Relative toxicity and comparative pathology of short-term exposure to select dehydropyrrolizidine alkaloids (riddelliine, senecionine, seneciphylline, heliotrine, lasiocarpine, riddelliine n-oxide, and senecionine n-oxide) in mice

Dehydropyrrolizidine alkaloid (PA) poisoning is common in livestock, wildlife, and humans. Dehydropyrrolizidine alkaloids have varying toxicities, though comparisons characterizing individual alkaloid toxicities are incomplete. The objective of this work was to directly compare the toxicity of select PAs in male C57BL/6J mice. Mice were exposed to varying doses of riddelliine, senecionine, seneciphylline, lasiocarpine, heliotrine, riddelliine N-oxide, and senecionine N-oxide for 10 days. Hepatic necrosis, serum biochemistries, and hepatic pyrrole concentrations were compared. Riddelliine and senecionine free base and N-oxide, seneciphylline, and lasiocarpine caused hepatocellular degeneration and necrosis. Both senecionine alkaloids produced midzonal or periportal lesions. Similar, but less severe midzonal degeneration and necrosis were observed in high-dose seneciphylline-treated mice with minimal hepatocyte enlargement at low doses. Both riddelliine alkaloids induced centrilobular degeneration and necrosis. High-dose lasiocarpine caused periportal hepatocyte enlargement and necrosis. High-dose heliotrine did not cause necrosis. Hepatic necrosis scores, liver enzyme activities, and liver pyrrole concentrations correlated with dose and necrosis scores for all alkaloids except heliotrine and lasiocarpine. The affected lobular area, degree of hepatic degeneration and necrosis, and the production of pyrroles were PA-specific. Under these conditions, seneciphylline and senecionine alkaloids were most toxic followed by riddelliine alkaloids. Lasiocarpine and heliotrine were the least toxic. This differs from relative toxicities reported in other models. In conclusion, in these mice, there are unique individual PA toxicities, lesion distributions, and pyrrole concentrations.