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 413506
Title Physiologically based biokinetic (PBBK) model for safrole bioactivation and detoxification in rats
Author(s) Martati, E.; Boersma, M.G.; Spenkelink, A.; Khadka, D.B.; Punt, A.; Vervoort, J.J.M.; Bladeren, P.J. van; Rietjens, I.
Source Chemical Research in Toxicology 24 (2011)6. - ISSN 0893-228X - p. 818 - 834.
DOI http://dx.doi.org/10.1021/tx200032m
Department(s) Sub-department of Toxicology
Biochemistry
VLAG
Publication type Refereed Article in a scientific journal
Publication year 2011
Keyword(s) naturally-occurring alkenylbenzenes - post-labeling analysis - dna-adducts - mouse-liver - in-vivo - carcinogen 1'-hydroxysafrole - hepatocarcinogen safrole - estragole bioactivation - metabolic-activation - allylbenzene analogs
Abstract A physiologically based biokinetic (PBBK) model for alkenylbenzene safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hydroxysafrole glucuronide to levels of these metabolites reported in the literature to be excreted in the urine of rats exposed to safrole and by comparison of the predicted amount of total urinary safrole metabolites to the reported levels of safrole metabolites in the urine of safrole exposed rats. These comparisons revealed that the predictions adequately match observed experimental values. Next, the model was used to predict the relative extent of bioactivation and detoxification of safrole at different oral doses. At low as well as high doses, P450 mediated oxidation of safrole mainly occurs in the liver in which 1,2-dihydroxy-4-allylbenzene was predicted to be the major P450 metabolite of safrole. A dose dependent shift in P450 mediated oxidation leading to a relative increase in bioactivation at high doses was not observed. Comparison of the results obtained for safrole with the results previously obtained with PBBK models for the related alkenylbenzenes estragole and methyleugenol revealed that the overall differences in bioactivation of the three alkenylbenzenes to their ultimate carcinogenic 1'-sulfooxy metabolites are limited. This is in line with the generally less than 4-fold difference in their level of DNA binding in in vitro and in vivo studies and their almost similar BMDL10 values (lower confidence limit of the benchmark dose that gives 10% increase in tumor incidence over background level) obtained in in vivo carcinogenicity studies. It is concluded that in spite of differences in the rates of specific metabolic conversions, overall the levels of bioactivation of the three alkenylbenzenes are comparable which is in line with their comparable carcinogenic potential.
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