title: 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.
authors.affiliation: University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Atieh
authors.initials: A
authors.lastname: Hajirahimkhan
authors.forename: Charlotte
authors.initials: C
authors.lastname: Simmler
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Anderson
authors.forename: Shao-Nong
authors.initials: SN
authors.lastname: Chen
authors.forename: Dejan
authors.initials: D
authors.lastname: Nikolić
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Dietz
authors.forename: Guido F
authors.initials: GF
authors.lastname: Pauli
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology; D002853:Chromatography, Liquid; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006035:Glycyrrhiza / Q000737:chemistry*; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D013058:Mass Spectrometry; D008593:Menopause / Q000187:drug effects*; D048789:Phytoestrogens / Q000737:chemistry / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D028321:Plant Preparations / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014462:Ultrafiltration
chemical_list: D047188:Chalcones; D044950:Flavanones; D008024:Ligands; D048789:Phytoestrogens; D010936:Plant Extracts; D028321:Plant Preparations; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C040920:isoliquiritigenin; D008156:Luciferases; D000469:Alkaline Phosphatase; C083152:liquiritigenin