The red wine polyphenol resveratrol reduces polycyclic aromatic hydrocarbon-induced DNA damage in MCF-10A cells.

Polycyclic aromatic hydrocarbons (PAH) are procarcinogens that can be commonly found in our food and environment. Upon biotransformation in our body system, they can cause DNA damage through the generation of genotoxic species and oxidative stress. Phase I and II enzymes are pivotal in the process of proximate carcinogen formation and elimination. Some dietary phytochemicals are strong inhibitors to the phase I enzymes. In the present study, we investigated the effect of the red wine compound resveratrol on DNA damage induced by PAH in a non-tumorigenic breast cell line MCF-10A. Resveratrol ranging from 1 to 5 microm could significantly suppress the expressions of cytochrome P450 (CYP) 1A1, CYP1B1 and UDP-glucuronosyltransferase (UGT) 1A1 induced by 7,12-dimethylbenz[a]anthracene (DMBA). The comet assay indicated that DMBA introduced DNA damage to these cells, and co-treatment of resveratrol at 5 or 10 microm could alleviate the damage. Further investigation illustrated that resveratrol reduced the binding of DMBA metabolites to DNA with no effect on DMBA-induced oxidative DNA damage. Since the phase II enzyme UGT1A1 was suppressed, the elimination of DMBA metabolites would not have contributed to the reduction in the DMBA metabolite-DNA binding. In summary, resveratrol might protect breast cells against PAH-induced DNA damage. The underlying mechanism was mediated by phase I enzyme suppression rather than phase II enzyme induction or oxidative DNA repair.

Genistein protects against polycyclic aromatic hydrocarbon-induced oxidative DNA damage in non-cancerous breast cells MCF-10A.

Polycyclic aromatic hydrocarbons (PAH) are established cancer initiators that can be found in our food and environment. Some dietary phytochemicals are strong inhibitors of PAH-induced mutagenesis. The soya isoflavone genistein has been shown previously in our laboratory to be an inhibitor of PAH metabolite binding to DNA. In the present study, we investigated the effect of genistein on oxidative DNA damage induced by PAH in the non-tumorigenic breast cell line MCF10A. 7,12-Dimethyl-benz[a]anthracene (DMBA) can induce expressions of CYP1A1 and CYP1B1 which are known to be responsive to PAH. These enzymes, in turn, will metabolise the PAH into their ultimate carcinogenic forms. Genistein can significantly suppress the expressions within 5 microm. The comet assay indicated that DMBA introduced DNA damage to these cells, and co-treatment with genistein at 5 or 10 microm could alleviate the damage. In addition to the chelation of DMBA metabolites to DNA, flow cytometry results revealed that oxidation was also a factor of DNA damage. The oxidative DNA damage could be removed by co-treating with 10 microm-genistein. Because no increased oxidative DNA repair was observed, suppression on the cytochrome enzymes appeared to be the underlying mechanism.

Differential effect of over-expressing UGT1A1 and CYP1A1 on xenobiotic assault in MCF-7 cells.

Gene mutation has been considered as a major step of carcinogenesis. Some defective genes may induce spontaneous tumorigenesis, while others are required to interact with the environment to induce cancer. CYP1A1 and UGT1A1 are encoded for the respective phase I and II drug-metabolizing enzymes. Their expressions have been associated with breast cancer incidence in women, and some xenobiotics are substrates of these two enzymes. In the current study, cytochrome P450 (CYP) 1A1 and UDP-glucuronosyltransferase (UGT) 1A1 were over-expressed in the breast cancer MCF-7 cells, and potential interactions between these enzymes and estrogen or polycyclic aromatic hydrocarbon were evaluated. Compared with control cells (MCF-7(VEC)), reduced cell proliferation was seen in cells expressing UGT1A1 (MCF-7(UGT1A1)) under estradiol treatment. 7,12-Dimethylbenz[a]anthracene (DMBA) is an established breast cancer initiator in animal model. Over-expressing UGT1A1 reduced the binding of DMBA to DNA, and increased MCF-7(UGT1A1) intact cells under DMBA treatment was verified by comet assay. On the other hand, intensified DMBA binding and damages were observed in MCF-7(CYP1A1) cells. This study supported that UGT1A1 but not CYP1A1 expression could protect against xenobiotic assault.