Equol, a metabolite of daidzein, reduces DMBA- and tamoxifen-associated DNA damage in peripheral blood mononuclear cells and liver cells.

B65 7,8-Dihydro-8-oxo-29-deoxyguanosine (8-oxo-dG) is one of the most critical DNA lesions leading to carcinogenesis. We have recently reported that a diet containing tamoxifen (TAM) and daidzein (DAI) significantly reduced the ratio of 8-oxo-dG /dG in normal mammary tissue of Sprague-Dawley rats when compared to both the 7,12-dimethylbenz[a]anthracene (DMBA, positive control) and oil (negative control) treated groups. TAM modestly increased DNA damage compared to the experimental positive and negative controls while DAI reduced oxidative damage compared to the positive control but not the negative control when administered alone ( European Journal of Cancer 41: 647-654, 2005). These results have been attributed to the DAI metabolite equol, due to an almost 100% metabolic conversion by rats. These data suggest that the combination of TAM and DAI protects DNA from oxidative damage at the site of DMBA-induced carcinogenesis and can reduce the levels of endogenous DNA damage in normal mammary tissue. Both TAM and DMBA are metabolized in the liver to their active analogs by members of the cytochrome P450 family. These conversions can lead to increased oxidative stress in the liver. Furthermore, TAM and DMBA metabolites have been shown to form adducts with DNA in circulating peripheral mononuclear blood cells (PBMCs) and as a result increase DNA damage. In an effort to determine the effects of these diets on DNA damage in secondary tissues, we examined DNA damage in PBMCs and isolated liver cells by single cell gel electrophoresis (comet assay), a sensitive method for assessing DNA damage in single cells. Comet scores were elevated in PBMCs and liver cells in animals fed the DMBA and TAM diets. The scores were reduced to endogenous levels (comparable to negative control) in animals fed the DAI and TAM/DAI diets. Further, we determined the effects of the above diets on tamoxifen induced DNA damage in the absence of DMBA to assess the application of equol as an adjunct treatment to help reduce tamoxifen-related toxicity when it is administered as a preventive measure. There was no significant effect in PBMCs by any diet compared to animals fed the basal diet. In liver cells, TAM significantly induced DNA damage and DAI had no effect. However, the TAM/DAI diet brought the comet score to the level of the basal treated animals, indicating a protective effect by equol. DNA damage in tissues caused by exogenous compounds increases the rate of DNA repair enzyme activity by thereby increasing the potential for disrepair. The disrepair of DNA damage or the inability to repair lesions can lead to cancer-causing mutations. Our results indicate that DAI, by way of its metabolite equol, can help to reduce the toxic influence of DMBA and TAM in the breast, liver, and PBMCs in rats.