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

Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells
Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells
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.
0143-3334
1285-1293
Fussell, Karma C.
0e577047-121f-4ee0-a022-89ac2edea454
Udasin, Ronald G.
01264bc8-50e2-45c4-ab8d-691acdea43a3
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gallo, Michael A.
ad5db824-9fb5-462e-b76c-cd1bfb74b3a9
Laskin, Jeffrey D.
8c4377b4-ba21-4811-8cb1-35904f35e1d5
Fussell, Karma C.
0e577047-121f-4ee0-a022-89ac2edea454
Udasin, Ronald G.
01264bc8-50e2-45c4-ab8d-691acdea43a3
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Gallo, Michael A.
ad5db824-9fb5-462e-b76c-cd1bfb74b3a9
Laskin, Jeffrey D.
8c4377b4-ba21-4811-8cb1-35904f35e1d5

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), 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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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

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Date deposited: 02 Dec 2011 15:30
Last modified: 15 Mar 2024 03:39

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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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