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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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.

Original languageEnglish (US)
Pages (from-to)150-158
Number of pages9
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume105
Issue number1-5
DOIs
StatePublished - Jun 1 2007

Keywords

  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
  • Catechol-O-methyltransferase
  • Depurinating estrogen-DNA adducts
  • Estrogen metabolism
  • MCF-10F cells

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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