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.
Highlights
Because of an increased life expectancy in recent years, many women spend the last third of their lives in post menopause [1]
The conversion of LigF and its precursor chalcone (LigC) to LigF during bioassays was monitored by LC-MS and LC-UV. These results suggest that licorice species are less estrogenic than hops, they contain an ERb selective phytoestrogen, LigF and an estrogenic chalcone LigC which in turn can convert to LigF
The analyses showed that the Glycyrrhiza uralensis (GU) extract contained the highest amount of LigF (0.16% w/w) compared to Glycyrrhiza inflata (GI) (0.06% w/ w) and Glycyrrhiza glabra (GG) (0.05% w/w)
Summary
Because of an increased life expectancy in recent years, many women spend the last third of their lives in post menopause [1]. In light of the results published from the Women’s Health Initiative (WHI), which demonstrated an increased risk of developing hormone dependent cancers, cardiovascular problems, and stroke among women taking HT, many women have turned to alternative therapies such as botanical dietary supplements to alleviate menopausal discomfort [5,6,7]. Hops and its phytoconstituents, including 8-prenylnaringenin (8PN) and its metabolic precursor chalcone, xanthohumol (XH) (Figure 1) have been studied for their estrogenic and chemopreventive properties [11,12,13,14,15,16]. One of its bioactive compounds, 8-PN, the most potent phytoestrogen known to date [17], has been shown to be an equipotent ligand of estrogen receptor (ER) subtypes and exhibits estrogenic activity in hormone responsive cell-based assays as well as animal models [11,12,18]. XH, which does not have estrogenic properties, has been reported to possess chemopreventive potential, through the induction of detoxification enzymes [15]
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