Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Free Radic Biol Med. 2011 Jan 1;50(1):78-85. doi: 10.1016/j.freeradbiomed.2010.10.662. Epub 2010 Oct 8.
Substantial evidence suggests that catechol estrogen-3,4-quinones react with DNA to form predominantly the depurinating adducts 4-hydroxyestrone (estradiol)-1-N3Ade [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(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-OHE(2). Resv and NAcCys directed the metabolism of 4-OHE(2) 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-OHE(1)(E(2)). Resv was more effective at increasing the amount of 4-OCH(3)E(1)(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.
大量证据表明，儿茶酚雌激素-3,4-醌与 DNA 反应，主要形成脱嘌呤加合物 4-羟基雌酮（雌二醇）-1-N3Ade [4-OHE(1)(E(2))-1-N3Ade]和 4-OHE(1)(E(2))-1-N7Gua。这些加合物产生的无嘌呤位点会引发关键突变，从而引发癌症。癌症发生的范例基于雌激素代谢之间的失衡，这种失衡存在于导致雌激素-DNA 加合物的激活途径和导致雌激素代谢物和缀合物的失活途径之间。通过使用抗氧化剂，如白藜芦醇（Resv）和 N-乙酰半胱氨酸（NAcCys），可以改善这种不平衡，以最大程度地减少加合物的形成。为了比较 Resv 和 NAcCys 阻断雌激素-DNA 加合物形成的能力，我们使用经 4-OHE(2)处理的人乳腺上皮细胞系 MCF-10F。Resv 和 NAcCys 将 4-OHE(2)的代谢引导到保护途径。NAcCys 与醌反应，并将半醌还原为儿茶酚。这条途径也可以由 Resv 完成。此外，Resv 诱导了保护性酶醌还原酶，它将 E(1)(E(2))-3,4-醌还原为 4-OHE(1)(E(2))。Resv 比 NAcCys 更有效地增加 4-OCH(3)E(1)(E(2))的量。在较低剂量下，抑制雌激素-DNA 加合物形成的效果相似，但在较高剂量下，Resv 的效果比 NAcCys 约高出 50%。它们的联合作用是相加的。因此，这两种抗氧化剂为保护儿茶酚雌激素免受氧化为儿茶酚醌提供了极好的组合。
