title: Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds in U2OS human osteosarcoma cells.
abstract: 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.
authors.affiliation: Molekulare Zellphysiologie & Endokrinologie, Institut für Zoologie, Technische Universitat Dresden, 01062 Dresden, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Möller
authors.forename: Oliver
authors.initials: O
authors.lastname: Zierau
authors.forename: Anett
authors.initials: A
authors.lastname: Jandausch
authors.forename: Reinhard
authors.initials: R
authors.lastname: Rettenberger
authors.forename: Marietta
authors.initials: M
authors.lastname: Kaszkin-Bettag
authors.forename: Günter
authors.initials: G
authors.lastname: Vollmer
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism*; D012250:Rheum
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C525447:ERr 731; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010936:Plant Extracts; D011960:Receptors, Estrogen