Estrogenic Activity of the Phytoestrogens Naringenin, 6-(1,1-Dimethylallyl)naringenin and 8-Prenylnaringenin

Abstract

Chemically synthesized naringenin derivatives, identical to natural occurring compounds, were tested for their estrogenic activity using two independent estrogen screening assays. Using a yeast based estrogen receptor assay, strong estrogenic activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable estrogenic activity. In MVLN cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10^-6 M and 5 × 10^-6 M respectively. Naringenin demonstrated estrogenic activity but only at a concentration of 10^-5 M. These estrogenic effects are mediated by the ER, as the antiestrogen 4-hydroxytamoxifen inhibited these activities. In summary, this study provides the further confirmation that 8-prenylnaringenin demonstrates high estrogenic activity, and demonstrated for the first time for 6-(1,1-dimethylallyl)naringenin a reasonable high estrogenic activity, while naringenin exhibit low or no estrogenic activity.

References

• 1 Knight D C, Eden J A. A review of the clinical effects of phytoestrogens.  Obstet. Gynecol.. 1996;  87 897-904
• 2 Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag P T, van der Burg B, Gustafsson J A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.  Endocrinology.. 1998;  139 4252-63
• 3 Whitten P L, Patisaul H B. Cross-species and interassay comparisons of phytoestrogen action.  Environ Health Perspect.. 2001;  109 Suppl 1 5-20
• 4 Kitaoka M, Kadokawa H, Sugano M, Ichikawa K, Taki M, Takaishi S, Iijima Y, Tsutsumi S, Boriboon M, Akiyama T. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 1). Isolation of 8-isopentenylnaringenin and an initial study on its structure-activity relationship.  Planta Med.. 1998;  64 511-5
• 5 Miyamoto M, Matsushita Y, Kiyokawa A, Fukuda C, Iijima Y, Sugano M, Akiyama T. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 2). Estrogenic effects of 8-isopentenylnaringenin on bone metabolism.  Planta Med.. 1998;  64 516-9
• 6 Milligan S R, Kalita J C, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer.  J Clin Endocrinol Metab. 1999;  84 2249-52
• 7 Milligan S R, Kalita J C, Pocock V, Van De Kauter V, Stevens J F, Deinzer M L, Rong H, De Keukeleire D. The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavonoids.  J Clin Endocrinol Metab. 2000;  85 4912-5
• 8 Ruh M F, Zacharewski T, Connor K, Howell J, Chen I, Safe S. Naringenin: a weakly estrogenic bioflavonoid that exhibits antiestrogenic activity.  Biochem Pharmacol. 1995;  50 1485-93
• 9 Zand R S, Jenkins D J, Diamandis E P. Steroid hormone activity of flavonoids and related compounds.  Breast Cancer Res Treat.. 2000;  62 35-49
• 10 Seo E K, Silva G L, Chai H B, Chagwedera T E, Farnsworth N R, Cordell G A, Pezzuto J M, Kinghorn A D. Cytotoxic prenylated flavanones from Monotes engleri .  Phytochemistry.. 1997;  45 509-15
• 11 Gester S, Metz P, Zierau O, Vollmer G. An efficient synthesis of the potent phytoestrogens 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin by europium(III)-catalyzed Claisen rearrangement.  Tetrahedron. 2001;  57 1015-8
• 12 Routiedge E, Sumpter J P. Oestrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen.  Environ. Tox. Chem.. 1996;  15 241-8
• 13 Pons M, Gagne D, Nicolas J C, Mehtali M. A new cellular model of response to estrogens: a bioluminescent test to characterize (anti) estrogen molecules.  Biotechniques.. 1990;  9 450-9
• 14 Demirpence E, Duchesne M J, Badia E, Gagne D, Pons M. MVLN cells: a bioluminescent MCE-7-derived cell line to study the modulation of estrogenic activity.  Steroid Biochem Mol Biol.. 1993;  46 355-64