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

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

In: Toxicological Sciences, 2009, vol. 113, no. 2, p. 337-348

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    Title
    • Evaluation of Human Interindividual Variation in Bioactivation of Estragole Using Physiologically Based Biokinetic Modeling
    Author
    • Punt, Ans. Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands
    • Jeurissen, Suzanne M.. Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands
    • Boersma, Marelle G.. Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands
    • Delatour, Thierry. Nestlé Research Center, P.O. Box 44 Lausanne, 26 Switzerland
    • Scholz, Gabriele. Nestlé Research Center, P.O. Box 44 Lausanne, 26 Switzerland
    • Schilter, Benoît. Nestlé Research Center, P.O. Box 44 Lausanne, 26 Switzerland
    • van Bladeren, Peter J.. Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands
    • Rietjens, Ivonne M. C. M.. Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Toxicological Sciences, 2009, vol. 113, no. 2, p. 337-348. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:296474
    Summary
    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