Estrogenic And Chemopreventive Properties of Licorice Species Used For Menopausal Symptoms

Hormone therapy (HT) has been the most efficacious treatment for relieving menopausal symptoms. However, Women’s Health Initiative showed an increased breast cancer risk associated with HT. Therefore, menopausal women have turned to alternative options such as licorice. Glycyrrhiza glabra (GG), Glycyrrhiza uralensis (GU), and Glycyrrhiza inflata (GI) have been considered medicinal licorice; however, their estrogenic efficacy and their role in chemoprevention have not been well documented. In this study GG, GU, and GI induced estrogen responsive alkaline phosphatase activity in Ishikawa cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased as GU > GI > GG. Liquiritigenin (LigF) the principle phytoestrogen of licorice showed better binding affinity for estrogen receptor (ER) β. Isoliquiritigenin (LigC) the precursor chalcone of LigF demonstrated estrogenic activity which could be the result of its cyclization to LigF under physiological conditions. GG, GU, and LigF did not exhibit uterine proliferation in immature rats; however, LigF suppressed E2-induced uterine growth which could be associated with its ERβ as well as partial agonist effects. Licorice species were studied for activating a chemoprevention marker, NAD(P)H:quinone oxidoreductase 1 (NQO1) as they contain Michael acceptors such as LigC and also licochalcone A (LicA) from GI. Extracts activated NQO1 in hepa1c1c7 cells with the rank order GI > GG ≅ GU. The rank order for the compounds was LigC > LicA ≫ LigF. GG, GU, and LigC enhanced NQO1 levels in MCF-10A cells. Activation of antioxidant response element in HepG2-ARE-C8 cells suggested the involvement of Keap1-Nrf2 pathway. When GG and GU were orally administered to mature female rats LigC and LigF were detected in liver, serum, and mammary tissues with a significant increase in NQO1 activity in mammary glands. LigC did not enhance NQO1 activity in vivo likely due to rapid metabolism. This study showed the impact of chemical profile on the biological activities of licorice species and further supported the importance of simultaneous chemical and biological evaluation as well as standardization of botanicals.