RESUMO
Large amounts of phytoestrogen, a group of estrogen derived from plant sources, are taken from the diet by Asians, but a sign of feminization has not been fully recognized. In this study, we found that some flavonoids inhibited an effect on estrogen action without estrogen receptor (ER) binding. Considering the report that dioxin, an aryl hydrocarbon receptor (AhR) agonist, disrupts the transcriptional activity of ER without binding to the ER, 14 flavonoids were examined for the transcriptional activity of AhR by the yeast reporter assay (AhR). Among them, 2-phenylchromone (flavone, FLA) showed the highest activity. FLA increased the expression of CYP1A1 mRNA, and inhibited the expression of progesterone receptor and pS2 mRNA in MCF-7 cells via non-ER-mediated pathway. Further studies showed that FLA had agonist activity for AhR and enhanced the proteosome-dependent degradation of ERalpha protein. Thus, FLA inhibited the estrogen action without binding to the ER by acting as a competitive agonist for AhR, which meaning that there can be anti-estrogenic flavonoids such as FLA as well as estrogenic ones such as isoflavones.
Assuntos
Cromonas/farmacologia , Estrogênios/farmacologia , Flavonas/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Antineoplásicos/farmacologia , Ligação Competitiva/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Cromonas/química , Citocromo P-450 CYP1A1/genética , Relação Dose-Resposta a Droga , Flavanonas/química , Flavanonas/farmacologia , Flavonas/química , Flavonoides/química , Flavonoides/farmacologia , Flavonóis/química , Flavonóis/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Leupeptinas/farmacologia , Estrutura Molecular , Coativador 2 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Técnicas do Sistema de Duplo-Híbrido , Leveduras/genéticaRESUMO
We examined the anti-estrogenic activity of 50 chemicals by the yeast two-hybrid assay and detected the activity of hexachlorophene, pentachlorophenol, and vitamin K3 (menadione), in that order. These chemicals were also observed to inhibit the transcriptional activity of 17beta-estradiol in a reporter gene assay system using MCF-7 cells, estrogen receptor-positive breast cancer cells, and to bind directly to estrogen receptor alpha in a competitive binding assay system, although the order of the activity was slightly different among the 3 assays. These findings suggested that three of fifty chemicals could inhibit estrogen activity by competitive binding with 17beta-estradiol to the estrogen receptor.