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.
Pearce
Virginia
V
Department of Cell Biology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-8595, USA.
Nawaz
Zafar
Z
Xiao
Wu
W
Wiedenfeld
David
D
Boyle
Nick
N
Smith
Don
D
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