Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, United States.
J Steroid Biochem Mol Biol. 2011 Jul;125(3-5):169-80. doi: 10.1016/j.jsbmb.2011.03.008. Epub 2011 Mar 21.
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-OHE(1)(E(2))-1-N3Ade and 4-OHE(1)(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.
在体内众多的小分子中，极少数芳香族小分子包括雌激素和多巴胺。就癌症的起始而言，雌激素应被视为化学物质，而不是激素。雌激素的代谢有两条主要途径。一条是羟化形成 2-和 4-儿茶酚雌激素，另一条是在 16α 位羟化。在儿茶酚途径中，代谢进一步氧化为半醌和醌，包括形成儿茶酚雌激素-3,4-醌，这是雌激素的主要致癌代谢物。这些亲电化合物与 DNA 反应形成去嘌呤加合物 4-OHE(1)(E(2))-1-N3Ade 和 4-OHE(1)(E(2))-1-N7Gua。该反应产生的无嘌呤位点会导致突变，从而可能引发癌症。儿茶酚雌激素氧化为醌通常处于动态平衡中，这最大限度地减少了醌的形成及其与 DNA 的反应。当动态平衡被打破时，会形成大量的儿茶酚雌激素醌，导致去嘌呤 DNA 加合物的增加，从而引发癌症。大量证据表明雌激素代谢物具有致突变性和诱导小鼠和人乳腺上皮细胞转化以及实验动物肿瘤的能力。此外，患有乳腺癌高风险或已确诊患有乳腺癌的女性、患有前列腺癌的男性和患有非霍奇金淋巴瘤的男性，与匹配的对照组相比，其雌激素-DNA 加合物水平相对较高。特定的抗氧化剂，如 N-乙酰半胱氨酸和白藜芦醇，可以阻断儿茶酚雌激素氧化为醌及其与 DNA 的反应。因此，可以预防癌症的发生。
