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: 6173698
• 负责人: WILLIAM J BODELL
• 金额: $ 19.6万
• 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 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173698
• 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：(改编自研究人员摘要)他莫昔芬(TMX)是 一种用于治疗乳腺癌的抗雌激素化合物。近期 临床研究表明，接受TMX治疗的女性患者的 子宫癌的RIS增加。博德尔博士实验室的结果 提示代谢物4-羟基-三苯氧胺(4-OH-TMX)可能在 在这一进程中发挥重要作用。在拟议的研究中，他将评估 活化4-羟基-TM形成DNA加合物。他认为这些研究 将为TMX增加 患子宫癌的风险。博德尔博士建议：[1]使用肝脏和子宫 微粒体激活系统子宫过氧化物酶的研究 4-OH-TMX的进一步氧化。建议的甲基苯二酚(QM)产品 会被困在DNA加合物中。4-羟基-TMX(QM)的还原 将检查DT-黄递酶。这些研究的目标是 探讨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(S) 4-OH-TMX的活化和解毒及其活性的确定 4-OH-TMX的中间体，导致加合物的形成。[2]调查 代谢物和DNA加合物在女性组织中的积累 TMX或非致癌类似物对SD大鼠的治疗 托瑞米芬。剂量和治疗计划将与所示相同 建立SD大鼠子宫内膜癌模型。经济衰退带来的影响 化学预防性药物OltiPraz对TMX Will形成DNA加合物的影响 要下定决心。这些研究将提供有关这一角色的重要信息 糖尿病肾病加合物在TMX诱发子宫内膜癌病因中的作用 行政管理。[3]优化32P-后标记程序 4-羟基-TMX。这些已鉴定的加合物将用于研究DNA 4-羟基-TMX和过氧化物酶活化形成的加合物及 TMX处理的大鼠子宫组织中检测到加合物。直接分析 TMX对大鼠子宫标本中加合物(S)的影响 采用电喷雾电离质谱仪进行分析。

项目成果

Peroxidase-mediated dealkylation of tamoxifen, detected by electrospray ionization-mass spectrometry, and activation to form DNA adducts.

• DOI: 10.1016/j.freeradbiomed.2011.10.433
• 发表时间: 2012-01-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Gaikwad, Nilesh W.;Bodell, William J.
• 通讯作者: Bodell, William J.