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Saeed M, Rogan E, Fernandez SV, Sheriff F, Russo J, Cavalieri E
Formation of depurinating N3Adenine and N7Guanine adducts by MCF-10F cells cultured in the presence of 4-hydroxyestradiol
International Journal of Cancer (2007) 120:1821-1824.
Metabolic conversion of endogenous estrogens, estradiol (E-2) and estrone (E-1), to the catechol estrogens 4-hydroxyE(1)(E-2) [4-OHE1(E-2) has been implicated in the initiation of cancer in rodents and humans. Evidence collected in our laboratories has shown that 4-OHE1(E-2) are enzymatically oxidized to E-1(E-2)4-quinones [E-1(E-2)-3,4-Q], which have the potential to damage DNA by forming predominantly depurinating adducts, 4-OHE1(E-2)-1-N3Ade and 4-OHE1(E-2)-1-N7Gua, leading to the accumulation of mutations and probably cell transformation. The human breast epithelial cell line MCF-10F has been transformed by treatment with E-2 or 4OHE(2). We have used MCF-10F cells to study the presence of adducts and conjugates after treatment with 4-OHE2. To mimic the intermittent exposure of breast cells to endogenous estrogens, MCF-10F cells were treated with 1 mu M 4-OHE2 for a 24-h period at 72, 120, 192 and 240 h postplating. Culture media were collected at each point, extracted by solid-phase extraction and analyzed by HPLC connected with a multichannel electrochemical detector and/or ultraperformance liquid chromatography/tandem mass spectrometry. Media from successive treatments with 4-OHE2 showed the formation of methoxy and cysteine conjugates, and the depurinating adducts 4-OHE1(E2)-1-N3Ade. The amount of 4-OHE1(E-2)1-N3Ade adducts was higher after the third treatment; smaller amounts of the 4-OHE1(E2)-1-N7Gua adducts were detected after the second and third treatments. These results demonstrate that MCF-10F cells oxidize 4-OHE2 to.E-1(E-2)-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. This DNA damage can play an important role in the 4-OHE2-induced mutations and transformation of MCF-10F cells to malignant cells. (c) 2007 Wiley-Liss, Inc.
Publication Date: 2007-04-01.
Last updated on Wednesday, July 08, 2020