Abstract
Endogenous estrogens become carcinogens when excessive catechol estrogen quinone metabolites are formed. Specifically, the catechol estrogen-3,4-quinones can react with DNA to produce a large amount of specific depurinating estrogen-DNA adducts, formed at the N-3 of Ade and N-7 of Gua. Loss of these adducts leaves apurinic sites in the DNA, which can generate subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of the depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from studies in vitro, in cell culture, in animal models and in human subjects. High levels of estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, and in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Two dietary supplements, N-acetylcysteine and resveratrol, complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these epithelial cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. Blocking initiation of cancer prevents promotion, progression and development of the disease. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.
Highlights
Journal of Rare Diseases Research & Treatment catechol estrogens to semiquinones and to quinones, catalyzed by Cytochrome P450 (CYP) or peroxidases, can occur (Figure 2)
Blocking initiation of cancer prevents promotion, progression and development of the disease. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer
Catechol estrogen quinones covalently bind to DNA to form two types of adducts: stable ones that remain in DNA unless removed by repair and depurinating adducts that are lost from DNA by destabilization of the glycosyl bond[13,14]
Summary
Estrogens are metabolized via two major pathways: formation of 16α-hydroxyestrone (estradiol) [E1(E2)] (not shown in Figure 2) and formation of the catechol estrogens 2-OHE1(E2) and 4-OHE1(E2)[1]. The most common pathway of conjugation of catechol estrogens in extrahepatic tissues is O-methylation, catalyzed by catechol-O-methyltransferase (COMT)[8,9]. Catechol estrogens to semiquinones and to quinones, catalyzed by CYP or peroxidases, can occur (Figure 2). Following formation of catechol estrogen quinones, they can be inactivated by reaction with glutathione (GSH) or reduction to their catechols by quinone reductase (NQO1)[10,11], a protective enzyme induced by various compounds[12]. If the catechol estrogen quinones are not eliminated by protective processes, they can react with DNA (Figure 2). Catechol estrogen quinones covalently bind to DNA to form two types of adducts: stable ones that remain in DNA unless removed by repair and depurinating adducts that are lost from DNA by destabilization of the glycosyl bond[13,14]
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