4-ethoxymethylphenol: a novel phytoestrogen that acts as an agonist for human estrogen receptors.
Estrogen is the natural agonist of the estrogen receptor (ER). However, certain plant-derived compounds or phytoestrogens have been identified that mimic estrogens and act as agonists and/or antagonists of ERs, depending on subtype and target tissue. Using thin layer chromatography (TLC), gas chromatography-mass spectrometry (GC-MS), and proton nuclear magnetic resonance (1H-NMR), we identified a simple phenol, 4-ethoxymethylphenol (4EM), found in Maclura pomifera that acts as an agonist of ER-alpha and ER-beta in HeLa and MCF-7 cells. To study the effect of 4EM on ER-alpha and ER-beta activity, we performed transient transfection assays and showed that 4EM activated ER-dependent gene transcription in a dose-dependent manner on both ER subtypes and this activity was inhibited by trans-4-hydroxytamoxifen (4HT). Further, 4EM-mediated transcription in ER-alpha, like estrogen, was enhanced in the presence of coactivators, steroid receptor coactivator-1 (SRC-1), CREB binding proteins (CBP), and E6-associated protein (E6-AP). We found that 4EM was specific for ER and did not activate transcription of the progesterone receptor.
Department of Cell Biology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-8595, USA.
Virginia
V
Pearce
Zafar
Z
Nawaz
Wu
W
Xiao
David
D
Wiedenfeld
Nick
N
Boyle
Don
D
Smith
D001667:Binding, Competitive; D050882:CREB-Binding Protein; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007529:Isoflavones; D008025:Ligases / Q000378:metabolism; D031624:Maclura / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009687:Nuclear Proteins / Q000378:metabolism; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D048789:Phytoestrogens; D028321:Plant Preparations; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000819:agonists*; D011980:Receptors, Progesterone / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
C475020:4-ethoxymethylphenol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D009687:Nuclear Proteins; D010636:Phenols; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D015534:Trans-Activators; D013629:Tamoxifen; C016601:afimoxifene; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases