Equine Estrogen Metabolite 4-Hydroxyequilenin Induces DNA Damage in the Rat Mammary Tissues: Formation of Single-Strand Breaks, Apurinic Sites, Stable Adducts, and Oxidized Bases

详细信息    查看全文

• 作者：Fagen Zhang ; Steven M. Swanson ; Richard B. van Breemen ; Xuemei Liu ; Yanan Yang ; Chungang Gu ; and Judy L. Bolton
• 刊名：Chemical Research in Toxicology
• 出版年：2001
• 出版时间：December 2001
• 年：2001
• 卷：14
• 期：12
• 页码：1654 - 1659
• 全文大小：71K
• 年卷期：v.14,no.12(December 2001)
• ISSN：1520-5010

文摘

Epidemiological data strongly suggest that a woman's risk of developing breast cancer isdirectly related to her lifetime estrogen exposure. Estrogen replacement therapy in particularhas been correlated with an increased cancer risk. Previously we showed that the equineestrogens equilin and equilenin, which are major components of the estrogen replacementformulation Premarin (Wyeth-Ayerst), are metabolized to the catechol, 4-hydroxyequileninwhich autoxidizes to an o-quinone causing oxidation and alkylation of DNA in vitro [Bolton, J.L., Pisha, E., Zhang, F., and Qiu, S. (1998) Chem. Res. Toxicol. 11, 1113-1227]. In the presentstudy, we injected 4-hydroxyequilenin into the mammary fat pads of Sprague-Dawley rats.Analysis of cells isolated from the mammary tissue for DNA single-strand breaks and oxidizedbases using the comet assay showed a dose-dependent increase in both types of lesions. Inaddition, LC-MS-MS analysis of extracted mammary tissue showed the formation of analkylated depurinating guanine adduct. Finally, extraction of mammary tissue DNA, hydrolysisto deoxynucleosides, and analysis by LC-MS-MS showed the formation of stable cyclicdeoxyguanosine and deoxyadenosine adducts as well as oxidized bases. This is the first reportshowing that 4-hydroxyequilenin is capable of causing DNA damage in vivo. In addition, thedata showed that 4-hydroxyequilenin induced four different types of DNA damage that mustbe repaired by different mechanisms. This is in contrast to the endogenous estrogen4-hydroxyestrone where only depurinating guanine adducts have been detected in vivo. Theseresults suggest that 4-hydroxyequilenin has the potential to be a potent carcinogen throughthe formation of variety of DNA lesions in vivo.