Modulation of Estrogen-Depurinating DNA Adducts by Sulforaphane for Breast Cancer
Final rept. 15 Sep 2011-14 Sep 2014
PITTSBURGH UNIV PA
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The goal of this study is to test the hypothesis sulforaphane SFN, an isothiocyanate found in cruciferous vegetables, may alter estrogen metabolism and thus protect against estrogen-mediated DNA damage and carcinogenesis. SFN is a potent inducer of detoxification enzymes such as NADPHquinone oxidoreductase 1 NQO1 and glutathione-S-transferase GST via the Keap1-Nrf2 signaling pathway. In summary of the findings, the standards of four heavy isotope labeling estrogen-DNA adducts were successfully synthesized. In cell model, human breast epithelial MCF-10A cells were treated with either vehicle or SFN and either estradiol E2 or its metabolite 4-hydroxyestradiol 4-OHE2. Estrogen metabolites and depurinating DNA adducts were analyzed by mass spectrometry. Following E2 or 4-OHE2 treatment, the depurinated adducts, 4-OHE12-1- N3Adenine and 4-OHE12-1-N7Guanine, were reduced by around 60 in both of SFN-treated and siKEAP1-treated cells. However, pharmacologic and genetic approaches have different effects on estrogen metabolism to O-methyl and glutathione conjugates. In animal model, being pre-treated with SFNVehicle for one week, ACI rats were implanted E2Vehicle and treated SFNVehicle for 6 weeks. The results show that depurinating estrogen-DNA adducts in urine were significantly inhibited in SFN treatment. In human studies, the urine samples were collected for three continuous days from 14 female subjects in Qidong, China. The results show that there are no significant differences among day 1, day 2 and day 3 for the 4-hydroxy adducts in the urine, which support that one 12-hour urine assay could reasonably reflect current estrogen metabolism.
- Medicine and Medical Research
- Organic Chemistry