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: 2666120
• 负责人: WILLIAM J BODELL
• 金额: $ 14万
• 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/2666120
• 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 临床研究表明，用TMX治疗的妇女有高达6倍的 增加子宫癌的风险。 博德尔博士实验室的结果 表明代谢产物4-羟基-他莫昔芬（4-OH-TMX）可能在 在这个过程中的重要作用。 在拟议的研究中，他将评估 活化4-OH-TM以形成DNA加合物。 他认为这些研究 将提供新的见解的机制，TMX增加 子宫癌的风险。 Bodell博士建议：[1]使用肝脏和子宫 微粒体激活系统和子宫过氧化物酶，以研究 4-OH-TMX的进一步氧化。 拟定醌甲基化物（QM）产品 会以DNA加合物的形式被捕获 4-OH-TMX（QM）的还原 将检查DT-心肌黄酶。 这些研究的目的是 研究P450、子宫过氧化物酶和DT-黄递酶在子宫内膜异位症中的作用。 4-OH-TMX的活化和解毒，并确定反应性 4-OH-TMX的中间体，导致加合物形成。 [2]探讨 代谢物和DNA加合物在女性组织中蓄积 用TMX或非致癌类似物处理的Sprague-Dawley大鼠 托瑞米芬 剂量和治疗方案与所示相同 诱发Sprague-Dawley大鼠子宫内膜癌 的影响 化学预防剂Oltipraz对TMX形成DNA加合物的作用将 被确定。 这些研究将提供重要的信息， DN加合物在TMX诱发子宫内膜癌中的作用 局 [3]为了优化32 P-后标记程序， 4-OH-TMX。 这些鉴定的加合物将用于研究DNA 微粒体和过氧化物酶活化4-OH-TMX形成的加合物， 在TMX处理的大鼠子宫组织中检测到加合物。 直接分析 TMX处理大鼠子宫样本中检测到的加合物 通过电喷雾电离质谱法制备。