title: Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities.
abstract: Licorice root extracts are often consumed as botanical dietary supplements by menopausal women as a natural alternative to pharmaceutical hormone replacement therapy. In addition to their components liquiritigenin (Liq) and isoliquiritigenin (Iso-Liq), known to have estrogenic activity, licorice root extracts also contain a number of other flavonoids, isoflavonoids, and chalcones. We have investigated the estrogenic activity of 7 of these components, obtained from an extract of Glycyrrhiza glabra powder, namely Glabridin (L1), Calycosin (L2), Methoxychalcone (L3), Vestitol (L4), Glyasperin C (L5), Glycycoumarin (L6), and Glicoricone (L7), and compared them with Liq, Iso-Liq, and estradiol (E2). All components, including Liq and Iso-Liq, have low binding affinity for estrogen receptors (ERs). Their potency and efficacy in stimulating the expression of estrogen-regulated genes reveal that Liq and Iso-Liq and L2, L3, L4, and L6 are estrogen agonists. Interestingly, L3 and L4 have an efficacy nearly equivalent to E2 but with a potency ca. 10,000-fold less. The other components, L1, L5 and L7, acted as partial estrogen antagonists. All agonist activities were reversed by the antiestrogen, ICI 182,780, or by knockdown of ERα with siRNA, indicating that they are ER dependent. In HepG2 hepatoma cells stably expressing ERα, only Liq, Iso-Liq, and L3 stimulated estrogen-regulated gene expression, and in all cases gene stimulation did not occur in HepG2 cells lacking ERα. Collectively, these findings classify the components of licorice root extracts as low potency, mixed ER agonists and antagonists, having a character akin to that of selective estrogen receptor modulators or SERMs.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States; Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Nittaya
authors.initials: N
authors.lastname: Boonmuen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, MS 38677, United States.
authors.forename: Zulfiqar
authors.initials: Z
authors.lastname: Ali
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, MS 38677, United States.
authors.forename: Amar G
authors.initials: AG
authors.lastname: Chittiboyina
authors.affiliation: National Center for Natural Products Research, University of Mississippi, Oxford, MS 38677, United States.
authors.forename: Ikhlas
authors.initials: I
authors.lastname: Khan
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Helferich
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
authors.forename: Teresa
authors.initials: T
authors.lastname: Martin
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; Chakri Naruebodindra Medical Institute, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States. Electronic address: katzenel@illinois.edu.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D044950:Flavanones / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006035:Glycyrrhiza / Q000737:chemistry*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D010936:Plant Extracts / Q000494:pharmacology; D018517:Plant Roots / Q000737:chemistry*; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*
chemical_list: D004965:Estrogen Antagonists; D004967:Estrogens; D044950:Flavanones; D019394:Ki-67 Antigen; D010936:Plant Extracts; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C083152:liquiritigenin
keywords: Botanical estrogens; Estrogen receptor; Licorice root estrogens; Selective estrogen receptor modulator