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.
- aryl-hydrocarbon receptor
- nad(p)h-quinone oxidoreductase
- transcriptional regulation
- dietary polyphenols
- quinone reductase
- signaling pathway
Lee, Y. Y., ter Borg, S., van Berkel, W. J. H., Rietjens, I. M. C. M., & Aarts, J. M. M. J. G. (2008). Shifted concentration dependency of EpRE- and XRE-mediated gene expression points at monofunctional EpRE-mediated induction by flavonoids at physiologically relevant concentrations. Toxicology in Vitro, 22(4), 921-926. https://doi.org/10.1016/j.tiv.2008.01.008