Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene.
Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene.
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雌激素-核酸加合物：鸟嘌呤是3,4-雌酮醌与COIII基因相互作用的主要位点。
DOI：
10.1093/carcin/18.6.1247
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发表时间：
1997
期刊：
影响因子：
4.7
通讯作者：
Abul-Hajj,YJ
中科院分区：
文献类型：
--
作者：
Roy,D;Abul-Hajj,YJ
雌激素在啮齿动物和人类中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。雌二醇的代谢活化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-羟基喜树碱是仓鼠肿瘤的有效诱导物。先前的研究表明，3，4-雌酮醌（3，4-EQ）可以在MCF-7乳腺癌细胞中进行氧化还原循环，并且能够诱导仅单链DNA断裂，以及与包括氨基酸和核酸在内的各种亲核试剂反应以产生Michael加成产物。本文用~（32）P后标记法研究了3，4-EQ与COIII基因相互作用的性质，并分析了雌激素-DNA加合物。3，4-EQ与COIII基因的反应，随后进行聚合酶阻滞试验，显示了几个终止位点，其中鸟嘌呤优先受到3，4-EQ的攻击，并在较小程度上受到Ade、Cyt和Thy的攻击。3，4-EQ与COIII基因反应的32 P-后标记分析得到一种主要加合物，发现其与从dGMP与3，4-EQ反应获得的加合物相同。COIII模板与3，4-EQ结合的体外复制受阻的观察结果表明，雌激素醌加合损伤可以阻止DNA聚合酶。这些结果表明3，4-EQ可能具有遗传毒性，并可能为雌激素的致癌作用提供一种可能的解释。
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 is a potent inducer of tumors in hamsters. Previous studies have shown that 3,4-estrone quinone (3,4-EQ) 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 including amino acids and nucleic acids to give Michael addition products. In this paper we examined the nature of the interaction of 3,4-EQ with COIII gene and analysed the estrogen-DNA adducts by 32P-post-labeling. The reaction of 3,4-EQ with the COIII gene followed by polymerase arrest assay showed several stop sites in which guanine was preferentially attacked by 3,4-EQ and, to a lesser extent, with Ade, Cyt and Thy. 32P-Post-labeling analysis of the reaction of 3,4-EQ with COIII gene gave one major adduct which was found to be identical to that obtained from reaction of dGMP with 3,4-EQ. The observation that obstruction of in vitro replication of COIII template bound to 3,4-EQ suggests that estrogen quinone adducted lesions can arrest DNA polymerase. These results indicate that 3,4-EQ may be genotoxic and may provide one possible explanation for the carcinogenic effects of estrogens.