Print Email Facebook Twitter A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat Title A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat Author Punt, A. Freidig, A.P. Delatour, T. Scholz, G. Boersma, M.G. Schilter, B. van Bladeren, P.J. Rietjens, I.M.C.M. TNO Kwaliteit van Leven Publication year 2008 Abstract The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene estragole in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model consists of eight compartments including liver, lung and kidney as metabolizing compartments, and additional compartments for fat, arterial blood, venous blood, rapidly perfused tissue and slowly perfused tissue. Evaluation of the model was performed by comparing the PBBK predicted dose-dependent formation of the estragole metabolites 4-allylphenol and 1′-hydroxyestragole glucuronide to literature reported levels of these metabolites, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of estragole at different oral doses was examined. At low doses formation of 4-allylphenol, leading to detoxification, is observed to be the major metabolic pathway, occurring mainly in the lung and kidney due to formation of this metabolite with high affinity in these organs. Saturation of this metabolic pathway in the lung and kidney leads to a relative increase in formation of the proximate carcinogenic metabolite 1′-hydroxyestragole, occurring mainly in the liver. This relative increase in formation of 1′-hydroxyestragole leads to a relative increase in formation of 1′-hydroxyestragole glucuronide and 1′-sulfooxyestragole the latter being the ultimate carcinogenic metabolite of estragole. These results indicate that the relative importance of different metabolic pathways of estragole may vary in a dose-dependent way, leading to a relative increase in bioactiviation of estragole at higher doses. © 2008 Elsevier Inc. All rights reserved. Subject Food and NutritionBiologyHealthy LivingBiomedical ResearchBioactivationDetoxificationEstragoleIn vitroPBPKRat1' hydroxyestragole glucuronide1' sulfooxyestragoleBenzene derivativeChavicolEstragoleGlucuronidePhenol derivativeUnclassified drugAnimal tissueArterial bloodBody fatControlled studyDetoxificationIn vitro studyKineticsLiverNonhumanPartition coefficientRatTissue perfusionVenous bloodAllyl CompoundsAnimalsAnisolesCarcinogensDose-Response Relationship, DrugFemaleGlucuronidesKidneyLungMaleMetabolic Detoxication, DrugModels, BiologicalPhenolsRatsRats, Sprague-DawleyRats, WistarSulfonesTissue DistributionRattus To reference this document use: http://resolver.tudelft.nl/uuid:127924b6-57bb-4d52-9bc3-a574a893039e DOI https://doi.org/10.1016/j.taap.2008.04.011 TNO identifier 240987 ISSN 0041-008X Source Toxicology and Applied Pharmacology, 231 (2), 248-259 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.