Mutagenic Activity of 4-Hydroxyestradiol,but Not 2-Hydroxyestradiol,in BB Rat2 Embryonic Cells,and the Mutational Spectrum of 4-Hydroxyestradiol

摘要

Estrogens are hypothesized to contribute to breast cancer via estrogen receptor-mediated increases in cell proliferation and via genotoxic processes leading to mutations.In this latter process,estradiol(E_2)is thought to be oxidized to 4-hydroxyestradiol and then to E_2-3,4-quinone,which reacts with DNA leading to apurinic sites.These sites represent premutagenic lesions.Additionally,E_2-3,4-quinone can undergo redox cycling with E_2-3,4-hydroquinone,leading to the release of reactive oxygen species.Although there is evidence that estradiol and E_2-3,4-quinone are carcinogenic or mutagenic in several systems,4-hydroxyestradiol,a key intermediate in the proposed genotoxic pathway,has thus far been negative in mutagenesis assays.Another major metabolite of estradiol,2-hydroxyestradiol,is essentially inactive in carcinogenicity or mutagenicity assays.Here,we report that when using multiple low-dose exposures 4-hydroxyestradiol is mutagenic in the cII assay in BB rat2 cells.Under similar conditions,2-hydroxyestradiol is inactive.Furthermore,the mutational spectrum of 4-hydroxyestradiol contains a considerable proportion of mutations at A:T base pairs,consistent with the known ability of E_2-3,4-quinone to form a significant fraction of DNA adducts at adenines.Thus,the results of this study support the proposal that estradiol can contribute to carcinogenesis via a genotoxic pathway.