Evaluation of Estrogenic Activity of Licorice Species in Comparison with Hops Used in Botanicals for Menopausal Symptoms

Abstract

The increased cancer risk associated with hormone therapies has encouraged many women to seek non-hormonal alternatives including botanical supplements such as hops (Humulus lupulus) and licorice (Glycyrrhiza spec.) to manage menopausal symptoms. Previous studies have shown estrogenic properties for hops, likely due to the presence of 8-prenylnarigenin, and chemopreventive effects mainly attributed to xanthohumol. Similarly, a combination of estrogenic and chemopreventive properties has been reported for various Glycyrrhiza species. The major goal of the current study was to evaluate the potential estrogenic effects of three licorice species (Glycyrrhiza glabra, G. uralensis, and G. inflata) in comparison with hops. Extracts of Glycyrrhiza species and spent hops induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells, estrogen responsive element (ERE)-luciferase in MCF-7 cells, and Tff1 mRNA in T47D cells. The estrogenic activity decreased in the order H. lupulus > G. uralensis > G. inflata > G. glabra. Liquiritigenin was found to be the principle phytoestrogen of the licorice extracts; however, it exhibited lower estrogenic effects compared to 8-prenylnaringenin in functional assays. Isoliquiritigenin, the precursor chalcone of liquiritigenin, demonstrated significant estrogenic activities while xanthohumol, a metabolic precursor of 8-prenylnaringenin, was not estrogenic. Liquiritigenin showed ERβ selectivity in competitive binding assay and isoliquiritigenin was equipotent for ER subtypes. The estrogenic activity of isoliquiritigenin could be the result of its cyclization to liquiritigenin under physiological conditions. 8-Prenylnaringenin had nanomolar estrogenic potency without ER selectivity while xanthohumol did not bind ERs. These data demonstrated that Glycyrrhiza species with different contents of liquiritigenin have various levels of estrogenic activities, suggesting the importance of precise labeling of botanical supplements. Although hops shows strong estrogenic properties via ERα, licorice might have different estrogenic activities due to its ERβ selectivity, partial estrogen agonist activity, and non-enzymatic conversion of isoliquiritigenin to liquiritigenin.

Pharmacological Effects ofGlycyrrhizaspp. and Its Bioactive Constituents: Update and Review

“…Recently, the estrogenic effects of Glycyrrhiza spp. were compared and found to follow the order G. uralensis > G. inflata > G. glabra in MCF-7 and T47D cells (Hajirahimkhan et al, 2013). In this study, liquiritigenin also selectively activated ERβ.…”

Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma

“…ISL is a naturally occurring flavonoid that is nontoxic to humans, and has various biological properties such as antidiabetic, antioxidant, and antitumor activity, as well as vasorelaxant and estrogenic effects [22][23][24][25][26]. Our previous work showed that antioxidant ISL induced oxidative stress by disturbing the redox status and ultimately enhancing the radiosensitivity of HepG2 cells [27].…”

Glycyrrhiza uralensis 甘草 (Gancao, Licorice)

“…Extracts of Glycyrrhiza species induced estrogen responsive alkaline phosphatase activity in endometrial cancer cells. Meanwhile, increase of estrogen responses of these extracts were approved using estrogen responsive element (ERE)-luciferase reporter system in MCF-7 cells, and increased Tff1 mRNA expression was found in T47D cells [24]. Isoliquiritigenin was demonstrated to be the major estrogenic compound in the licorice extract due to its ERβ selectivity, partial estrogen activity, and non-enzymatic conversion of isoliquiritigenic to liquiritigenin [24].…”