Genotoxicity of Estrogen Compounds in Endocrine Therapy

内分泌治疗中雌激素化合物的遗传毒性

• 批准号: 7618442
• 负责人: SHINYA SHIBUTANI
• 金额: $ 27.37万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-04 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618442
• 关键词: Biochemical; Biological Markers; Breast; DNA; DNA Adducts; DNA Damage; DNA lesion; Detection; Drug Design; Endometrial; Endometrial Carcinoma; Equilenin; Equilin; Equus caballus; Estrogen Replacement Therapy; Estrogens; Goals; High Risk Woman; Hormones; Human; Incidence; Kidney; Knockout Mice; Laboratories; Leukocytes; Malignant Neoplasms; Mammalian Cell; Mammary gland; Menopause; Methods; Organ; Osteoporosis; Ovarian; Play; Property; Rattus; Research; Research Design; Risk; Role; Sampling; Site; Site-Directed Mutagenesis; Subgroup; Symptoms; Techniques; Therapeutic; Tissues; Woman; adduct; detector; genotoxicity; hormone therapy; malignant breast neoplasm; oxidative DNA damage; oxidative damage; repaired; reproductive; stereochemistry

DESCRIPTION (provided by applicant): Estrogen replacement therapy (ERT) is widely used to decrease symptoms associated with menopause and to protect women against osteoporosis. ERT, composed of estrogens, equilin, and equilenin, is associated with increased risk of breast, ovarian, and endometrial cancers. As the major metabolites of estrogen and equine estrogen generate oxidative DNA damage and, in some cases react with DNA to form covalent adducts, it is possible that DNA damage plays a central role in the initiation of estrogen-associated cancers. The proposed studies are designed to determine the level of covalent DNA adducts and oxidative damage generated in mammary and reproductive tissues of rats treated with equine estrogens or their metabolites, as well as establish the mutagenic and repair potential of equine estrogen-derived DNA adducts. Leukocytes and endometrial tissue will be collected from women receiving ERT and analyzed for DNA adducts using ultrasensitive 32P-postlabeling and HPLC/electrochemical detection techniques developed in our laboratory. If such adducts are not fully repaired, DNA lesions will persist in target tissues where they may initiate breast, ovarian, and/or endometrial cancer. By demonstrating that certain components of ERT are genotoxic and by defining the biochemical mechanism involved, it should be possible to design drugs that retain desirable therapeutic properties of ERT but lack its carcinogenic effects. This research will also provide biomarkers that can be used to identify subgroups of women at high risk of developing ERT-induced cancer.

描述（由申请人提供）：雌激素替代疗法（ERT）被广泛用于减轻与更年期相关的症状并保护女性免受骨质疏松症。由雌激素，平衡和平衡蛋白组成的ERT与乳腺癌，卵巢和子宫内膜癌的风险增加有关。由于雌激素和马雌激素的主要代谢产物会产生氧化性DNA损伤，并且在某些情况下与DNA反应形成共价加合物，因此DNA损伤可能在雌激素相关的癌症的开始中起着核心作用。拟议的研究旨在确定用马雌激素或其代谢产物处理的大鼠的乳腺和生殖组织中产生的共价DNA加合物和氧化损伤的水平，并建立了雌激素源性DNA加盖剂的诱变和修复潜力。将从接受ERT的妇女中收集白细胞和子宫内膜组织，并使用超敏感的32p固定标签以及在我们实验室开发的HPLC/电化学检测技术进行DNA加合物进行分析。如果这种加合物未完全修复，DNA病变将持续在可能启动乳腺癌，卵巢和/或子宫内膜癌的目标组织中。通过证明ERT的某些成分是遗传毒性的，并且通过定义涉及的生化机制，应该可以设计保留ERT的理想治疗特性但缺乏其致癌作用的药物。这项研究还将提供生物标志物，可用于鉴定患有ERT诱发癌症的高风险的女性亚组。

项目成果

Mechanism of translesion synthesis past an equine estrogen-DNA adduct by Y-family DNA polymerases.

Y 家族 DNA 聚合酶通过马雌激素-DNA 加合物的跨损伤合成机制。

• DOI: 10.1016/j.jmb.2007.06.009
• 发表时间: 2007
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Yasui,Manabu;Suzuki,Naomi;Liu,Xiaoping;Okamoto,Yoshinori;Kim,SungYeon;Laxmi,YRSantosh;Shibutani,Shinya
• 通讯作者: Shibutani,Shinya

Translesion synthesis past equine estrogen-derived 2'-deoxyadenosine DNA adducts by human DNA polymerases eta and kappa.

通过人类 DNA 聚合酶 eta 和 kappa 跨损伤合成马雌激素衍生的 2-脱氧腺苷 DNA 加合物。

• DOI: 10.1021/bi0525324
• 发表时间: 2006
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Yasui,Manabu;Laxmi,YRSantosh;Ananthoju,SreenivasaR;Suzuki,Naomi;Kim,SungYeon;Shibutani,Shinya
• 通讯作者: Shibutani,Shinya

Quantitative detection of 4-hydroxyequilenin-DNA adducts in mammalian cells using an immunoassay with a novel monoclonal antibody.

使用新型单克隆抗体进行免疫测定，定量检测哺乳动物细胞中的 4-羟基马萘醌-DNA 加合物。

• DOI: 10.1093/nar/gkq233
• 发表时间: 2010-07
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Okahashi, Yumiko;Iwamoto, Takaaki;Suzuki, Naomi;Shibutani, Shinya;Sugiura, Shigeki;Itoh, Shinji;Nishiwaki, Tomohisa;Ueno, Satoshi;Mori, Toshio
• 通讯作者: Mori, Toshio