Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells. The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction and catechol-O-methyltransferase inhibition |
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Authors: | Lu Fang Zahid Muhammad Saeed Muhammad Cavalieri Ercole L Rogan Eleanor G |
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Institution: | aEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, United States |
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Abstract: | Formation of estrogen metabolites that react with DNA is thought to be a mechanism of cancer initiation by estrogens. The estrogens estrone (E1) and estradiol (E2) can form catechol estrogen (CE) metabolites, catechol estrogen quinones E1(E2)-3,4-Q], which react with DNA to form predominantly depurinating adducts. This may lead to mutations that initiate cancer. Catechol-O-methyltransferase (COMT) catalyzes an inactivation (protective) pathway for CE. This study investigated the effect of inhibiting COMT activity on the levels of depurinating 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua adducts in human breast epithelial cells. MCF-10F cells were treated with TCDD, a cytochrome P450 inducer, then with E2 and Ro41-0960, a COMT inhibitor. Estrogen metabolites and depurinating DNA adducts in culture medium were analyzed by HPLC with electrochemical detection. Pre-treatment of cells with TCDD increased E2 metabolism to 4-OHE1(E2) and 4-OCH3E1(E2). Inclusion of Ro41-0960 and E2 in the medium blocked formation of methoxy CE, and depurinating adducts were observed. With Ro41-0960, more adducts were detected in MCF-10F cells exposed to 1 μM E2, whereas without the inhibitor, no increases in adducts were detected with E2 ≤ 10 μM. We conclude that low COMT activity and increased formation of depurinating adducts can be critical factors leading to initiation of breast cancer. |
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Keywords: | Estrogen metabolism Catechol-O-methyltransferase 2 3 7 8-Tetrachlorodibenzo-p-dioxin (TCDD) Depurinating estrogen-DNA adducts MCF-10F cells |
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