Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloid clivorine.

Clivorine is a representative naturally occurring hepatotoxic otonecine-type pyrrolizidine alkaloid. Our previous study has demonstrated that clivorine induces liver damage via metabolic activation to form the reactive pyrrolic ester followed by covalent binding to liver tissue constituents. The present study investigated species differences in the in vitro metabolic activation of clivorine in the male rat and guinea pig of both sexes. In the male rat, the activation of clivorine to form the reactive pyrrolic ester was found as the only metabolic pathway. Moreover, the toxic tissue-bound pyrroles and four isolatable metabolites identified, namely DHR, 7-GSH-DHR, 7,9-diGSH-DHR, and clivoric acid, were all generated from further metabolism of this reactive intermediate. In the case of both sexes of guinea pig, the same activation was observed as the minor biotransformation, while an additional metabolic pathway, a direct hydrolysis of clivorine to form novel clivopic acid was identified as the predominant d...