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Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells

Fussell, Karma C., Udasin, Ronald G., Smith, Peter J.S., Gallo, Michael A. and Laskin, Jeffrey D. (2011) Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells Carcinogenesis, 32, (8), pp. 1285-1293. (doi:10.1093/carcin/bgr109). (PMID:21665890).

Record type: Article

Abstract

Estrogens are major risk factors for the development of breast cancer; they can be metabolized to catechols which are further oxidized to DNA-reactive quinones and semiquinones. These metabolites are mutagenic and may contribute to the carcinogenic activity of estrogens. Redox cycling of the semiquinones and subsequent generation of reactive oxygen species (ROS) is also an important mechanism leading to DNA damage. The semiquinones of exogenous estrogens have been shown to redox cycle, however, redox cycling and the generation of ROS by endogenous estrogens has never been characterized. In the present studies we determined whether the catechol metabolites of endogenous estrogens including 2-hydroxyestradiol, 4-hydroxyestradiol, 4-hydroxyestrone, and 2-hydroxyestriol, can redox cycle in breast epithelial cells. These catechol estrogens, but not estradiol, estrone, estriol or 2-methoxyestradiol, were found to redox cycle and generate hydrogen peroxide and hydroxyl radicals in lysates of three different breast epithelial cell lines: MCF-7, MDA-MB-231 and MCF-10A. The generation of ROS required NADPH as a reducing equivalent and was inhibited by diphenyleneiodonium, a flavoenzyme inhibitor, indicating that redox cycling is mediated by flavin-containing oxidoreductases. Using extracellular microsensors, catechol estrogen metabolites stimulated the release of hydrogen peroxide by adherent cells, indicating that redox cycling occurs in viable intact cells. Taken together, these data demonstrate that catechol metabolites of endogenous estrogens undergo redox cycling in breast epithelial cells, resulting in ROS production. Depending on the localized concentrations of catechol estrogens and enzymes that mediate redox cycling, this may be an important mechanism contributing to the development of breast cancer.

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More information

e-pub ahead of print date: 10 June 2010
Published date: 8 August 2011
Organisations: Faculty of Natural and Environmental Sciences

Identifiers

Local EPrints ID: 204905
URI: http://eprints.soton.ac.uk/id/eprint/204905
ISSN: 0143-3334
PURE UUID: f63e4b73-3aa3-49e7-92de-6cf854e51acd
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

Catalogue record

Date deposited: 02 Dec 2011 15:30
Last modified: 18 Jul 2017 11:05

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Contributors

Author: Karma C. Fussell
Author: Ronald G. Udasin
Author: Michael A. Gallo
Author: Jeffrey D. Laskin

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