Lack of genotoxicity of tamoxifen in human endometrium.
Lack of genotoxicity of tamoxifen in human endometrium.
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他莫昔芬对人子宫内膜缺乏遗传毒性。
作者：
P. Carmichael;A. Ugwumadu;P. Neven;A. Hewer;G. K. Poon;D. Phillips
研究了抗乳腺癌药物他莫昔芬[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1，2-diphenyl-1-butene])]在体内和体外对人子宫内膜的遗传毒性损伤作用。对未服用三苯氧胺的子宫切除患者的子宫内膜进行切片，并在短期器官培养中保存。培养物用溶剂载体、他莫昔芬、α-羟基三苯氧胺[(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1，2-diphenyl-1-buten-3-醇(大鼠体内主要的dna反应代谢物)或苯并(A)芘处理。提取DNA，用32P后标记技术进行分析。在聚乙烯亚胺-纤维素薄层板上的层析显示，经α-羟基他莫昔芬处理的子宫内膜中的DNA加合物与以前在大鼠肝脏中看到的相同。然而，他莫昔芬本身的治疗中没有发现加合物。通过对苯并(A)芘诱导的预期DNA加合物的检测，证明了子宫内膜酶代谢系统的可行性。经他莫昔芬处理的子宫内膜外植体培养上清液的液质联用检测显示，α-羟基代谢物以剂量依赖的方式存在，尽管其水平显然不足以产生可检测到的DNA加合物。对18例每日服用他莫昔芬10~40 mg，治疗3个月~9年的患者的子宫内膜DNA进行分析。在接受检查的任何患者中，都没有发现他莫昔芬诱导的任何DNA加合物的证据。这些数据表明，在大鼠身上观察到的他莫昔芬的遗传毒性事件可能不适用于人类子宫内膜。
The potential for the anti-breast cancer drug tamoxifen [(Z)-1-[4-[2-( dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene] to induce genotoxic damage (DNA adducts) in the human endometrium was investigated in vivo and in vitro. Endometria from hysterectomy patients who were not on tamoxifen were sectioned and maintained in short-term organ culture. The cultures were treated with either solvent vehicle (DMSO), tamoxifen, alpha-hydroxytamoxifen [(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-buten-3- ol; the major DNA-reactive metabolite in the rat], or benzo(a)pyrene. DNA was isolated and analyzed by 32P postlabeling. Chromatography on polyethyleneimine-cellulose TLC plates revealed DNA adducts in endometria treated with alpha-hydroxytamoxifen identical to those seen previously in the rat liver. However, no adducts were seen from treatment with tamoxifen itself. The viability of the enzyme-metabolizing systems of the endometrial samples was demonstrated by the detection of expected DNA adducts induced by benzo(a)pyrene. Examination by liquid chromatography-mass spectrometry of the explant culture media from endometria treated with tamoxifen revealed the presence of the alpha-hydroxy metabolite in a dose-dependent manner, although apparently at levels insufficient to produce detectable DNA adducts. Endometrial DNA obtained from 18 patients undergoing daily treatment with 10-40 mg tamoxifen for 3 months-9 years was also analyzed. No evidence for any DNA adducts induced by tamoxifen was found in any of the patients examined. These data suggest that the genotoxic events observed with tamoxifen in the rat may not apply to the human endometrium.
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他莫昔芬与大鼠和人肝微粒体激活系统形成 DNA 加合物。
影响因子：
4.7
作者：
Pathak,DN;Bodell,WJ
通讯作者：
Bodell,WJ
他莫昔芬在啮齿动物中诱导共价 DNA 加合物。
影响因子：
11.2
作者：
Han,XL;Liehr,JG
通讯作者：
Liehr,JG
细胞色素 P-450 介导的激活以及抗雌激素他莫昔芬与大鼠和人肝脏中蛋白质的不可逆结合：含黄素单加氧酶可能参与他莫昔芬的激活。
影响因子：
11.2
作者：
Mani,C;Kupfer,D
通讯作者：
Kupfer,D
在雌性斯普拉格-道利大鼠体内单次给药后，他莫昔芬可诱导肝脏非整倍体和有丝分裂纺锤体破坏。
影响因子：
11.2
作者：
Sargent,LM;Dragan,YP;Bahnub,N;Wiley,JE;Sattler,CA;Schroeder,P;Sattler,GL;Jordan,VC;Pitot,HC
通讯作者：
Pitot,HC