title: Evaluation of human interindividual variation in bioactivation of estragole using physiologically based biokinetic modeling.
abstract: 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 17beta-hydroxysteroid dehydrogenase type 2 (17beta-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 17beta-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.
authors.affiliation: Division of Toxicology, Wageningen University, Wageningen, The Netherlands.
authors.forename: Ans
authors.initials: A
authors.lastname: Punt
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Jeurissen
authors.forename: Marelle G
authors.initials: MG
authors.lastname: Boersma
authors.forename: Thierry
authors.initials: T
authors.lastname: Delatour
authors.forename: Gabriele
authors.initials: G
authors.lastname: Scholz
authors.forename: Benoît
authors.initials: B
authors.lastname: Schilter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Bladeren
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000081248:Allylbenzene Derivatives; D000840:Anisoles / Q000378:metabolism* / Q000493:pharmacokinetics; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005421:Flavoring Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D009010:Monte Carlo Method; D010084:Oxidation-Reduction
chemical_list: D000081248:Allylbenzene Derivatives; D000840:Anisoles; D002273:Carcinogens; D005421:Flavoring Agents; C014037:1'-hydroxyestragole; D003577:Cytochrome P-450 Enzyme System; C007633:estragole