Ding Shuang, Shapiro Robert, Geacintov Nicholas E, Broyde Suse
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, USA.
Chem Res Toxicol. 2003 Jun;16(6):695-707. doi: 10.1021/tx0340246.
Exposure to estrogen through estrogen replacement therapy increases the risk of women developing cancer in hormone sensitive tissues. Premarin (Wyeth), which has been the most frequent choice for estrogen replacement therapy in the United States, contains the equine estrogens equilin and equilenin as major components. 4-Hydroxyequilenin (4-OHEN) is a phase I metabolite of both of these substances. This catechol estrogen autoxidizes to potent cytotoxic quinoids that can react with dG, dA, and dC to form unusual stereoisomeric cyclic adducts (Bolton, J. L., et al. (1998) Chem. Res. Toxicol. 11, 1113-1127). Like other bulky DNA adducts, these lesions may exhibit different susceptibilities to DNA repair and mutagenic potential, if not repaired in a structure-dependent manner. To ultimately gain insights into structure-function relationships, we computed conformations of stereoisomeric guanine, adenine, and cytosine base adducts using density functional theory. We find near mirror image conformations in stereoisomer adduct pairs for each modified base, suggesting opposite orientations with respect to the 5' --> 3' direction of the modified strand when the stereoisomer pairs are incorporated into duplex DNA. Such opposite orientations could cause stereoisomer pairs of lesions to respond differently to DNA replication and repair enzymes.
通过雌激素替代疗法接触雌激素会增加女性在激素敏感组织中患癌的风险。在美国，倍美力（惠氏公司）一直是雌激素替代疗法最常用的选择，其主要成分包含马雌激素马萘雌酮和马烯雌酮。4-羟基马烯雌酮（4-OHEN）是这两种物质的I相代谢产物。这种儿茶酚雌激素会自动氧化为具有强细胞毒性的醌类物质，它们能与dG、dA和dC反应形成不寻常的立体异构环状加合物（博尔顿，J.L.等人（1998年）《化学研究毒理学》11卷，1113 - 1127页）。与其他大分子DNA加合物一样，如果这些损伤不能以依赖结构的方式修复，它们可能对DNA修复和诱变潜力表现出不同的敏感性。为了最终深入了解结构 - 功能关系，我们使用密度泛函理论计算了立体异构鸟嘌呤、腺嘌呤和胞嘧啶碱基加合物的构象。我们发现每个修饰碱基的立体异构体加合物对中存在近乎镜像的构象，这表明当立体异构体对被纳入双链DNA时，相对于修饰链的5'→3'方向存在相反的取向。这种相反的取向可能导致损伤的立体异构体对在DNA复制和修复酶作用下有不同的反应。
