Strong evidence supports the idea that specific metabolites of
estrogens, mainly
catechol estrogen-3,4-quinones, can react with
DNA to become endogenous initiators of breast, prostate, and other human
cancers. Oxidation of the
catechol estrogen metabolites
4-hydroxyestradiol (4-OHE2) and 2-OHE2 leads to the
quinones,
estradiol-3,4-quinone (E2-3,4-Q) and
estradiol-2,3-quinone (E2-2,3-Q), respectively. The reaction of
E2-3,4-Q with
DNA affords predominantly the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua, whereas the reaction of E2-2,3-Q with
DNA yields the newly synthesized depurinating adduct 2-OHE2-6-N3Ade. The N3Ade adducts are lost from
DNA by rapid depurination, while the N7Gua adduct is lost from
DNA with a half-life of approximately 3 h at 37 degrees C. To compare the relative reactivity of
E2-3,4-Q and E2-2,3-Q, the compounds were reacted individually with
DNA for 0.5-20 h at 37 degrees C, as well as in mixtures (3:1, 1:1, 1:3, and 5:95) for 10 h at 37 degrees C. Depurinating and stable adducts were analyzed. In similar experiments, the relative reactivity of 4-OHE2 and 2-OHE2 with
DNA was determined after activation by
lactoperoxidase,
tyrosinase,
prostaglandin H synthase (PHS), or 3-methylcholanthrene-induced rat liver microsomes. Starting with the
quinones, the levels of depurinating adducts formed from
E2-3,4-Q were much higher than that of the depurinating adduct from E2-2,3-Q. Similar results were obtained with
lactoperoxidase or
tyrosinase-catalyzed oxidation of 4-OHE2 and 2-OHE2, whereas with activation by PHS or microsomes, a relatively higher amount of the depurinating adduct from E2-2,3-Q was detected. These results demonstrate that the
E2-3,4-Q is much more reactive with
DNA than E2-2,3-Q. The relative reactivities of
E2-3,4-Q and E2-2,3-Q to form depurinating adducts correlate with the carcinogenicity, mutagenicity, and cell-transforming activity of their precursors, the
catechol estrogens 4-OHE2 and 2-OHE2. This is essential information for understanding the
cancer risk posed by oxidation of the two
catechol estrogens.