Inhibition of catechol-O-methyltransferase increases estrogen-DNA adduct formation

Muhammad Zahid, Muhammad Saeed, Fang Lu, Nilesh Gaikwad, Eleanor Rogan, Ercole Cavalieri

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of the disease. Studies on estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation, and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA forms depurinating adducts [4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua]. These adducts cause mutations leading to the initiation of breast cancer. Catechol-O-methyltransferase (COMT) is considered an important enzyme that protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinones. The goal of the present study was to investigate the effect of COMT inhibition on the formation of depurinating estrogen-DNA adducts. Immortalized human breast epithelial MCF-10F cells were treated with 4-OHE2 (0.2 or 0.5 μM) for 24 h at 120, 168, 216, and 264 h postplating or one time at 1-30 μM 4-OHE2 with or without the presence of COMT inhibitor (Ro41-0960). The culture media were collected at each point, extracted by solid-phase extraction, and analyzed by HPLC connected with a multichannel electrochemical detector. The results demonstrate that MCF-10F cells oxidize 4-OHE2 to E1(E2)-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. The COMT inhibitor Ro41-0960 blocked the methoxylation of catechol estrogens, with concomitant 3- to 4-fold increases in the levels of the depurinating adducts. Thus, low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer.

Original languageEnglish (US)
Pages (from-to)1534-1540
Number of pages7
JournalFree Radical Biology and Medicine
Volume43
Issue number11
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Keywords

  • COMT inhibition
  • Depurinating estrogen-DNA adducts
  • Estrogen metabolism
  • Estrogen protective enzymes

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

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