Liehr J G, Avitts T A, Randerath E, Randerath K
Proc Natl Acad Sci U S A. 1986 Jul;83(14):5301-5. doi: 10.1073/pnas.83.14.5301.
In animals and humans, estrogens are able to induce cancer in susceptible target organs, but the mechanism(s) of estrogen-induced carcinogenesis has not been elucidated. A well-known animal model is the development of renal carcinoma in estrogen-treated Syrian hamsters. Previous work demonstrated the presence of covalent DNA addition products (adducts) in premalignant kidneys of hamsters exposed to the synthetic estrogen, diethylstilbestrol, a known human carcinogen. In the present study, the natural hormone, 17 beta-estradiol, and several synthetic steroid and stilbene estrogens were examined by a 32P-postlabeling assay for their capacity to cause covalent DNA alterations in hamster kidney. Chronic exposure to each of the estrogens tested led to the gradual formation of five chromatographically distinct unusual nucleotides specifically in kidney DNA. Irrespective of the estrogen used, chromatograms exhibited identical mobilities of each of these adducts in seven different systems on PEI-cellulose anion-exchange TLC, in three different conditions on reversed-phase TLC, and in one system on silica gel partition TLC. Therefore, the DNA adducts observed did not contain moieties derived from the structurally diverse estrogens. It is concluded that each of the estrogens induced the binding of the same unknown endogenous compound (or compounds) to target tissue DNA. This novel property of estrogens is postulated to play a key role in hormone-induced malignancy.
在动物和人类中，雌激素能够在易感靶器官中诱发癌症，但雌激素诱导致癌作用的机制尚未阐明。一个著名的动物模型是经雌激素处理的叙利亚仓鼠发生肾癌。先前的研究表明，暴露于合成雌激素己烯雌酚（一种已知的人类致癌物）的仓鼠癌前肾组织中存在共价DNA加成产物（加合物）。在本研究中，通过32P后标记分析法检测了天然激素17β-雌二醇以及几种合成类固醇和芪类雌激素在仓鼠肾脏中引起共价DNA改变的能力。长期暴露于所测试的每种雌激素都会导致在肾脏DNA中逐渐形成五个色谱上不同的异常核苷酸。无论使用何种雌激素，在聚乙烯亚胺纤维素阴离子交换薄层层析的七个不同系统中、在反相薄层层析的三种不同条件下以及在硅胶分配薄层层析的一个系统中，这些加合物的色谱图都显示出相同的迁移率。因此，观察到的DNA加合物不包含源自结构多样的雌激素的部分。得出的结论是，每种雌激素都诱导了相同的未知内源性化合物与靶组织DNA的结合。雌激素的这种新特性被认为在激素诱导的恶性肿瘤中起关键作用。
