between MCT and LPS in producing cytot oxicity. In summary, coexposure of rats to noninjurious doses of MCT and LP S resulted in pronounced liver injury. Results in vitro suggest that the en hanced toxicity does not result from a direct interaction of MCT and LPS wi th hepatic parenchymal cells. These results provide additional evidence tha t exposure to small amounts of LPS may be a determinant of susceptibility t o food-borne hepatotoxins. (C) 2000 Academic Press.