Cavalieri Ercole L, Rogan Eleanor G
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA.
Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198-4388, USA.
J Rare Dis Res Treat. 2017;2(3):22-29. doi: 10.29245/2572-9411/2017/3.1093. Epub 2017 May 2.
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, -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 -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.
当形成过量的儿茶酚雌激素醌代谢产物时，内源性雌激素会变成致癌物。具体而言，儿茶酚雌激素 -3,4-醌可与DNA反应，产生大量特定的脱嘌呤雌激素 -DNA加合物，这些加合物形成于腺嘌呤（Ade）的N-3位和鸟嘌呤（Gua）的N-7位。这些加合物的丢失会在DNA中留下脱嘌呤位点，进而可能引发后续的致癌突变。雌激素代谢失衡会产生过量的儿茶酚雌激素 -3,4-醌，增加脱嘌呤雌激素 -DNA加合物的形成以及引发癌症的风险。这种癌症起始机制的证据来自体外研究、细胞培养、动物模型和人体研究。在患有乳腺癌、卵巢癌或甲状腺癌的女性以及患有前列腺癌或非霍奇金淋巴瘤的男性中，均观察到高水平的雌激素 -DNA加合物。在乳腺癌出现之前，在高危女性中观察到高水平的脱嘌呤雌激素 -DNA加合物，这表明加合物的形成是乳腺癌起始的关键因素。两种膳食补充剂，N-乙酰半胱氨酸和白藜芦醇，在减少儿茶酚雌激素 -3,4-醌的形成以及抑制培养的人和小鼠乳腺上皮细胞中雌激素 -DNA加合物的形成方面相互补充。它们还抑制这些上皮细胞的恶性转化。此外，遵循包括N-乙酰半胱氨酸和白藜芦醇在内的健康乳腺方案的女性，其加合物的形成有所减少。阻断癌症起始可预防疾病的促进、进展和发展。这些结果表明，减少脱嘌呤雌激素 -DNA加合物的形成可降低患多种人类癌症的风险。
