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 441357
Title Physiologically Based Biokinetic (PBBK) Modeling of Safrole Bioactivation and Detoxification in Humans as Compared With Rats
Author(s) Martati, E.; Boersma, M.G.; Spenkelink, A.; Khadka, D.B.; Bladeren, P.J. van; Rietjens, I.; Punt, A.
Source Toxicological sciences 128 (2012)2. - ISSN 1096-6080 - p. 301 - 316.
DOI http://dx.doi.org/10.1093/toxsci/kfs174
Department(s) Sub-department of Toxicology
VLAG
Publication type Refereed Article in a scientific journal
Publication year 2012
Keyword(s) human cytochrome-p450 enzymes - risk-assessment - alkenylbenzene methyleugenol - carcinogen 1'-hydroxysafrole - estragole bioactivation - allylbenzene analogs - dna-adducts - oral-cancer - metabolism - mouse
Abstract A physiologically based biokinetic (PBBK) model for the alkenylbenzene safrole in humans was developed based on in vitro- and in silico-derived kinetic parameters. With the model obtained, the time- and dose-dependent formation of the proximate and ultimate carcinogenic metabolites, 1'-hydroxysafrole and 1'-sulfooxysafrole in human liver were estimated and compared with previously predicted levels of these metabolites in rat liver. In addition, Monte Carlo simulations were performed to predict interindividual variation in the formation of these metabolites in the overall population. For the evaluation of the model performance, a comparison was made between the predicted total amount of urinary metabolites of safrole and the reported total levels of metabolites in the urine of humans exposed to safrole, which adequately matched. The model results revealed no dose-dependent shifts in safrole metabolism and no relative increase in bioactivation at dose levels up to 100 mg/kg body weight/day. Species differences were mainly observed in the detoxification pathways of 1'-hydroxysafrole, with the formation of 1'-oxosafrole being a main detoxification pathway of 1'-hydroxysafrole in humans but a minor pathway in rats, and glucuronidation of 1'-hydroxysafrole being less important in humans than in rats. The formation of 1'-sulfooxysafrole was predicted to vary 4- to 17-fold in the population (fold difference between the 95th and median, and 95th and 5th percentile, respectively), with the median being three to five times higher in human than in rat liver. Comparison of the PBBK results for safrole with those previously obtained for the related alkenylbenzenes estragole and methyleugenol revealed that differences in 1'-sulfooxy metabolite formation are limited, being only twofold to fivefold.
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