Non-prenylated isoflavone aglycones are known to have phyto-estrogenic properties and act as agonistic ligands on ERα and ERβ due to their structural resemblance to 17β-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 ERα- and ERβ-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 ERα-LBD and ERβ-LBD-coregulator interactions. Glucuronidation changed the preferential activation of genistein from ERβ-LBD to ERα-LBD and further increased the slightly preferential activation of daidzein for ERα-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 ERα-LBD and ERβ-LBD in their conjugated form with a higher relative preference for ERα-LBD than the corresponding aglycones. This shift in receptor preference is of special interest as the preferential activation of ERβ is considered one of the possible modes of action underlying the supposed beneficial instead of adverse health effects of isoflavones.
Keywords: Coregulator binding; Estrogen receptor alpha; Estrogen receptor beta; Glucuronidation; Isoflavone; Ligand binding domain.
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