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Modulation of Estrogenic Activity in Estrogen Receptor α and β by Flavinoids in Women’s Health Botanicals

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thesis
posted on 01.12.2019, 00:00 by Obinna Chidi Mbachu
Menopausal women have been choosing natural alternatives over conventional hormone treatments to manage their symptoms, partly due to a reported increase in risk of breast carcinogenesis from hormone therapy that consists of conjugated estrogens and medroxyprogesterone. The popular botanicals-hops, red clover, licorice, and epimedium-are some of the dietary supplements used to alleviate these symptoms, which include hot flashes and night sweats. They contain phytoestrogens-compounds that behave like estrogens-known as flavonoids and isoflavonoids. These activate estrogen receptors (ER) α and β when consumed. ERα activity includes cellular proliferation, while ERβ attenuates this ERα-induced function, thus regulating proliferation. ERβ is also suggested to have a chemoprotective role in vivo. We hypothesized that botanicals containing ERβ-preferential (iso)flavonoids may be able to provide ERβ-related protective benefits by counterbalancing ERα proliferation. In this study, the initial aims included optimizing estrogenic screening assays to identify ERβ-preferential (iso)flavonoids present in select botanicals. Using bioassay-guided fractionation, 8-prenylapigenin (8-PA) was isolated from the tested licorice extract and identified as a potent ERβ-preferential agonist with nanomolar EC50 values. Secondly, a structure activity relationship (SAR) study was conducted to identify (iso)flavonoid structures that favor ERβ-preferential activity. Notable (iso)flavonoids analyzed included 8-prenylnaringenin, 8-prenylapigenin, apigenin, naringenin, genistein, 8-prenylgenistein. Results showed that prenylation on the 8-position of the A-ring of flavonoids increased overall estrogenic activity, and when combined with C2-C3 unsaturation on the C-ring, this resulted in an increase in ERβ potency. In contrast, this same prenylation on isoflavonoids resulted in a decrease in overall estrogenic activity, while the absence of prenylation with C2-C3 unsaturation on the C-ring increased ERβ-preferential potency. Select women’s health botanicals are used for menopausal symptoms, and these induce ERα activity when consumed. However, if they contain ERβ-preferential (iso)flavonoids, these may contribute chemoprotective benefits through ERβ activity that attenuates ERα-induced proliferation, reducing the risk of breast carcinogenesis. These botanicals may offer a beneficial safety profile, while providing potential health benefits.

History

Advisor

Bolton, Judy

Chair

DiMagno, Stephen

Department

Medicinal Chemistry

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Burdette, Joanna Moore, Terry Johnson, Jeremy Dietz, Birgit Bosland, Maarten

Submitted date

December 2019

Thesis type

application/pdf

Language

en

Issue date

25/11/2019

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