Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 441374
Title Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat
Author(s) Al-Subeihi, A.A.; Spenkelink, A.; Punt, A.; Boersma, M.G.; Bladeren, P.J. van; Rietjens, I.
Source Toxicology and Applied Pharmacology 260 (2012)3. - ISSN 0041-008X - p. 271 - 284.
DOI https://doi.org/10.1016/j.taap.2012.03.005
Department(s) Sub-department of Toxicology
VLAG
Publication type Refereed Article in a scientific journal
Publication year 2012
Keyword(s) human liver-microsomes - estragole bioactivation - fischer-344 rat - methyl eugenol - dna-adducts - allylbenzene - genotoxicity - derivatives - metabolism - safrole
Abstract This study defines a physiologically based kinetic (PBK) model for methyleugenol (ME) in human based on in vitro and in silico derived parameters. With the model obtained, bioactivation and detoxification of methyleugenol (ME) at different doses levels could be investigated. The outcomes of the current model were compared with those of a previously developed PBK model for methyleugenol (ME) in male rat. The results obtained reveal that formation of 1'-hydroxymethyleugenol glucuronide (1'HMEG), a major metabolic pathway in male rat liver, appears to represent a minor metabolic pathway in human liver whereas in human liver a significantly higher formation of 1'-oxomethyleugenol (1'OME) compared with male rat liver is observed. Furthermore, formation of 1'-sulfooxymethyleugenol (1'HMES), which readily undergoes desulfonation to a reactive carbonium ion (CA) that can form DNA or protein adducts (DA), is predicted to be the same in the liver of both human and male rat at oral doses of 0.0034 and 300 mg/kg bw. Altogether despite a significant difference in especially the metabolic pathways of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol (1'HME) between human and male rat, the influence of species differences on the ultimate overall bioactivation of methyleugenol (ME) to 1'-sulfooxymethyleugenol (1'HMES) appears to be negligible. Moreover, the PBK model predicted the formation of 1'-sulfooxymethyleugenol (1'HMES) in the liver of human and rat to be linear from doses as high as the benchmark dose (BMD10) down to as low as the virtual safe dose (VSD). This study shows that kinetic data do not provide a reason to argue against linear extrapolation from the rat tumor data to the human situation.
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