ACTIVATION OF 4 HYDROXY TAMOXIFEN TO FORM DNA ADDUCTS

激活 4 羟基他莫昔芬形成 DNA 加合物

• 批准号: 6029687
• 负责人: WILLIAM J BODELL
• 金额: $ 4.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6029687
• 关键词: DNA damage; adduct; analog; animal genetic material tag; biotransformation; chemical carcinogen; chemical carcinogenesis; chemoprevention; dihydrolipoamide dehydrogenase; electrospray ionization mass spectrometry; enzyme activity; female; hydroxyl group; laboratory rat; liver metabolism; microsomes; neoplasm /cancer genetics; oltipraz; peroxidases; tamoxifen; unspecific monooxygenase; uterus; uterus neoplasms

DESCRIPTION: (Adapted from the investigator's abstract) Tamoxifen (TMX) is an antiestrogenic compound used in the treatment of breast cancer. Recent clinica studies indicate that women treated with TMX have up to a 6-fold increased ris of uterine cancer. Results from Dr. Bodell's laboratory suggest that the metabolite 4-hydroxy-tamoxifen (4-OH-TMX) may be playing an important role in this process. In the proposed studies he will assess the activation of 4-OH-TM to form DNA adducts. He believes that these studies will provide new insights as to the mechanisms by which TMX increases the risk of uterine cancer. Dr. Bodell proposes: [1] To use liver and uterine microsomal activation systems an uterine peroxidase to investigate the further oxidation of 4-OH-TMX. The proposed quinone methide (QM) product will be trapped as DNA adducts. The reduction of 4-OH-TMX (QM) by DT-diaphorase will be examined. The goals of these studies are to investigate the role(s) of P450, uterine peroxidase and DT-diaphorase in the activation and detoxification of 4-OH-TMX and to define the reactive intermediate of 4-OH-TMX leading to adduct formation. [2] To investigate the accumulation of metabolites and DNA adducts in tissues of female Sprague-Dawley rats treated with either TMX or the non-carcinogenic analogue Toremifine. The dose and treatment schedule will be the same as those shown to induce endometrial cancer in Sprague-Dawley rats. The effects of the chemopreventive agent Oltipraz on the formation of DNA adducts by TMX will be determined. These studies will provide important information on the role of DN adducts in the etiology of endometrial cancer induced by TMX administration. [3] To optimize the 32P-postlabeling procedure for 4-OH-TMX. These identified adducts will be used to investigate the DNA adducts formed by microsomal and peroxidase activation of 4-OH-TMX and the adduct detected in uterine tissues o rat treated with TMX. Direct analysis of the adduct(s) detected in uterine samples of rats treated with TMX will be made by electrospray ionization mass spectrometry.

描述：（改编自研究者的摘要）他莫昔芬 (TMX) 是 用于治疗乳腺癌的抗雌激素化合物。 最近的 临床研究表明，接受 TMX 治疗的女性的死亡率高达 6 倍 子宫癌风险增加。 Bodell 博士实验室的结果 表明代谢物 4-羟基-他莫昔芬 (4-OH-TMX) 可能发挥作用 在此过程中发挥重要作用。 在拟议的研究中，他将评估 激活4-OH-TM形成DNA加合物。 他认为这些研究 将为 TMX 增加的机制提供新的见解 子宫癌的风险。 Bodell博士建议：[1]利用肝脏和子宫 微粒体激活系统子宫过氧化物酶研究 4-OH-TMX进一步氧化。 拟议的醌甲基化物 (QM) 产品 将作为 DNA 加合物被捕获。 4-OH-TMX (QM) 的还原 将检查 DT-心肌黄酶。 这些研究的目标是 研究 P450、子宫过氧化物酶和 DT-心肌黄酶在 4-OH-TMX 的活化和解毒并定义反应性 4-OH-TMX 的中间体导致加合物形成。 [2] 调查 女性组织中代谢物和 DNA 加合物的积累 用 TMX 或非致癌类似物治疗的 Sprague-Dawley 大鼠 托米芬。 剂量和治疗方案与所示相同 在 Sprague-Dawley 大鼠中诱导子宫内膜癌。 的影响 化学预防剂 Oltipraz 对 TMX 形成 DNA 加合物的影响 被确定。 这些研究将提供有关角色的重要信息 DN 加合物在 TMX 诱发子宫内膜癌病因学中的作用 行政。 [3] 优化 32P 后标记程序 4-OH-TMX。 这些鉴定出的加合物将用于研究 DNA 由微粒体和过氧化物酶激活 4-OH-TMX 形成的加合物和 在用 TMX 处理的大鼠的子宫组织中检测到加合物。 直接分析 在用 TMX 治疗的大鼠子宫样本中检测到的加合物将 通过电喷雾电离质谱法制备。