Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation
Martina Plíškováa, Jan Vondráčeka, b, Vladimír Křenc, Radek Gažákc, Petr Sedmerac, Daniela Walterovád, Jitka Psotovád, Vilím Šimánekd, Miroslav Machalaa, ,
a Veterinary Research Institute, Brno, Czech Republic
b Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
c Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
d Institute of Medical Chemistry and Biochemistry, Palacký University, Olomouc, Czech Republic
Received 2 June 2005; revised 13 June 2005; Accepted 23 June 2005. Available online 1 August 2005.
Silymarin, a standardized mixture of flavonolignans, or its major constituents could be effective for prevention and treatment of hepatic damage or skin cancer. However, their potential side effects, such as modulation of endocrine functions via the disruption of estrogen receptor (ER) and/or aryl hydrocarbon receptor (AhR) activation, are largely unknown. In the present study, we investigated impact of silymarin, its constituents and a series of their synthetic derivatives on ER- and AhR-mediated activities using in vitro reporter gene assays. We found that none of the compounds under study affected the AhR-mediated activity in rat hepatoma cells. Contrary to that, several compounds behaved as either partial or full ER agonists. Silymarin elicited partial ER activation, with silybin B being probably responsible for a majority of the weak ER-mediated activity of silymarin; silybin A and other flavonolignans were found to be inactive and potent ER agonist taxifolin is only a minor constituent of silymarin. To our knowledge, this is probably the first time, when receptor-specific in vitro effects of separated diastereomers have been demonstrated. In contrast to silymarin constituents, the synthetic silybin derivatives, potentially useful as chemoprotective agents, did not modulate the ER-mediated activity, with exception of 23-O-pivaloylsilybin. Interestingly, 7-O-benzylsilybin potentiated ER-mediated activity of 17β-estradiol despite possessing no estrogenic activity. In conclusion, our data suggest that estrogenicity of some silymarin constituents should be taken in account as their potential side effect when considered as chemopreventive compounds. These results also stress the need to study biological activities of purified or synthesized diastereomers of silybin derivatives.
Keywords: Aryl hydrocarbon receptor; Estrogen receptor; Silybin diastereomers; Silymarin