Substitution of positions 6 and 8 lead to an increased anti-androgenic activity of the phytoestrogen naringenin

Phytoestrogens like the naturally occurring naringenin and its derivatives are appointed for their estrogenic activity. Some flavonoids of Naringenin matrix e.g. 8-prenylnaringenin (8-PN) and 6-(1,1-dimethylallyl)naringenin (6-DMAN) have already been shown as belonging to the most potent phytoestrogenic substances. Phytoestrogens have been discussed to act as chemo protective substances for example against breast cancer menopausal disorders. Almost nothing is known about other than estrogen receptor mediated actions. Because there are some evidences for anti-androgenic properties of estrogen-like compounds we tested 8-PN, 6-DMAN and naringenin in two independent (anti-)androgen screening assays. First using a yeast-based androgen receptor assay relatively strong anti-androgen activities were demonstrated for 6-DMAN and 8-PN, while the parent compound naringenin did not show recognizable anti-androgen 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 anti-androgenic activity of 6-DMAN was detected at concentrations of 10–5 M. 8-Prenylnaringenin or naringenin showed no anti-androgenic effect. In summary, for the first time we provide evidence of the anti-androgenic activity of 6-DMAN in two independent model systems. In conclusion, we demonstrated a bi-modular activity of the naturally occurring naringenin derivatives 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin. These prenylated naringenins not only to act via the estrogen receptor but also through the androgen receptor.