The special extract
ERr 731 from the roots of Rheum rhaponticum is the major constituent of
Phytoestrol N which is used for the alleviation of menopausal symptoms. Recently, we demonstrated that
ERr 731 and its aglycones trans-
rhapontigenin and
desoxyrhapontigenin as single test substances do not activate the
estrogen receptors-alpha (
ERalpha) in human endometrial adenoarcinoma cells. However, these substances together with the structurally related hydroxystilbenes cis-
rhapontigenin,
resveratrol and
piceatannol activated the
ERbeta-dependent reporter gene activity. To investigate if these substance are tissue selective ER activators,
ERr 731 and the single test substances were examined in bone-derived U2OS cells stably expressing
ERalpha or transiently expressing
ERbeta. In the
ERalpha expressing U2OS cells, a weak, but statistically significant
ERalpha-coupled
luciferase activity was detected with
ERr 731 and
desoxyrhapontigenin which was 10-times lower than with 10(8) M
17 beta-estradiol. In the
ERbeta test system, all test substances significantly induced the
luciferase activity in a magnitude comparable to 17beta-estradiol. All effects were abolished with the pure ER antagonist ICI 182 780, indicating an ER-specific effect. Intracellular actions were also examined with the glycosylated
ERr 731 constituents
rhaponticin and
desoxyrhaponticin. Treatment of U2OS cells with defined mixtures of both
glycosides resulted in a reporter gene activity comparable to that of
ERr 731, thereby providing evidence for the existence of cellular uptake mechanisms for glycosylated hydroxystilbenes. This report confirms the strong
ERbeta-dependent activity of
ERr 731 and provides evidence for a tissue selective ER agonistic activity by
ERr 731 and its aglycones, as demonstrated by the activation of
ERalpha in bone cells but not in endometrial cells.