Estrogens can be converted to electrophilic metabolites, particularly the
catechol estrogen-3,4-quinones, estrone(estradiol)-3,4-quinone [E(1)(E(2))-3,4-Q], which react with
DNA to form depurinating adducts. These adducts are released from
DNA to generate apurinic sites. Error-prone repair of this damage leads to the mutations that initiate breast, prostate, and other types of
cancer. The reaction of E(1)(E(2))-3,4-Q with
DNA forms the depurinating adducts 4-hydroxyE(1)(E(2))-1-N3adenine [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(E(2))-1-N7guanine(Gua). These two adducts constitute >99% of the total
DNA adducts formed. The E(1)(E(2))-2,3-Q forms small amounts of the depurinating 2-OHE(1)(E(2))-6-N3Ade adducts. Reaction of the
quinones with
DNA occurs more abundantly when
estrogen metabolism is unbalanced. Such an imbalance is the result of overexpression of
estrogen-activating
enzymes and/or deficient expression of deactivating (protective)
enzymes. Excessive formation of E(1)(E(2))-3,4-Q is the result of this imbalance. Oxidation of
catechols to semiquinones and
quinones is a mechanism of
tumor initiation not only for endogenous
estrogens, but also for
synthetic estrogens such as
hexestrol and
diethylstilbestrol, a human
carcinogen. This mechanism is also involved in the initiation of
leukemia by
benzene, rat olfactory
tumors by
naphthalene, and
neurodegenerative diseases such as
Parkinson's disease by
dopamine. In fact,
dopamine quinone reacts with
DNA similarly to the E(1)(E(2))-3,4-Q, forming analogous depurinating N3Ade and N7Gua adducts. The depurinating adducts that migrate from cells and can be found in body fluids can also serve as
biomarkers of
cancer risk. In fact, a higher level of
estrogen-
DNA adducts has been found in the urine of men with
prostate cancer and in women with
breast cancer compared to healthy controls. This unifying mechanism of the origin of
cancer and other diseases suggests preventive strategies based on the level of depurinating
DNA adducts that generate the first critical step in the initiation of diseases.