Oxidative transformation of 2-hydroxyestrone. Stability and reactivity of 2,3-estrone quinone and its relationship to estrogen carcinogenicity.
Oxidative transformation of 2-hydroxyestrone. Stability and reactivity of 2,3-estrone quinone and its relationship to estrogen carcinogenicity.
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DOI：
10.1021/tx950205z
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发表时间：
1996-07
影响因子：
4.1
通讯作者：
K. Tabakovic;W. B. Gleason;W. Ojala;Y. Abul-Hajj
中科院分区：
文献类型：
--
作者：
K. Tabakovic;W. B. Gleason;W. Ojala;Y. Abul-Hajj
雌激素对啮齿动物和人类的致癌性归因于细胞大分子的烷基化和/或氧化还原循环、活性自由基的产生和DNA损伤。雌二醇的代谢激活导致儿茶酚雌激素的形成被认为是其遗传毒性作用的先决条件。 4-羟基雌二醇虽然不是 2-羟基雌二醇，但却是仓鼠肿瘤的有效诱导剂。先前的研究表明，3,4-雌酮醌可以进行氧化还原循环，并且能够在 MCF-7 乳腺癌细胞中诱导单链 DNA 断裂，并与各种亲核试剂（硫醇、咪唑、氨基、酚盐和乙酰氧基）反应产生迈克尔加成产物。这些结果支持 3,4-儿茶酚/醌雌激素可能参与雌激素的致癌性。为了解释 2-羟基雌激素的致癌性降低，研究了 2,3-雌酮醌 (2,3-EQ) 与亲核试剂的反应。 4-甲基咪唑与 2,3-EQ 的反应产生复杂的产物混合物，导致形成儿茶酚、C-O 二聚产物和 1,6-迈克尔加成产物，确定为 1-(4-甲基咪唑并)-2-羟基雌酮。 2,3-EQ 在弱碱性条件下与苯酚乙酯或乙酸酯反应，得到几种产物，其特征为 C-O 和 C-C 二聚体、儿茶酚和 3,5-二羟基-1(10), 3-雌二烯-2, 17-二酮。在这些实验条件下没有检测到迈克尔加成产物。在2,3-EQ的合成过程中也观察到了相同的产物，这使我们推测2-羟基雌激素缺乏致癌性可能与生理条件下醌的反应性增加和稳定性降低有关。这些结果与用 3,4-EQ 获得的结果形成对比，3,4-EQ 更稳定，因此可以从形成部位扩散到靶组织。这些结果以及快速甲基化和清除很可能是 2-羟基雌激素致癌性降低的解释。
The carcinogenicity of estrogens in rodents and man has been attributed to either alkylation of cellular macromolecules and/or redox-cycling, generation of active radicals, and DNA damage. Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. 4-Hydroxyestradiol, although not 2-hydroxyestradiol, is a potent inducer of tumors in hamsters. Previous studies have shown that 3,4-estrone quinone can redox-cycle and is capable of inducing exclusively single strand DNA breaks in MCF-7 breast cancer cells, as well as react with various nucleophiles (thiol, imidazole, amino, phenolate, and acetoxy) to give Michael addition products. These results support the possible involvement of 3,4-catechol/quinone estrogens in estrogen's carcinogenicity. To explain the decreased carcinogenicity of 2-hydroxyestrogens, the reactions of 2,3-estrone quinone (2,3-EQ) with nucleophiles were investigated. Reactions of 4-methylimidazole with 2,3-EQ gave a complex mixture of products leadng to the formation of the catechol, C-O dimerization product, and a 1,6-Michael addition product identified as the 1-(4-methylimidazolo)-2-hydroxyestrone. Reactions of 2,3-EQ under mildly basic conditions with either ethyl phenolate or acetate gave several products which were characterized as the C-O and C-C dimers, catechol, and 3,5-dihydroxy-1(10), 3-estradiene-2, 17-dione. No Michael addition products were detected under these experimental conditions. The same products were also observed during the synthesis of 2,3-EQ, which led us to postulate that the lack of carcinogenicity of 2-hydroxyestrogens may be related to the increased reactivity and decreased stability of the quinone under physiological conditions. These results are contrasted with those obtained with 3,4-EQ which is much more stable and therefore could diffuse from the site of formation to the target tissue. These results along with rapid methylation and clearance may be very likely explanations for the decreased carcinogenicity of 2-hydroxyestrogens.