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Female hormone, 17β-estradiol (E2) is a known risk factor in the development of breast cancer. We have previously shown that due to redox cycling, Cu2+-mediated activation of 4-E2 produces polar oxidative DNA adducts, and that the adduct formation can be inhibited by known or potential antioxidants, including ellagic acid. Dietary administration of ellagic acid and raspberries, a rich source of ellagic acid, also reduced the baseline polar oxidative DNA adducts in CDl mice. In this study, we have tested the efficacy of different berries and ellagic acid on the modulation of polar oxidative adducts in E2-induced rat mammary tumorigenesis model. Female ACI rats were implanted with E2-filled silastic tubes. Animals (n = 4) were provided either control diet or diet supplemented with 2.5% powdered mixed berries (1:1 mixture of strawberries, raspberries, blueberries, blackberries and black raspberries), 2.5% blueberries, 2.5% blueberries plus ellagic acid (400 ppm), or ellagic acid (400 ppm). Animals received experimental diets 2 weeks prior to the implants and until the termination of the study. The animals were euthanized 60 d after the implant and the liver DNA was analyzed for polar DNA adducts by 32P-postlabeling adducteomics technology. Adducts were resolved in order of decreasing polarities and were categorized as: P-1, P-2, PL-1, PL-2 and L-1. Compared to the control diet, the adduct levels were significantly decreased by the test diets: The P-1 adducts were reduced by >75% with blueberries and >50% each with blueberries plus ellagic acid, and ellagic acid alone. Ellagic acid was more effective (60%) in diminishing the P-2 adducts, followed by blueberries, or blueberries plus ellagic acid (30-40 %). The mixed berries, however showed no change in the adduct levels. The less polar subgroup, PL-1 was also diminished with the test diets and the decline, in general, paralleled the decline observed for the more polar adducts. These results, especially with respect to ellagic acid, corroborate our earlier findings with the mice. Taken together, our data suggest that the newly discovered polar DNA adducts may, in part, originate from oxidative mechanisms, and their accumulation can be significantly prevented by dietary intervention. These findings may have a direct impact in elucidating the mechanism by which certain dietary principles inhibit carcinogenesis. (Supported by USPHS grant CA-90892.)

[Proc Amer Assoc Cancer Res, Volume 45, 2004]