S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Journal Papers (저널논문_분자의학 및 바이오제약학과)
4-Hydroxyestradiol induces oxidative stress and apoptosis in human mammary epithelial cells: possible protection by NF-κB and ERK/MAPK
- Chen, Zhi-Hua; Na, Hye-Kyung; Hurh, Yeon-Jin; Surh, Young-Joon
- Issue Date
- Toxicology and Applied Pharmacology, Vol.208 No.1, pp.46-56
- Catechol estrogens, the hydroxylated metabolites of 17 beta-estradiol (E-2) have been considered to be implicated in estrogen-induced carcinogenesis. 4-Hydroxyestradiot (4-OHE2), an oxidized metabolite of E-2 formed preferentially by cytochrome P450 1B1, reacts with DNA to form depurinating adducts thereby exerting genotoxicity and carcinogenicity. 4-OHE2 undergoes 2-electron oxidation to quinone via semiquinone, and during this process, reactive oxygen species (ROS) can be generated to cause DNA damage and cell death. In the present study, 4-OHE2 was found to elicit cytotoxicity in cultured human mammary epithelial (MCF-10A) cells, which was blocked by the antioxidant trolox. MCF-10A cells treated with 4-OHE2 exhibited increased intracellular ROS accumulation and 8-oxo-7,8-dihydroxy-2'-deoxyguanosine formation, and underwent apoptosis as determined by poly(ADP-ribose)polymerase cleavage and disruption of mitochondrial transmembrane potential. The redox-sensitive transcription factor nuclear factor kappa B (NF-kappa B) was transiently activated by 4-OHE2 treatment. Cotreatment of MCF-10A cells with the NF-kappa B inhibitor, L-1-tosylamido-2-phenylethyl chloromethyl ketone, exacerbated 4-OHE2-induced cell death. 4-OHE2 also caused transient activation of extracellular signal-regulated protein kinases (ERK) involved in transmitting cell survival or death signals. A pharmacological inhibitor of ERK aggravated the 4-OHE2-induced cytotoxicity, supporting the pivotal role of ERK in protecting against catechol estrogen-induced oxidative cell death. (c) 2005 Elsevier Inc. All rights reserved.
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