We previously reported that antiestrogen-liganded estrogen receptor b (ERb) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:- quinone oxidoreductase). Our studies also indicate that upregulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites. We now report on the upregulation of glutathione S-transferases Pi (GST-Pi) and gamma-glutamylcysteine synthetase heavy subunit (GCSh) expression by antiestrogens. Studies indicate the regulation of GST-Pi and GCSh transcriptional activity by ER. While ER regulation is mediated by an electrophile response element (EpRE), we identified mechanistic differences in the involvement of other transcription factors. Regardless of these differences, ERb-mediated regulation of GST-Pi and GCSh point towards an important role for ERb in cellular protection against oxidative stress. A protective role is supported by our observation of inhibition of estrogeninduced DNA damage upon upregulation of GST-Pi and GCSh expression.