TY - JOUR
T1 - Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer
AU - Cavalieri, Ercole L.
AU - Rogan, Eleanor G.
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 fine scientists with whom we have worked over the years. We particularly acknowledge our long-term collaboration with Dr. D. Chakravarti of our research group. In addition we express our gratitude to Drs. N. Gaikwad, K.-M. Li, M. Saeed, S. Singh, D. Venugopal and M. Zahid, our graduate students F. Lu and L. Yang and our technical support P. Mailander and S. Higginbotham. 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.
PY - 2011/7
Y1 - 2011/7
N2 - Among the numerous small molecules in the body, the very few aromatic ones include the estrogens and dopamine. In relation to cancer initiation, the estrogens should be considered as chemicals, not as hormones. Metabolism of estrogens is characterized by two major pathways. One is hydroxylation to form the 2- and 4-catechol estrogens, and the second is hydroxylation at the 16α position. In the catechol pathway, the metabolism involves further oxidation to semiquinones and quinones, including formation of the catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. These electrophilic compounds react with DNA to form the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E 2)-1-N7Gua. The apurinic sites obtained by this reaction generate the mutations that may lead to the initiation of cancer. Oxidation of catechol estrogens to their quinones is normally in homeostasis, which minimizes formation of the quinones and their reaction with DNA. When the homeostasis is disrupted, excessive amounts of catechol estrogen quinones are formed and the resulting increase in depurinating DNA adducts can lead to initiation of cancer. Substantial evidence demonstrates the mutagenicity of the estrogen metabolites and their ability to induce transformation of mouse and human breast epithelial cells, and tumors in laboratory animals. Furthermore, women at high risk for breast cancer or diagnosed with the disease, men with prostate cancer, and men with non-Hodgkin lymphoma all have relatively high levels of estrogen-DNA adducts, compared to matched control subjects. Specific antioxidants, such as N-acetylcysteine and resveratrol, can block the oxidation of catechol estrogens to their quinones and their reaction with DNA. As a result, the initiation of cancer can be prevented.
AB - Among the numerous small molecules in the body, the very few aromatic ones include the estrogens and dopamine. In relation to cancer initiation, the estrogens should be considered as chemicals, not as hormones. Metabolism of estrogens is characterized by two major pathways. One is hydroxylation to form the 2- and 4-catechol estrogens, and the second is hydroxylation at the 16α position. In the catechol pathway, the metabolism involves further oxidation to semiquinones and quinones, including formation of the catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. These electrophilic compounds react with DNA to form the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E 2)-1-N7Gua. The apurinic sites obtained by this reaction generate the mutations that may lead to the initiation of cancer. Oxidation of catechol estrogens to their quinones is normally in homeostasis, which minimizes formation of the quinones and their reaction with DNA. When the homeostasis is disrupted, excessive amounts of catechol estrogen quinones are formed and the resulting increase in depurinating DNA adducts can lead to initiation of cancer. Substantial evidence demonstrates the mutagenicity of the estrogen metabolites and their ability to induce transformation of mouse and human breast epithelial cells, and tumors in laboratory animals. Furthermore, women at high risk for breast cancer or diagnosed with the disease, men with prostate cancer, and men with non-Hodgkin lymphoma all have relatively high levels of estrogen-DNA adducts, compared to matched control subjects. Specific antioxidants, such as N-acetylcysteine and resveratrol, can block the oxidation of catechol estrogens to their quinones and their reaction with DNA. As a result, the initiation of cancer can be prevented.
KW - Cancer etiology
KW - Cancer prevention
KW - Catechol estrogen-3,4-quinones
KW - Depurinating estrogen-DNA adducts
KW - Estrogen genotoxicity
KW - Estrogen mutagenicity
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U2 - 10.1016/j.jsbmb.2011.03.008
DO - 10.1016/j.jsbmb.2011.03.008
M3 - Review article
C2 - 21397019
AN - SCOPUS:79957791696
SN - 0960-0760
VL - 125
SP - 169
EP - 180
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3-5
ER -