A physiologically based biokinetic (PBBK) model for estragole bioactivation and detoxification in rat.
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.
Punt
Ans
A
Division of Toxicology, Wageningen University, Tuinlaan 5, 6703HE Wageningen, The Netherlands. ans.punt@wur.nl
Freidig
Andreas P
AP
Delatour
Thierry
T
Scholz
Gabriele
G
Boersma
Marelle G
MG
Schilter
Benoît
B
van Bladeren
Peter J
PJ
Rietjens
Ivonne M C M
IM
D000498:Allyl Compounds / Q000378:metabolism; D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D008658:Inactivation, Metabolic; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010636:Phenols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013450:Sulfones / Q000378:metabolism; D014018:Tissue Distribution
D000498:Allyl Compounds; D000081248:Allylbenzene Derivatives; D000840:Anisoles; D002273:Carcinogens; D020719:Glucuronides; D010636:Phenols; D013450:Sulfones; C014037:1'-hydroxyestragole; C007633:estragole