A variety of evidence has been obtained that
estrogens are weak
tumor initiators. A major step in the multi-stage process leading to
tumor initiation involves metabolic formation of 4-catechol
estrogens from
estradiol (E2) and/or
estrone and further oxidation of the
catechol estrogens to the corresponding
catechol estrogen quinones. The electrophilic
catechol quinones react with
DNA mostly at the N-3 of
adenine (Ade) and N-7 of
guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the
DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the
catechol estrogen-3,4-quinones, the synthetic nonsteroidal
estrogen hexestrol-3',4'-quinone (HES-3',4'-Q) reacts with
DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural
estrogen E2 and the
synthetic estrogen HES, namely, the slow loss of
deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of
E2-3,4-Q or
HES-3',4'-Q with dG. The half-life of the loss of
deoxyribose from the N7dG adducts to form the corresponding 4-OHE2-1-N7Gua and 3'-OH-HES-6'-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in
DNA seems to limit the ability of these adducts to induce mutations.