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Title: The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells.

Authors: Lavigne, J A; Goodman, J E; Fonong, T; Odwin, S; He, P; Roberts, D W; Yager, J D

Published In Cancer Res, (2001 Oct 15)

Abstract: Many of the major identified risk factors for breast cancer are associated with exposure to endogenous estrogen. In addition to the effects of estrogen as a growth factor, experimental and epidemiological evidence suggest that catechol metabolites of estrogen also contribute to estrogen carcinogenesis by both direct and indirect genotoxic mechanisms. O-Methylation catalyzed by catechol-O-methyltransferase (COMT) is a Phase II metabolic inactivation pathway for catechol estrogens. We and others have found that a polymorphism in the COMT gene, which codes for a low activity variant of the COMT enzyme, is associated with an increased risk of developing breast cancer; therefore, the goal of the current study was to investigate the role of decreased COMT activity on estrogen catechol levels and on oxidative DNA damage, as measured by 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) levels. MCF-7 cells were pretreated with dioxin as a means to increase estrogen metabolism to catechol estrogens, then treated with estradiol (E2) +/- Ro 41-0960, a COMT-specific inhibitor. After extraction from culture medium, estrogen metabolites were separated using an high-performance liquid chromatography-electrochemical detection method. As expected, dioxin dramatically increased E2 oxidative metabolism, primarily to its 2-OH and 2-methoxy metabolites. The COMT inhibitor blocked 2-methoxy E2 formation. This was associated with increased 2-hydroxy E2 (2-OH E2) and 8-oxo-dG levels. In the presence of COMT inhibition, increased oxidative DNA damage was detected in MCF-7 cells exposed to as low as 0.1 microM E2, whereas in the absence of COMT inhibition, no increase in 8-oxo-dG was detected at E2 concentrations < or =10 microM. This study is the first to show that O-methylation of 2-OH E2 by COMT is protective against oxidative DNA damage caused by 2-OH E2, a major oxidative metabolite of E2.

PubMed ID: 11606384 Exiting the NIEHS site

MeSH Terms: Benzophenones/pharmacology; Breast Neoplasms/enzymology; Breast Neoplasms/genetics; Breast Neoplasms/metabolism*; Catechol O-Methyltransferase/antagonists & inhibitors*; DNA Damage*; DNA, Neoplasm/metabolism; Deoxyguanosine/analogs & derivatives*; Deoxyguanosine/metabolism; Enzyme Inhibitors/pharmacology; Estradiol/metabolism*; Estradiol/pharmacology*; Estrogens, Catechol/metabolism*; Humans; Oxidative Stress/physiology; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Tumor Cells, Cultured

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