The effect of glucuronidation on isoflavone induced estrogen receptor (ER)a and ERß mediated coregulator interactions

K. Beekmann, L.H.J. de Haan, L. Actis Goretta, R. Houtman, P.J. van Bladeren, I.M.C.M. Rietjens

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)


Non-prenylated isoflavone aglycones are known to have phyto-estrogenic properties and act as agonistic ligands on ERa and ERß due to their structural resemblance to 17ß-estradiol (E2). Genistein and daidzein are the two main dietary isoflavones; upon uptake they are extensively metabolized and exist nearly exclusively as their conjugated forms in biological fluids. Little is known about the effect of conjugation on the intrinsic estrogenic activities of these isoflavones. To characterize and compare the intrinsic estrogenic activities of genistein and daidzein, and their respective 7-O-glucuronide metabolites a cell-free assay system was employed that determines the ligand-induced changes in ERa- and ERß-ligand binding domain (LBD) interactions with 154 different binding motifs derived from 66 different nuclear receptor coregulators. The glucuronides were 8 to 4400 times less potent than their respective aglycones to modulate ERa-LBD and ERß-LBD–coregulator interactions. Glucuronidation changed the preferential activation of genistein from ERß-LBD to ERa-LBD and further increased the slightly preferential activation of daidzein for ERa-LBD. The tested isoflavone compounds were less potent than E2 (around 5 to 1580 times for the aglycones) but modulated the LBD–coregulator interactions in a manner similar to E2. Our results show that genistein and daidzein remain agonistic ligands of ERa-LBD and ERß-LBD in their conjugated form with a higher relative preference for ERa-LBD than the corresponding aglycones. This shift in receptor preference is of special interest as the preferential activation of ERß is considered one of the possible modes of action underlying the supposed beneficial instead of adverse health effects of isoflavones
Original languageEnglish
Pages (from-to)245-253
JournalJournal of Steroid Biochemistry and Molecular Biology
Publication statusPublished - 2015

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