Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the invivo predictive value

A. Punt, W. Brand, A.J. Murk, A.P. van Wezel, M. Schriks, M.B. Heringa

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)

Abstract

With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three model compounds (bisphenol A, genistein, and 4-nonylphenol) relative to ethinylestradiol (EE2), determined with the estrogen receptor alpha (ERa) transcriptional activation assay using hER-HeLa-9903 cells, were taken from literature and used to calculate the EE2 equivalent (EE2EQ) effect doses in the predominantly ERa-dependent rat uterotrophic assay. Compound-specific differences in hepatic clearance relative to the reference compound EE2 were determined in vitro to examine whether in vivo estrogenic potencies reported in literature could be more accurately estimated. The EE2EQ doses allowed to predict in vivo uterotrophic responses within a factor of 6-25 and the inclusion of the hepatic clearance further improved the prediction with a factor 1.6-2.1 for especially genistein and bisphenol A. Yet, the model compounds still were less potent in vivo than predicted based on their EE2 equivalent estrogenic potency and hepatic clearance. For further improvement of the in vitro to in vivo predictive value of in vitro assays, the relevance of other kinetic characteristics should be studied, including binding to carrier proteins, oral bioavailability and the formation of estrogenic metabolites
Original languageEnglish
Pages (from-to)44-51
JournalToxicology in Vitro
Volume27
Issue number1
DOIs
Publication statusPublished - 2013

Keywords

  • rat uterotrophic bioassay
  • human-liver-microsomes
  • bisphenol-a
  • physicochemical properties
  • er-alpha
  • antiestrogenic activity
  • drug-discovery
  • receptor-alpha
  • oecd program
  • binding

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