Physiologically based biokinetic model of bioactivation and detoxification of the alkenylbenzene methyleugenol in rat
| Autor: | Novalia Rachmawati, Ans Punt, Marelle G. Boersma, Jacques Vervoort, Bert Spenkelink, Ala′ A.A. Al-Subeihi, Ivonne M.C.M. Rietjens, Peter J. van Bladeren |
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| Rok vydání: | 2010 |
| Předmět: |
Male
mice Metabolite Glucuronidation safety assessment Biochemie Expert Systems Pharmacology Alkenes 1'-hydroxyestragole Toxicology Biochemistry species-differences Models Biological Rats Sprague-Dawley chemistry.chemical_compound Species Specificity estragole bioactivation Detoxification Eugenol Animals carcinogen 1'-hydroxysafrole Toxicologie Carcinogen Biotransformation VLAG Sex Characteristics Dose-Response Relationship Drug Chemistry human liver-microsomes glucuronidation Computational Biology General Medicine Metabolism Rats Inbred F344 Rats Kinetics safrole Methyleugenol Biocatalysis Carcinogens Microsomes Liver Estragole Female Glucuronide metabolism Mutagens |
| Zdroj: | Toxicology in Vitro 25 (2011) 1 Toxicology in Vitro, 25(1), 267-285 |
| ISSN: | 1879-3177 0887-2333 |
| Popis: | The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene methyleugenol in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model was based on the model previously developed for the related alkenylbenzene estragole and consists of eight compartments including liver, lung, and kidney as metabolizing compartments, and separate compartments for fat, arterial blood, venous blood, richly perfused and slowly perfused tissues. Evaluation of the model was performed by comparing the PBBK predicted concentration of methyleugenol in the venous compartment to methyleugenol plasma levels reported in the literature, by comparing the PBBK predicted dose-dependent percentage of formation of 2-hydroxy-4,5-dimethoxyallylbenzene, 3-hydroxy-4-methoxyallylbenzene, and 1'-hydroxymethyleugenol glucuronide to the corresponding percentage of metabolites excreted in urine reported in the literature, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of methyleugenol at different oral doses was examined. At low doses, formation of 3-(3,4-dimethoxyphenyl)-2-propen-1-ol and methyleugenol-2',3'-oxide leading to detoxification appear to be the major metabolic pathways, occurring in the liver. At high doses, the model reveals a relative increase in the formation of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol, occurring in the liver. This relative increase in formation of 1'-hydroxymethyleugenol leads to a relative increase in formation of 1'-hydroxymethyleugenol glucuronide, 1'-oxomethyleugenol, and 1'-sulfooxymethyleugenol the latter being the ultimate carcinogenic metabolite of methyleugenol. These results indicate that the relative importance of different metabolic pathways of methyleugenol may vary in a dose-dependent way, leading to a relative increase in bioactiviation of methyleugenol at higher doses. |
| Databáze: | OpenAIRE |
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