Use of physiologically based biokinetic (PBBK) modeling to study estragole bioactivation and detoxification in humans as compared to male rats.

Toxicol Sci. 2009 May 15; Punt A, Paini A, Boersma MG, Freidig AP, Delatour T, Scholz G, Schilter B, van Bladeren PJ, Rietjens IMThe extent of bioactivation of the herbal constituent estragole to its ultimate carcinogenic metabolite, 1'-sulfooxyestragole depends on the relative levels of both bioactivation and detoxification pathways. The present study investigated the kinetics of the metabolic reactions of both estragole and its proximate carcinogenic metabolite 1'-hydroxyestragole in humans in incubations with relevant tissue fractions. Based on the kinetic data obtained a PBBK model for estragole in human was defined to predict the relative extent of bioactivation and detoxification at different dose levels of estragole. The outcomes of the model were subsequently compared to those previously predicted by a PBBK model for estragole in male rat to evaluate the occurrence of species differences in metabolic activation. The results obtained reveal that formation of 1'-oxoestragole, which represents a minor metabolic route for 1'-hydroxyestragole in rat, is the main detoxification pathway of 1'-hydroxyestragole in humans. Due to a high level of this 1'-hydroxyestragole oxidation pathway in human liver, the predicted species differences in formation of 1'-sulfooxyestragole remain relatively low, with the predicted formation of 1'-sulfooxyestragole being 2-fold higher in human compared to male rat, even though the formation of its precursor 1'-hydroxyestragole was predicted to be 4-fold higher in human. Overall, it is concluded that in spite of significant differences in the relative extent of different metabolic pathways between human and male rat there is a minor influence of species differences on the ultimate overall bioactivation of estragole to 1'-sulfooxyestragole.