Activation of 17beta-estradiol and estrone by dimethyldioxirane and inhibition of rat liver nuclear and nucleolar RNA synthesis in vitro.
17beta-estradiol (E2), estrone and diethylstilbestrol (DES) had no effect on nuclear and nucleolar RNA synthesis in vitro. However, after reacting with dimethyldioxirane (DMDO), a versatile epoxide-forming oxidant, these estrogens were able to inhibit and in a dose-dependent manner nuclear and nucleolar RNA synthesis in vitro. It was also found that the time required for the maximal activation of these chemicals by DMDO varied: estrone, 10 min; E2, 30 min; DES, 60 min. Tamoxifen (TAM) was also able to inhibit nuclear and nucleolar RNA synthesis in a dose-dependent manner, but the mechanism of this inhibition was more complex. Control experiments clearly indicated, unlike E2, estrone and DES, TAM per se was able to directly inhibit RNA synthesis in vitro. TAM after activation by DMDO was able to further inhibit RNA synthesis contributing part of the total observed inhibition. These data show for the first time that E2, estrone, DES and TAM can be activated by DMDO and possibly to epoxides. We propose that epoxidation of E2 and estrone may be the underlying mechanism of carcinogenesis for these estrogens in vivo.
Yu
F L
FL
Department of Biomedical Sciences, University of Illinois, College of Medicine at Rockford, 61107, USA.
Bender
W
W
D000818:Animals; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D004970:Estrone / Q000378:metabolism / Q000494:pharmacology*; D006157:Guanosine Monophosphate / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D012313:RNA / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology
D004852:Epoxy Compounds; D013629:Tamoxifen; D004970:Estrone; D004958:Estradiol; D012313:RNA; D004054:Diethylstilbestrol; D006157:Guanosine Monophosphate; C064455:dimethyldioxirane