Planta Med 2008; 74(1): 25-32
DOI: 10.1055/s-2007-993760
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Estrogenic Activities of Isoflavones and Flavones and their Structure-Activity Relationships

Sun Young Choi1 , Tae Youl Ha1 , Ji Yun Ahn1 , Sung Ran Kim1 , Kyung Sun Kang2 , In Kyeong Hwang3 , Suna Kim1
  • 1Food Function Research Group, Korea Food Research Institute, Gyeonggi-do, Republic of Korea
  • 2Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
  • 3Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, Seoul, Republic of Korea
Further Information

Publication History

Received: May 30, 2007 Revised: October 28, 2007

Accepted: October 30, 2007

Publication Date:
19 December 2007 (online)

Abstract

In this study, we assessed the relationships between the structure and estrogenicity of flavonoid derivatives. We evaluated estrogenicity via yeast transactivation assays, E-screen assays, and ER binding assays. Genistein and coumestrol in the yeast transactivation assay and biochanin A, genistein, and equol in the E-screen assay, have been shown to have profound estrogenic activities. Flavonoids, with the exception of biochanin A and daidzein, exhibit more profound selectivity for ERβ than for ERα. We compared several flavonoids in terms of estrogenicity, as well as relatively small structural differences including the position of the phenol ring and hydroxy groups, the substitution of hydroxy groups or methoxy groups, the opening of the phenol ring; glycitein vs. 4′,6,7-trihydroxyisoflavone, biochanin A vs. genistein, apigenin vs. genistein, 7,4′-dihydroxyflavone vs. isoliquiritigenin. A quantitative structure-activity relationship study design was utilized to develop model equations for the estrogenic activities of flavonoid derivatives. The prediction of estrogenicity with regard to ERα shows a positive correlation with MW and AlogP, and a negative correlation with Apol and Area (r2 = 0.89 and q2 = 0.83). The prediction of estrogenicity with regard to ERβ reveals a positive correlation with the AlogP and Hbond acceptors, and a negative correlation with RadOfGyration (r2 = 0.77 and q2 = 0.72).

Abbreviations

AlogP:log of the partition coefficient

Apol:sum of atomic polarizabilities

CD-FBS:charcoal-dextran-treated fetal bovine serum

E2:17β-estradiol

ER:estrogen receptor

GFA:genetic function approximation

Hbond acceptor:number of H bond acceptors

LOO:leave-one-out

MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

MW:molecular weight

O.D.:optical density

QSAR:quantitative structure-activity relationship

RadOfGyration:radius of gyration

RBA:relative binding affinity

Rotlbonds:number of rotatable bonds

References

  • 1 Rosenberg R S, Jenkins D JA, Diamandis E P. Steroid hormone activity of flavonoids and related compounds.  Breast Cancer Res Treat. 2000;  62 35-49
  • 2 Cos P, Bruyne T D, Apers S, Berghe D V, Pieters L, Vlietinck A J. Phytoestrogens: recent developments.  Planta Med. 2003;  69 589-99
  • 3 Collins-Burow B M, Burow M E, Duong B N, McLachlan J A. Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and -independent mechanisms.  Nutr Cancer. 2000;  38 229-44
  • 4 Green S, Walter P, Greene G, Krust A, Goffin C, Jensen E. et al . Cloning of the human oestrogen receptor cDNA.  J Steroid Biochem. 1986;  24 77-83
  • 5 Levenson A S, Jordan V C. Selective oestrogen receptor modulation: molecular pharmacology for the millennium.  Eur J Cancer. 1999;  35 1628-39
  • 6 Pike A, Brzozowski A, Hubbard R, Bonn T, Thorsell A -G, Engström O. et al . Structure of the ligand-binding domain of estrogen receptor beta in the presence of a partial agonist and a full antagonist.  EMBO J. 1999;  18 4608-18
  • 7 Miksicek R J. Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor.  J Steroid Biochem Mol Biol. 1994;  49 153-60
  • 8 Routledge E J, White R, Parker M G, Sumpter J P. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor(ER)α and ERβ.  J Biol Chem. 2000;  275 35 986-93
  • 9 Jordan V C, Mittal S, Gosden B, Koch R, Lieberman M E. Structure-activity relationships of estrogens.  Environ Health Perspect. 1985;  61 97-110
  • 10 Soto A M, Sonnenschein C, Chung K L, Fernandez M F, Olea N, Serrano F O. The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants.  Environ Health Perspect. 1995;  103 113-22
  • 11 Routledge E J, Sumpter J P. Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen.  Environ Toxicol Chem. 1996;  15 241-8
  • 12 Pons M, Gagne D, Nicolas J C, Mehtali R. A new cellular model of response to estrogens: a bioluminescent test to characterize (anti)estrogen molecules.  Biotechniques. 1990;  9 450-9
  • 13 Legler J, van den Brink C E, Brouwer A, Murk A J, van der Saag P T, Vethaak A D. et al . Development of a stably transfected estrogen receptor-mediated luciferase reporter gene assay in the human T47D breast cancer cell line.  Toxicol Sci. 1999;  48 55-66
  • 14 Zacharewski T. In vitro bioassays for estrogenic substances.  Environ Sci Technol. 1997;  31 613-23
  • 15 Zacharewski T. Identification and assessment of endocrine disruptors: limitations of in vivo and in vitro assays.  Environ Health Perspect. 1998;  106 577-82
  • 16 Jacobs M N. In silico tools to aid risk assessment of endocrine disrupting chemicals.  Toxicology. 2004;  205 43-53
  • 17 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.  J Immunol Methods. 1983;  65 55-63
  • 18 Ohno Y, Azuma Y, Date K, Nakano S, Kobayashi T, Nagao Y. et al . Evaluation of styrene oligomers eluted from polystyrene for estrogenicity in estrogen receptor binding assay, reporter gene assay, and uterotrophic assay.  Food Chem Toxicol. 2003;  41 131-41
  • 19 Roberge M, Hakk H, Larsen G. Atrazine is a competitive inhibitor of phosphodiesterase but does not affect the estrogen receptor.  Toxicol Lett. 2004;  154 61-8
  • 20 Nikolovska-Coleska Z, Suturkova L, Dorevski K, Krbavcic A, Solmajer T. Quantitative structure-activity relationship of flavonoid inhibitors of p56lck protein tyrosine kinase: A classical/quantum chemical approach.  Quant Structure-Activity Relat. 1998;  17 7-13
  • 21 Tong W, Perkins R. QSAR models for binding of estrogenic compounds to estrogen receptor α and β subtypes.  Endocrinology. 1997;  138 4022-5
  • 22 Maggiolini M, Bonofiglio D, Marsico S, Panno M L, Cenni B, Picard D. et al . Estrogen receptor α mediates the proliferative but not cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells.  Mol Pharmacol. 2001;  60 595-602
  • 23 Walker E H, Pacold M E, Perisic O, Stephens L, Hawkins P T, Wymann M P. et al . Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY 294 002, quercetin, myricetin, and staurosporine.  Mol Cell. 2000;  6 909-19
  • 24 Fang H, Tong W, Shi L M, Blair R, Perkins R, Branham W. et al . Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens.  Chem Res Toxicol. 2001;  14 280-94
  • 25 Peterson T G, Coward L, Kirk M, Falany C N, Barnes S. The role of metabolism in mammary epithelial cell growth inhibition by the isoflavones genistein and biochanin A.  Carcinogenesis. 1996;  17 1861-9
  • 26 Wenzel D G, Rosenberg P. Estrogenic activity of some flavonoids.  J Am Pharm Assoc. 1956;  45 367-9
  • 27 Lerner L J, Turkheimer A R, Borman A. Phloretin, a weak estrogen and estrogen antagonist.  Proc Soc Exp Biol Med. 1963;  114 115-7
  • 28 Miksicek R J. Estrogenic flavonoids: structural requirements for biological activity.  Proc Soc Exp Biol Med. 1995;  208 44-50

Dr. Suna Kim

Food Function Research Group

Korea Food Research Institute

516 Baekhyun-Dong

Bundang-Ku

Sungnam-Si

Gyeonggi-Do 463-746

Republic of Korea

Phone: +82-31-780-9301

Fax: +82-31-780-9225

Email: suna@kfri.re.kr

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