Evidence for the DNA binding and adduct formation of estrone and 17beta-estradiol after dimethyldioxirane activation.

Estrogens, used widely from hormone replacement therapy to cancer treatment, are themselves carcinogenic, causing uterine and breast cancers. However, the mechanism of their carcinogenic action is still not known. Recently, we found that estrone (E1) and 17beta-estradiol (E2) could be activated by the versatile epoxide-forming oxidant dimethyldioxirane (DMDO), resulting in the inhibition of rat liver nuclear and nucleolar RNA synthesis in a dose-dependent manner in vitro. Since epoxidation is often required for the activation of chemical carcinogens, we proposed that estrogen epoxidation is the underlying mechanism for the initiation of estrogen carcinogenesis (Carcinogenesis 17 (1996) 1957-1961). It is known that initiation requires the binding of a carcinogen to DNA with the formation of DNA adducts. One of the critical tests of our hypothesis is therefore to determine whether E1 and E2 after activation are able to bind DNA. This paper reports that after DMDO activation, [3H]E1 and [3H]E2 were able to bind to both A-T and G-C containing DNAs. Furthermore. the formation of E1-DNA and E2-DNA adducts was detected by 32P-postlabeling analysis.