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Botanical Modulation of AhR-ERÎ± by Crosstalk Inhibitors Promotes Estrogen (E2) Detoxification

串扰抑制剂对 AhR-ERα 的植物调节促进雌激素 (E2) 解毒

基本信息

批准号：
9977925
负责人：
Ryan Thomas Hitzman
金额：
$ 4.13万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2021-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977925
关键词：
Agonist Alkaline Phosphatase Animals Antibodies Aryl Hydrocarbon Receptor Benign Binding Biological Assay Botanical dietary supplements Botanicals Breast Cancer Risk Factor CYP1A1 gene CYP1B1 gene Cancer Etiology Cell Culture Techniques Cell Line Cells Cessation of life Chemopreventive Agent Collaborations Complex Cytochrome P450 DNA Binding Down-Regulation Drug Metabolic Detoxication Endometrial Carcinoma Enzymes Epigenetic Process Epimedium Estradiol Estrogen Antagonists Estrogen Metabolism Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive Estrogens Exhibits Failure Fluorescence Polarization Fractionation Fright Gene Expression Genetic Transcription Goals Health HepG2 Hormone replacement therapy Human Humulus Immunohistochemistry In Vitro Knowledge Lead Luciferases MCF7 cell MG132 Measures Mediating Menopausal Symptom Methods Methylation Microsomes Modeling Mutation Outcome Pathway interactions Pharmacologic Substance Postmenopause Progesterone Property Proteasome Inhibitor Quantitative Reverse Transcriptase PCR Quinones Rattus Receptor Cell Reporter Reporting Research Response Elements Risk Safety Signal Transduction Standard Model Standardization Testing Tissue Stains Translating Up-Regulation Uterus Weight Woman Women&apos s Health Xenobiotics adduct aryl hydrocarbon receptor ligand carcinogenesis chemical carcinogenesis chromatin immunoprecipitation estrogenic genotoxicity hormone therapy horny goat weed in vivo inhibitor/antagonist insight malignant breast neoplasm novel chemoprevention

项目摘要

Botanical Modulation of AhR-ERα by Crosstalk Inhibitors Promotes Estrogen (E2) Detoxification Estrogen receptor (ER) positive breast cancer poses significant health risks for postmenopausal women, and is in part mediated by the estrogen (E2) metabolite, estradiol-3,4-quinone, which causes depurinating adducts and leads to mutations. P450 1B1 is the primary enzyme for the conversion of estradiol to the 4-hydroxylated product, which can result in a genotoxic 4-quinone, while P450 1A1, which is normally epigenetically inhibited by E2-activated estrogen receptor alpha (ERα), converts estradiol to a nongenotoxic 2-hydroxylated product. Activated aryl hydrocarbon receptor (AhR) induces degradation of ERα as well as the transcription of both CYP1A1 and CYP1B1, which are translated into P450 1A1 and 1B1 respectively. Activators and ligands of AhR (Crosstalk Inhibitors) have been shown to preferentially upregulate CYP1A1 and ultimately the nongenotoxic 2-hydroxylated estradiol metabolite (estrogen detoxification pathway), through downregulation of the epigenetic inhibition of CYP1A1. Women have increasingly turned to botanical dietary supplements (BDS), instead of traditional hormone replacement therapy (HRT), since the release of the findings that estrogen + progesterone increases breast cancer risk. Interestingly, icaritin, a bioactive compound from Epimedium sp., a botanical used for women's health purposes, has been shown to activate AhR. The hypothesis of this proposal is that some women's health botanicals contain antiestrogenic, AhR activating compounds which degrade ERα (Aim 1) and reverse epigenetic CYP1A1 inhibition to preferentially activate the estrogen detoxification pathway in an in vitro cell culture model (Aim 2) and an in vivo ovariectomized rat model (Aim 3). Inhibition of estrogen-dependent alkaline phosphatase activity in Ishikawa cells, and a failure to inhibit a fluorescent estradiol-ERα complex by botanical compounds in a fluorescence polarization enzyme assay will provide antiestrogenic compounds which do not act through ERα. These compounds will be subjected to in- cell western of MCF-7 (ER+) cells against an ERα antibody to find compounds which degrade ERα. Additional XRE-luciferase activity in HepG2 cells will indicate AhR activating compounds, while a decrease in methylation through a ChIP assay of DNMT and XRE, and qRT-PCR of CYP1A1/1B1 will show that the reversal of estradiol mediated epigenetic CYP1A1 inhibition leads to upregulation of the estrogen detoxification pathway by Crosstalk Inhibitors in vitro. This premise will be taken to an ovariectomized rat model involving E2 and botanical compounds before sacrificing and analyzing uterine weight, performing LC-MS analysis of the E2 metabolites, and quantifying ERα expression levels using immunohistochemistry. This research may reveal mechanisms by which some bioactive women's health BDS compounds exhibit antiestrogenic outcomes, and the importance of the E2 detoxification pathway in promoting wellness in an in vivo postmenopausal model.

串扰抑制剂对AhR-ERα的植物调节促进雌激素（E2）解毒