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United States Department of Agriculture

Agricultural Research Service

Title: Glyceollin I Enantiomers Distinctly Regulate ER-Mediated Gene Expression)

Author
item Payton-stewart, Florastina
item Khupse, Rahul
item Boue, Stephen
item Elliott, Steven
item Zimmerman, Carla
item Skripnikova, Elena
item Ashe, Hasina
item Tilghman, Syreeta
item Beckman, Barbara
item Cleveland, Thomas
item Mclachlan, John
item Bhatnagar, Deepak
item Wiese, Thomas
item Erhardt, Paul
item Burow, Matthew

Submitted to: Steroids
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/11/2010
Publication Date: 5/21/2010
Citation: Payton-Stewart, F., Khupse, R.S., Boue, S.M., Elliott, S., Zimmerman, C.M., Skripnikova, E.V., Ashe, H., Tilghman, S.L., Beckman, B.S., Cleveland, T.E., Mclachlan, J.A., Bhatnagar, D., Wiese, T.E., Erhardt, P., Burow, M.E. 2010. Glyceollin I Enantiomers Distinctly Regulate ER-Mediated Gene Expression. Steroids. 75:870-878.

Interpretive Summary: Glyceollins (GLYs) are phytoalexins elicited in high concentrations when soybeans are stressed. We have previously reported that the three most common glyceollin isomers (GLY I, II, and III) exhibit antiestrogenic properties, which may have significant biological effects following human exposure. Of the three isomers, we have also previously shown that the Glyceollin I is the most potent antiestrogen. Glyceollin I was recently synthesized and produced a racemic mixture of two enantiomers, glyceollin I (natural and unnatural). Glyceollin I (natural) isomer is known to be the enantiomer produced in soybean. In this study, we compared the two glyceollin I enantiomers in several assays for estrogenic/antiestrogenic activity and gene expression. The unnatural glyceollin I was shown to be estrogenic, and the natural glyceollin I displayed estrogenic activity. Additionally, each enantiomer induced unique gene expression profiles in a PCR array panel of genes commonly altered in breast cancer. Taken together, these results demonstrate for the first time the (natural)-glyceollin I enantiomer is responsible for the marked antiestrogenic and antagonistic properties observed by glyceollin I.

Technical Abstract: Glyceollins (GLYs) are pterocarpan, phytoalexins elicited in high concentrations when soybeans are stressed. We have previously reported that the three most common glyceollin isomers (GLY I, II, and III) exhibit antiestrogenic properties, which may have significant biological effects following human exposure. Of the three isomers, we have also previously shown that the Glyceollin I is the most potent antiestrogen. Glyceollin I was recently synthesized and produced a racemic mixture of two enantiomers, glyceollin I (+/-). Glyceollin I (-) isomer is known to be the enantiomer produced in soybean. In this study, we compared the glyceollin I (+/-) enantiomers ER binding affinity, ability to inhibit estrogen responsive element transcriptional (ERE) activity and endogenous gene expression in MCF-7 cells. In vitro binding studies utilizing recombinant ERa and ERß present both glyceollin I enantiomers with similar relative binding affinity (RBA) for ER subtypes. Reporter gene assays in MCF-7 cells revealed that while (+)-glyceollin I stimulated ERE transcriptional activity, (-)-glyceollin I decreased activity induced by estrogen. Cotransfection reporter assays performed in HEK 293 demonstrated that (+)-glyceollin I increased ERE transcriptional activity of ERa and ERß with and without estrogen with no antiestrogenic activity observed. Conversely, (-)-glyceollin I decreased the activity of both ER subtypes stimulated by estradiol demonstrating potent antiestrogenic properties. Additionally, each Glyc I enantiomer induced unique gene expression profiles in a PCR array panel of genes commonly altered in breast cancer. Taken together, these results demonstrate for the first time the (-)-glyceollin I enantiomer is responsible for the marked antiestrogenic and antagonistic properties observed by glyceollin I.

Last Modified: 8/24/2016
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