Abstract

Oxidative metabolism of the estrogens estrone (E1) and estradiol (E2) is the critical event in the initiation of cancer by estrogens. E1 and E2 are oxidized by cytochrome P450 (CYP) to the catechol estrogens 2-OHE1(E2) and 4-OHE1(E2) and then to the catechol estrogen quinones, which react with DNA to form estrogen-DNA adducts. The E1(E2)-3,4-quinones [E1(E2)-3,4-Q] react predominantly with DNA to form the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. Loss of these adducts forms apurinic sites in the DNA that can generate mutations leading to the initiation of cancer. When estrogen metabolism becomes unbalanced toward oxidation, larger amounts of adducts are formed, and the risk of initiating cancer is greater. Women at high risk of developing breast cancer, or diagnosed with the disease, have higher levels of estrogen-DNA adducts than women at normal risk. With unbalanced estrogen metabolism, women are six-times more likely to be diagnosed with ovarian cancer. These results and others in humans and cell culture indicate that unbalanced oxidative metabolism of estrogens with formation of estrogen-DNA adducts is a critical event in the initiation of cancer. Two compounds, N-acetylcysteine and resveratrol, efficiently block formation of estrogen-DNA adducts and, thus, are promising agents to prevent cancer.

Original languageEnglish (US)
Title of host publicationOxidative Stress
Subtitle of host publicationDiagnostics, Prevention, and Therapy Volume 2
EditorsSilvana Andreescu, Maria Hepel
PublisherAmerican Chemical Society
Pages35-51
Number of pages17
ISBN (Electronic)9780841231009
DOIs
StatePublished - 2015

Publication series

NameACS Symposium Series
Volume1200
ISSN (Print)0097-6156
ISSN (Electronic)1947-5918

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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  • Cite this

    Rogan, E. G., & Cavalieri, E. L. (2015). Oxidative metabolism of estrogens in cancer initiation and prevention. In S. Andreescu, & M. Hepel (Eds.), Oxidative Stress: Diagnostics, Prevention, and Therapy Volume 2 (pp. 35-51). (ACS Symposium Series; Vol. 1200). American Chemical Society. https://doi.org/10.1021/bk-2015-1200.ch002