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

Abstract

Naturally occurring naringenin derivatives, known for their estrogenic activity, were tested in two independent (anti-)androgen screening assays. Using a yeast-based androgen receptor assay relatively strong antiandrogen activities were demonstrated for 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin, while the parent compound naringenin did not show recognizable antiandrogen activity. In an androgen receptor activity assay based on the analysis of prostate specific antigen (PSA) concentrations in the supernatants of treated PC3(AR)2 cells the antiandrogenic activity of 6-(1,1-dimethylallyl)naringenin was detected at concentrations of 10^-5 M. 8-Prenylnaringenin or naringenin have no detectable antiandrogenic effect. In summary, for the first time we provide evidence of the antiandrogenic activity of 6-DMA-N in two independent model systems. In conclusion, we demonstrated the ability of prenylated naringenins not only to act via the estrogen receptor but also through the androgen receptor.

Abbreviations

DHT:dihydrotestosterone

PSA:prostate-specific antigen

Bic:bicalutamide

6-DMA-N:6-(1,1-dimethylallyl)naringenin

8-P-N:8-prenylnaringenin

E2:17-β estradiol

References

• 1 Knight D C, Eden J A. A review of the clinical effects of phytoestrogens.  Obstet Gynecol. 1996;  87 897-904
• 2 Whitten P L, Patisaul H B. Cross-species and interassay comparisons of phytoestrogen action.  Environ Health Perspect. 2001;  109 5-20
• 3 Rosenberg Zand R S, Jenkins D J, Brown T J, Diamandis E P. Flavonoids can block PSA production by breast and prostate cancer cell lines.  Clin Chim Acta. 2002;  317 7-26
• 4 Sohoni P, Sumpter J P. Several environmental oestrogens are also anti-androgens.  J Endocrinol. 1998;  158 327-39
• 5 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
• 6 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
• 7 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
• 8 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
• 9 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
• 10 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 1015-18
• 11 Zierau O, Gester S, Schwab P, Metz P, Kolba S, Wulf M, Vollmer G. Estrogenic activity of the phytoestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin.  Planta Medica. 2002;  68 449-51
• 12 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
• 13 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