In silico methods for physiologically based biokinetic models describing bioactivation and detoxification of coumarin and estragole: Implications for risk assessment

I. Rietjens, A. Punt, B. Schilter, G. Scholz, T. Delatour, P.J. van Bladeren

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)

Abstract

In chemical safety assessment, information on adverse effects after chronic exposure to low levels of hazardous compounds is essential for estimating human risks. Results from in vitro studies are often not directly applicable to the in vivo situation, and in vivo animal studies often have to be performed at unrealistic high levels of exposure. Physiologically based biokinetic (PBBK) modeling can be used as a platform for integrating in vitro metabolic data to predict dose- and species-dependent in vivo effects on biokinetics, and can provide a method to obtain a better mechanistic basis for extrapolations of data obtained in experimental animal studies to the human situation. Recently, we have developed PBBK models for the bioactivation of the alkenylbenzene estragole to its DNA binding ultimate carcinogenic metabolite 1-sulfooxyestragole in both rat and human, as well as rat and human PBBK models for the bioactivation of coumarin to its hepatotoxic o-hydroxyphenylacetaldehyde metabolite. This article presents an overview of the results obtained so far with these in silico methods for PBBK modeling, focusing on the possible implications for risk assessment, and some additional considerations and future perspectives.
Original languageEnglish
Pages (from-to)195-207
JournalMolecular Nutrition & Food Research
Volume54
Issue number2
DOIs
Publication statusPublished - 2010

Keywords

  • human liver-microsomes
  • variant cyp2a6 alleles
  • pharmacokinetic models
  • partition-coefficients
  • species-differences
  • safety assessment
  • cytochrome-p450 cyp2a6
  • 7-hydroxylase activity
  • metabolism
  • rats

Fingerprint Dive into the research topics of 'In silico methods for physiologically based biokinetic models describing bioactivation and detoxification of coumarin and estragole: Implications for risk assessment'. Together they form a unique fingerprint.

Cite this