An Estrogen—Nucleic Acid Adduct. Electroreductive Intermolecular Coupling of 3,4-Estrone-o-quinone and Adenine

摘要

Estrogens have been shown to induce mammary, pituitary, cervical, and uterine tumors in rats, mice, and guinea pigs. Estradiol and other estrogens induce renal carcinoma in 80— 100% of Syrian hamsters within 6-8 months. Although the exact mechanism for carcinogenesis induced by estrogenic compounds is not fully understood, it is generally believed that metabolic activation of estradiol leading to the formation of catechol estrogens is a prerequisite for its genotoxic activity. It has been proposed that the steroid estrogens may generate reactive intermediates, particularly arene oxides and quinones/ semiquinones, during their metabolism in analogy to the metabolism of aromatic polycyclic hydrocarbons which are known to be implicated in carcinogenesis. Thus, the estrogen o-quinones/semiquinones produced by the oxidation of catechol estrogens by phenol oxidase, prostaglandin H synthetase, and cytochrome P-450 oxidase have the potential to be cytotoxic and genotoxic. Studies in our laboratories have shown that 3,4-estronequinone (3,4-EQ), which can "redox-cycle" leading to the formation of hydrogen peroxide, the hydroxyl radical, and the semiquinone of 3,4-EQ, was capable of inducing exclusively single strand DNA breaks/alkali-labile sites in a human breast cancer cell line.