TY - CHAP
T1 - Oxidative metabolism of estrogens in cancer initiation and prevention
AU - Rogan, Eleanor G.
AU - Cavalieri, Ercole L.
N1 - Funding Information:
The progress in research on the etiology and prevention of cancer is due to the efforts, dedication, accomplishments and creativity of the many fine scientists with whom we have worked over the years. We particularly acknowledge our longterm collaboration with Dr. Muhammad Zahid. Preparation of this article was supported by Prevention LLC. Core support at the Eppley Institute was supported by grant P30 36727 from the National Cancer Institute.
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
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U2 - 10.1021/bk-2015-1200.ch002
DO - 10.1021/bk-2015-1200.ch002
M3 - Chapter
AN - SCOPUS:84957059171
T3 - ACS Symposium Series
SP - 35
EP - 51
BT - Oxidative Stress
A2 - Andreescu, Silvana
A2 - Hepel, Maria
PB - American Chemical Society
ER -