Comparative Study of Hepatotoxicity of Pyrrolizidine Alkaloids Retrorsine and Monocrotaline

Many pyrrolizidine alkaloids (PAs) can cause liver injury in animals and humans. Different hepatotoxic PAs can produce similar hepatotoxic effects, but the degree of their toxicities may vary widely. Retrorsine (RTS) and monocrotaline (MCT) share the same core structure (retronecine) and similar metabolic activation pathway. RTS and MCT both produced liver injury, but the former was more hepatotoxic than the latter. Enzyme kinetic study demonstrated that the value of Vmax/Km for RTS was 5.5-fold larger than that of MCT. Additionally, RTS produced higher levels of pyrrole–glutathione (GSH) conjugates and protein covalent binding than MCT at the same dose. Furthermore, RTS induced significant hepatic GSH depletion but MCT did little. This comparative study provides clear evidence that the generation of the reactive pyrrolic intermediates plays a critical role in PA-induced hepatotoxicity.