Shifted concentration dependency of EpRE- and XRE-mediated gene expression points at monofunctional EpRE-mediated induction by flavonoids at physiologically relevant concentrations

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6 Citations (Scopus)

Abstract

Flavonoids are important bioactive compounds, omnipresent in the human diet, and are reported to be bifunctional inducers. These phytochemicals are able to induce xenobiotic-responsive element (XRE)- and electrophile-responsive element (EpRE)-mediated gene expression, resulting in the induction of biotransformation enzymes. To test whether flavonoid-induced EpRE-mediated gene expression could be the result of upstream XRE-mediated gene expression, several flavonoids were tested for their ability to induce XRE- and EpRE-mediated gene expression using two stably transfected reporter gene cell lines constructed in the same mouse Hepa-1c1c7 hepatoma background. Although classified as bifunctional inducers, all flavonoids were found to induce EpRE- and XRE-mediated gene expression in a different concentration range, which presents an issue not considered by the current definition of a bifunctional inducer. At physiological relevant concentrations, the induction of gene expression via the EpRE transcriptional enhancer element is dominant, leading in particular to elevated levels of EpRE-regulated detoxifying enzymes. Furthermore, these results strongly suggest that EpRE-mediated gene expression induced by flavonoids is not a downstream reaction of XRE-mediated gene expression.
Original languageEnglish
Pages (from-to)921-926
JournalToxicology in Vitro
Volume22
Issue number4
DOIs
Publication statusPublished - 2008

Keywords

  • aryl-hydrocarbon receptor
  • drug-metabolizing-enzymes
  • ah-receptor
  • nad(p)h-quinone oxidoreductase
  • transcriptional regulation
  • dietary polyphenols
  • quinone reductase
  • signaling pathway
  • cell-lines
  • in-vitro

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