Journal Article

Evaluation of Human Interindividual Variation in Bioactivation of Estragole Using Physiologically Based Biokinetic Modeling

Ans Punt, Suzanne M. Jeurissen, Marelle G. Boersma, Thierry Delatour, Gabriele Scholz, Benoît Schilter, Peter J. van Bladeren and Ivonne M. C. M. Rietjens

in Toxicological Sciences

Volume 113, issue 2, pages 337-348
Published in print February 2010 | ISSN: 1096-6080
Published online November 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp272
Evaluation of Human Interindividual Variation in Bioactivation of Estragole Using Physiologically Based Biokinetic Modeling

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The present study investigates interindividual variation in liver levels of the proximate carcinogenic metabolite of estragole, 1′-hydroxyestragole, due to variation in two key metabolic reactions involved in the formation and detoxification of this metabolite, namely 1′-hydroxylation of estragole and oxidation of 1′-hydroxyestragole. Formation of 1′-hydroxyestragole is predominantly catalyzed by P450 1A2, 2A6, and 2E1, and results of the present study support that oxidation of 1′-hydroxyestragole is catalyzed by 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2). In a first approach, the study defines physiologically based biokinetic (PBBK) models for 14 individual human subjects, revealing a 1.8-fold interindividual variation in the area under the liver concentration-time curve (AUC) for 1′-hydroxyestragole within this group of human subjects. Variation in oxidation of 1′-hydroxyestragole by 17β-HSD2 was shown to result in larger effects than those caused by variation in P450 enzyme activity. In a second approach, a Monte Carlo simulation was performed to evaluate the extent of variation in liver levels of 1′-hydroxyestragole that could occur in the population as a whole. This analysis could be used to derive a chemical-specific adjustment factor (CSAF), which is defined as the 99th percentile divided by the 50th percentile of the predicted distribution of the AUC of 1′-hydroxyestragole in the liver. The CSAF was estimated to range between 1.6 and 4.0, depending on the level of variation that was taken into account for oxidation of 1′-hydroxyestragole. Comparison of the CSAF to the default uncertainty factor of 3.16 for human variability in biokinetics reveals that the default uncertainty factor adequately protects 99% of the population.

Keywords: estragole; PBBK or PBPK; metabolism; in vitro; interindividual differences; Monte Carlo simulation

Journal Article.  7728 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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