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The Effects of Catechol-O-Methyltransferase Inhibition on Estrogen Metabolite and Oxidative DNA Damage Levels in Estradiol-treated MCF-7 Cells¹

Department of Environmental Health Science, Division of Toxicological Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205-2179 [J. A L., J. E. G., T. F., S. O., P. H., J. D. Y.], and National Center for Toxicological Research, Department of Biochemical Toxicology, Jefferson, Arizona 72079-9502 [D. W. R.]

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 µM E₂, whereas in the absence of COMT inhibition, no increase in 8-oxo-dG was detected at E₂ concentrations 10 µM. 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.

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