Influence of soy isoflavonoids on the detoxification of catechol and quinoid estrogens in vitro

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Formation and lack of inactivation of genotoxic metabolites of the female hormone 17β- estradiol are crucial events in breast carcinogenesis. Studies conducted in our laboratory demonstrated that physiological concentrations of isoflavones occurring in soy modulated the gene expression and the enzyme activity of some 17β-estradiol-metabolizing enzymes in cultured breast cancer MCF-7 cells in a way which would favor the generation and persistence of those genotoxic metabolites. Thus, the aim of the present study is the elucidation of the impact of isoflavonoids on the metabolism of 17β-estradiol in cultured precision-cut tissue slices from normal human mammary glands obtained by reduction mammoplasty. The mRNA levels and enzyme activities of the most important 17β-estradiol-metabolizing enzymes will be determined in tissue slices treated with isoflavonoids by reverse transcription/competitive PCR and the use of model substrates (preferably 17β-estradiol or its most genotoxic metabolite), respectively. Furthermore, the impact of alterations in 17β-estradiol metabolism on the frequency of gene mutations will be determined using three different in vitro test systems (i) transgenic BigBlue® rat 2 cells, (ii) V79 cells, selectively transfected with 17β-estradiol activating and deactivating enzymes, and (iii) MCF-7 cells.