Oxidative stress in the metabolism of estrogens leading to cancer initiation: Prevention by specific antioxidants

Oxidative metabolism of the estrogens estrone (E₁) and estradiol (E₂) is the critical event in the initiation of cancer by estrogens. E₁ and E₂ are oxidized by cytochrome P450 (CYP) to the catechol estrogens 2-OHE₁(E₂) and 4-OHE₁(E ₂) and then to the catechol estrogen quinones, which react with DNA to form estrogen-DNA adducts. The E₁(E₂)-3,4-quinones [E₁(E₂)-3,4-Q] react predominantly with DNA to form the depurinating adducts 4-OHE₁(E₂)-1-N3Ade and 4-OHE ₁(E₂)-1-N7Gua. The resulting apurinic sites in the DNA can generate mutations leading to the initiation of cancer. Estrogen metabolism becomes unbalanced when expression of the activating enzymes CYP19 (aromatase) and CYP1B1 is higher and expression of the protective enzymes catechol-O-methyltransferase and quinone reductase is lower. In this case, larger amounts of adducts are formed, and the risk of initiating cancer is greater. Women at high risk of developing breast cancer, or diagnosed with the disease, have higher levels of estrogen-DNA adducts than women at normal risk. These results and others in humans and cell culture indicate that formation of estrogen-DNA adducts is a critical event in the initiation of cancer. Two antioxidant compounds, N-acetylcysteine and resveratrol, efficiently block formation of estrogen-DNA adducts and, thus, are promising agents to prevent cancer.