EVIDENCE FOR THE DNA-BINDING AND ADDUCT FORMATION OF ESTRONE AND 17-BETA-ESTRADIOL AFTER DIMETHYLDIOXIRANE ACTIVATION

Estrogens, used widely from hormone replacement therapy to cancer trea tment, are themselves carcinogenic, causing uterine and breast cancers . However, the mechanism of their carcinogenic action is still not kno wn. Recently, we found that estrone (E-1) and 17 beta-estradiol (E-1) could be activated by the versatile epoxide-forming oxidant dimethyldi oxirane (DMDO), resulting in the inhibition of rat liver nuclear and n ucleolar RNA synthesis in a dose-dependent manner in vitro. Since epox idation 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) 19 57-1961). It is that initiation requires the binding of a carcinogen t o DNA with the formation of DNA adducts. One of the critical tests of our hypothesis is therefore to determine whether E-1 and E-2 after act ivation are able to bind DNA. This paper reports that after DMDO activ ation, [H-3]E-1 and [H-3]E-2 were able to bind to both A-T and G-C con taining DNAs, Furthermore, the formation of E-1-DNA and E-2-DNA adduct s was detected by P-32-postlabeling analysis. (C) 1998 Elsevier Scienc e Ireland Ltd. All rights reserved.