Pyrrolizidine alkaloids: An update on their metabolism and hepatotoxicity mechanism

Pyrrolizidine alkaloids (PAs) are among the most hepatotoxic natural compounds that are widely distributed throughout the world. Most PAs are metabolically activated to trigger toxicity. Exposure to herbal medicine containing PAs and food supplements contaminated by PAs is considered to be one of the two main causes of hepatic sinusoidal obstruction syndrome (HSOS), which is a rare hepatic vascular disease with a high mortality rate. PAs-induced HSOS cases have been reported worldwide. However, there is no clinically effective therapy for PAs-induced HSOS, which is partially because the toxic mechanism is not fully understood. This review focuses on updating the information on the metabolism and the molecular mechanisms of PAs hepatotoxicity, including oxidative stress, apoptosis, and dysfunction of bile acid metabolism, and their interactions.