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 Nutrition
Biology
Healthy Living
Biomedical Research
Bioactivation
Detoxification
Estragole
In vitro
PBPK
Rat
1' hydroxyestragole glucuronide
1' sulfooxyestragole
Benzene derivative
Chavicol
Estragole
Glucuronide
Phenol derivative
Unclassified drug
Animal tissue
Arterial blood
Body fat
Controlled study
Detoxification
In vitro study
Kinetics
Liver
Nonhuman
Partition coefficient
Rat
Tissue perfusion
Venous blood
Allyl Compounds
Animals
Anisoles
Carcinogens
Dose-Response Relationship, Drug
Female
Glucuronides
Kidney
Lung
Male
Metabolic Detoxication, Drug
Models, Biological
Phenols
Rats
Rats, Sprague-Dawley
Rats, Wistar
Sulfones
Tissue Distribution
Rattus
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