Differential induction of quinone reductase by phytoestrogens and protection against oestrogen-induced DNA damage.

摘要

Quinone reductase (QR) is a phase II detoxification enzyme that plays an important role in detoxifying quinones and may help maintain the antioxidant function of the cell. QR has previously been observed to be up-regulated by anti-oestrogens, but not oestrogen, in breast cancer cells, via ERb (oestrogen receptor b) transactivation. Such QR induction appears to protect breast cells against oestrogen-induced oxidative DNA damage, most likely by reducing reactive oestrogen metabolites, termed catecholestrogen-quinones, back to hydroxy-catecholestrogens, which may be conjugated. This study investigated the possibility that phytoestrogens, biochanin A, genistein and resveratrol, also up-regulate QR expression in breast cancer cells. Functional studies demonstrated that biochanin A and resveratrol, but not genistein, could significantly protect against oestrogen-induced oxidative DNA damage in breast cancer cells. Antisense technology was used to determine whether such protection was dependent on ERb or QR. Regulation was found to occur at the transcriptional level, preferentially through ERb transactivation at the electrophile response element of the QR gene promoter. Chromatin immunoprecipitation analysis revealed the occurrence of binding of ERa and ERb to the QR promoter, with increased ERb binding in the presence of resveratrol. Results obtained with resveratrol were consistent with the hypothesis that the protective ability of resveratrol is partially dependent on the presence of ERb and QR. It is suggested that phytoestrogen-mediated induction of QR may represent an additional mechanism for breast cancer protection, although the effects may be specific for a given phytoestrogen.