Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 50, Issue 1, Pages 78-85Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.10.662
Keywords
Cancer prevention; Catechol estrogen quinones; Depurinating estrogen-DNA adducts; Balanced estrogen metabolism; Free radicals
Funding
- Prevention LLC.
- National Cancer Institute [CA P30 36727]
- NATIONAL CANCER INSTITUTE [P30CA036727] Funding Source: NIH RePORTER
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Substantial evidence suggests that catechol estrogen-3,4-quinones react with DNA to form predominantly the depurinating adducts 4-hydroxyestrone (estradiol)-1-N3Ade [4-OHE1(E-2)-1-N3Ade] and 4-OHE1(E-2)-1-N7Gua. Apurinic sites resulting from these adducts generate critical mutations that can initiate cancer. The paradigm of cancer initiation is based on an imbalance in estrogen metabolism between activating pathways that lead to estrogen-DNA adducts and deactivating pathways that lead to estrogen metabolites and conjugates. This imbalance can be improved to minimize formation of adducts by using antioxidants, such as resveratrol (Resv) and N-acetylcysteine (NAcCys). To compare the ability of Resv and NAcCys to block formation of estrogen-DNA adducts, we used the human breast epithelial cell line MCF-10F treated with 4-OHE2. Resv and NAcCys directed the metabolism of 4-OHE2 toward protective pathways. NAcCys reacted with the quinones and reduced the semiquinones to catechols. This pathway was also carried out by Resv. In addition, Resv induced the protective enzyme quinone reductase, which reduces E-1(E-2)-3,4-quinones to 4-OHE1(E-2). Resv was more effective at increasing the amount of 4-OCH3E1(E-2) than NAcCys. Inhibition of estrogen-DNA adduct formation was similar at lower doses, but at higher doses Resv was about 50% more effective than NAcCys. Their combined effects were additive. Therefore, these two antioxidants provide an excellent combination to protect catechol estrogens from oxidation to catechol quinones. (C) 2010 Elsevier Inc. All rights reserved.
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