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

Abstract

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. We have previously observed that QR is up-regulated by anti-oestrogens, but not oestrogen, in breast cancer cells via ERbeta (oestrogen receptor beta) 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 the hydroxy-catecholestrogens which may be conjugated. We now report that the phytoestrogens biochanin A, genistein and resveratrol also up-regulate QR expression in breast cancer cells. We observe that regulation can occur at the transcriptional level, preferentially through ERbeta transactivation at the electrophile response element of the QR gene promoter. By chromatin immunoprecipitation analysis, we show binding of ERalpha and ERbeta to the QR promoter, with increased ERbeta binding in the presence of resveratrol. Functional studies show that biochanin A and resveratrol, but not genistein, can significantly protect against oestrogen-induced oxidative DNA damage in breast cancer cells. Antisense technology was used to determine whether such protection was dependent on ERbeta or QR. Our results with resveratrol are consistent with our hypothesis that the protective ability of resveratrol is partially dependent on the presence of ERbeta and QR. In conclusion, we postulate 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.

Neuroprotective Effects of Genistein in Mongolian Gerbils: Estrogen Receptor–β Involvement

“…The antioxidant effect of genistein may be due its ability to up-regulate antioxidant genes (70,71). In line with our results, other recent studies have established that the induction of antioxidant detoxification genes is mediated by the direct binding of phytoestrogens to ERβ, with the subsequent gene transcription being mediated by binding to antioxidant or electrophilic response elements (72). Finally, ERβ has substantial effects on mitochondrial function, particularly during insults where it can affect transcription of critical mitochondrial genes (73).…”

Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones

“…Due to its broad substrate specificity, this cytosolic flavoprotein has a significant role in the toxicity and carcinogenicity mediated by various endogenous and exogenous quinones [1][2][3]. Detoxification of quinones by NQO1 has been confirmed by studies in NQO1-knockout mice that demonstrated the increased menadione and benzene toxicity in NQO1-deficient animals [4,5].…”

Induction of Metallothionein I by Arsenic via Metal-activated Transcription Factor 1

“…The cells were treated with As 3ϩ for 5 h. ChIP assay was performed as described previously with modifications (48). Briefly, DNA-proteins were cross-linked by incubation of cells with 1% formaldehyde at 37°C for 10 min.…”