Oxidative Stress in the Metabolism of Estrogens Leading to Cancer Initiation: Prevention by Specific Antioxidants

Abstract

Oxidative metabolism of the estrogens estrone (E 1 ) and estradiol (E 2 ) is the critical event in the initiation of cancer by estrogens. E 1 and E 2 are oxidized by cytochrome P450 (CYP) to the catechol estrogens 2-OHE 1 (E 2 ) and 4-OHE 1 (E 2 ) and then to the catechol estrogen quinones, which react with DNA to form estrogen-DNA adducts. The E 1 (E 2 )-3,4-quinones [E 1 (E 2 )-3,4-Q] react predominantly with DNA to form the depurinating adducts 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-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

Determination of estrogens in human serum using a novel chemical derivatization–assisted liquid chromatography‐electrospray ionization‐tandem mass spectrometry method

“…Ionization percentages were calculated according to the following equations for the acidic functional group (Equation [3]) and basic functional group (Equation [4]) for the investigated derivatives. 24,36 The pKa was derived from the conjugated acid form of the basic amine:…”

“…2 As the metabolism of estrogens tends to become unbalanced due to oxidation, many adducts will be formed, which potentially increases the risk of various cancers. [3][4][5][6][7] In addition, a tendency seems to appear in the earlier timing of puberty for some children. Such puberty onset might be associated with the increase in endogenous estrogen levels.…”

“…Estrogens can also prevent or reverse osteoporosis and increase cell viability in various tissues 2 . As the metabolism of estrogens tends to become unbalanced due to oxidation, many adducts will be formed, which potentially increases the risk of various cancers 3–7 . In addition, a tendency seems to appear in the earlier timing of puberty for some children.…”