ToxSci Advance Access originally published online on July 14, 2004
Toxicological Sciences 2004 81(2):316-324; doi:10.1093/toxsci/kfh216
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Toxicological Sciences vol. 81 no. 2 © Society of Toxicology 2004; all rights reserved.
Phytochemicals Inhibit Catechol-O-Methyltransferase Activity in Cytosolic Fractions from Healthy Human Mammary Tissues: Implications for Catechol Estrogen-Induced DNA Damage
* Institute for Risk Assessment Sciences (IRAS), Universiteit Utrecht, Utrecht, The Netherlands; and St. Antonius Hospital, Department of Internal Medicine, Nieuwegein, The Netherlands
Received May 4, 2004; accepted July 5, 2004
Phytochemicals are natural dietary constituents of fruits and vegetables. Some of these phytochemicals are known to affect estrogen-metabolizing enzymes. In breast tissue, estradiol can be metabolized to the catechol estrogens 2- and 4-hydroxyestradiol (2-OHE2 and 4-OHE2). Catechol estrogens are suspected carcinogens potentially involved in the etiology of breast cancer. Catechol-O-methyltransferase (COMT) converts the catechol estrogens to their inactive methoxy derivatives (2-MeOE2 and 4-MeOE2). In this study we investigated the effects of several phytochemicals on COMT activity in cytosolic fractions of seven healthy human mammary tissues from reduction mammoplasty. Large interindividual variations were observed in the constitutive levels of COMT activity. However, in all cytosol samples the catalytic efficiency of COMT was greater for 2-MeOE2 formation than for 4-MeOE2 formation. The known COMT inhibitor Ro 41-0960 and several phytochemicals with a catechol structure (quercetin, catechin, and (-)-epicatechin) concentration-dependently inhibited COMT activity, while phytochemicals without a catechol structure (genistein, chrysin, and flavone) showed no effect up to 30 µM. Distinct interindividual variations were observed in sensitivity toward COMT inhibition among the various tissue samples, as was shown by the range in IC50 values for Ro 41-0960 (5–42 nM). The toxicological relevance of COMT inhibition and the effect of reduced inactivation of catechol estrogens was studied by determining the amount of catechol estrogen-induced DNA damage in MCF-7 cells using the comet assay. Catechol estrogens alone caused no increase of DNA damage compared with control treated cells. However, both Ro 41-0960 and quercetin caused a decrease of methoxy estradiol formation and an increase of catechol estrogen-induced DNA damage in MCF-7 cells. This suggests that phytochemicals with a catechol structure have the potential to reduce COMT activity in mammary tissues and may consequently reduce the inactivation of potentially mutagenic estradiol metabolites and increase the chance of DNA damage.
Key Words: phytochemicals; catechol estrogens; COMT; DNA damage.
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