2-HYDROXYESTRADIOL INDUCES OXIDATIVE DNA DAMAGE AND APOPTOSIS IN HUMAN MAMMARY EPITHELIAL CELLS

Abstract

Catechol estrogens, the hydroxylated metabolites of 17β-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 ΦX174 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.

The first two authors equally contributed to the work described in this article. This study was supported by a grant from NITR/Korea FDA for Endocrine Disrupter Research (ED2004). Dr. Zhi-Hua Chen was supported by the Brain Korea 21 (BK 21) program for the postdoctoral fellowship.