Genotoxicity of the pyrrolizidine alkaloid jacobine in rats.

Jacobine (JAC) is a pyrolizidine alkaloid (PA) exhibiting adverse hepatic effects similar to those induced by another PA, monocrotaline (MCT). The in vitro reaction kinetics of JAC, however, have been reported to differ quantitively from those of MCT. We report results of experiments to detect and characterize hepatic DNA damage resulting from in vivo administration of JAC (5-60 mg/kg i.p.) to male Sprague-Dawley rats. Hepatic nuclei were isolated and served as the source of DNA in these experiments. Alkaline elution was employed to characterize the type(s) of DNA damage induced. At 4 h post administration, JAC induced significant dose-dependent DNA-DNA interstrand cross-linking over the entire range of doses. Significant DNA-protein cross-linking was also induced by doses of 15-60 mg/kg. No DNA single-strand breaks were detected. Previous studies in this laboratory have shown MCT to induce these same types of lesions. Results from these experiments demonstrate that despite a reported difference in vitro reaction kinetics, these compounds induce a similar spectrum of DNA damage in the target organ of a susceptible species, where the adverse effects induced are also similar. such similarities are consistent with the involvement of DNA damage in the adverse hepatic effects of PAs.