Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, stable adducts, and oxidized bases.
Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, stable adducts, and oxidized bases.
复制标题
马雌激素代谢物 4-羟基马萘雌酮可诱导大鼠乳腺组织 DNA 损伤：形成单链断裂、无嘌呤位点、稳定加合物和氧化碱基。
DOI：
10.1021/tx010158c
复制
发表时间：
2001
影响因子：
4.1
通讯作者：
Bolton,JL
中科院分区：
文献类型：
--
作者：
Zhang,F;Swanson,SM;vanBreemen,RB;Liu,X;Yang,Y;Gu,C;Bolton,JL
流行病学数据强烈表明，女性患乳腺癌的风险与其一生中雌激素暴露直接相关。特别是雌激素替代疗法与癌症风险增加有关。以前我们表明，马雌激素马雌激素和马雌激素，它们是雌激素替代制剂倍美力（Wyeth-Ayerst）的主要组分，被代谢成儿茶酚，4-羟基马雌激素，其在体外自动氧化成蒽醌，引起DNA的氧化和烷基化[博尔顿，J.L.，Pisha，E.，张福，和Qiu，S.（1998）Chem.Res.Toxicol.11，1113 - 1227]。在本研究中，我们将4-羟基马钱宁注射到Sprague−道利大鼠的乳腺脂肪垫中。使用彗星试验对从乳腺组织中分离的细胞进行DNA单链断裂和氧化碱基分析，结果显示两种类型的病变均呈剂量依赖性增加。此外，提取的乳腺组织的LC-MS-MS分析显示形成了烷基化脱嘌呤鸟嘌呤加合物。最后，提取乳腺组织DNA，水解为脱氧核苷，并通过LC-MS-MS分析表明形成了稳定的环状脱氧鸟苷和脱氧腺苷加合物以及氧化碱基。这是第一次报道4-hydroxyequilenin能够在体内引起DNA损伤。此外，数据显示4-hydroxyequilenin诱导了四种不同类型的DNA损伤，必须通过不同的机制进行修复。这与内源性雌激素4-羟基雌酮相反，在内源性雌激素4-羟基雌酮中，仅在体内检测到脱嘌呤鸟嘌呤加合物。这些结果表明，4-hydroxyequilenin有可能是一个强大的致癌物质，通过在体内形成各种DNA损伤。
Epidemiological data strongly suggest that a woman's risk of developing breast cancer is directly related to her lifetime estrogen exposure. Estrogen replacement therapy in particular has been correlated with an increased cancer risk. Previously we showed that the equine estrogens equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are metabolized to the catechol, 4-hydroxyequilenin which autoxidizes to ano-quinone causing oxidation and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. (1998)Chem. Res. Toxicol.11, 1113−1227]. In the present study, we injected 4-hydroxyequilenin into the mammary fat pads of Sprague−Dawley rats. Analysis of cells isolated from the mammary tissue for DNA single-strand breaks and oxidized bases using the comet assay showed a dose-dependent increase in both types of lesions. In addition, LC-MS-MS analysis of extracted mammary tissue showed the formation of an alkylated depurinating guanine adduct. Finally, extraction of mammary tissue DNA, hydrolysis to deoxynucleosides, and analysis by LC-MS-MS showed the formation of stable cyclic deoxyguanosine and deoxyadenosine adducts as well as oxidized bases. This is the first report showing that 4-hydroxyequilenin is capable of causing DNA damage in vivo. In addition, the data showed that 4-hydroxyequilenin induced four different types of DNA damage that must be repaired by different mechanisms. This is in contrast to the endogenous estrogen 4-hydroxyestrone where only depurinating guanine adducts have been detected in vivo. These results suggest that 4-hydroxyequilenin has the potential to be a potent carcinogen through the formation of variety of DNA lesions in vivo.