title: Use of physiologically based biokinetic (PBBK) modeling to study estragole bioactivation and detoxification in humans as compared with male rats.
abstract: The extent of bioactivation of the herbal constituent estragole to its ultimate carcinogenic metabolite 1'-sulfooxyestragole depends on the relative levels of 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 physiologically based biokinetic (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 with 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 twofold higher in human compared with male rat, even though the formation of its precursor 1'-hydroxyestragole was predicted to be fourfold 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.
authors.affiliation: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors.forename: Ans
authors.initials: A
authors.lastname: Punt
authors.forename: Alicia
authors.initials: A
authors.lastname: Paini
authors.forename: Marelle G
authors.initials: MG
authors.lastname: Boersma
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Freidig
authors.forename: Thierry
authors.initials: T
authors.lastname: Delatour
authors.forename: Gabriele
authors.initials: G
authors.lastname: Scholz
authors.forename: Benoît
authors.initials: B
authors.lastname: Schilter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Bladeren
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D008658:Inactivation, Metabolic; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results; D013045:Species Specificity; D018675:Toxicity Tests
chemical_list: D000081248:Allylbenzene Derivatives; D000840:Anisoles; D002273:Carcinogens; D020719:Glucuronides; C014037:1'-hydroxyestragole; C007633:estragole