2-Hydroxyestradiol induces oxidative DNA damage and apoptosis in human mammary epithelial cells.
Catechol estrogens, the hydroxylated metabolites of 17beta-estradiol (E2), have been considered to be implicated in estrogen-induced carcinogenesis. 2-Hydroxyestradiol (2-OHE2), a major oxidized metabolite of E2 formed preferentially by cytochrome P-450 1A1, reacts with DNA to form stable adducts and exerts genotoxicity. 2-OHE2 can be oxidized to quinone, which is accompanied by generation of reactive oxygen species (ROS). In the present study, 2-OHE2 induced strand scission in phiX174 phage DNA and oxidative base modifications in calf thymus DNA in the presence of cupric ion. In cultured human mammary epithelial (MCF-10A) cells, 2-OHE2 treatment produced ROS accumulation, 8-oxo-7,8-dihydroxy-2'-deoxyguanosine formation, cytotoxicity, and disruption of mitochondrial transmembrane potential, all of which were prevented by N-acetylcysteine. These findings, taken together, suggest that 2-OHE2-induced oxidative DNA damage and apoptosis in MCF-10A cells might be mediated by ROS generated via the redox cycling of this catechol estrogen.
Hurh
Yeon-Jin
YJ
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Chen
Zhi-Hua
ZH
Na
Hye-Kyung
HK
Han
Soon-Young
SY
Surh
Young-Joon
YJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D002417:Cattle; D018929:Cell Culture Techniques; D004249:DNA Damage; D004847:Epithelial Cells; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity*; D006801:Humans; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013950:Thymus Gland
D017382:Reactive Oxygen Species; D004958:Estradiol; C001390:2-hydroxyestradiol