8-hydroxyguanine and 4-hydroxyestrone

Free radical generation by metabolic redox cycling between catechol estrogens and their quinones and subsequent hydroxyl radical damage to DNA have been proposed to mediate estrogen-induced renal carcinogenesis in the hamster. In this study the content of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a marker product of hydroxyl radical action, was examined in DNA incubated with a liver microsomal activating system and with catechol estrogens, equilenin-3,4-quinone or with parent estrogens. Equilenin-3,4-quinone increased the formation of 8-OHdG by 50% over control levels. 4-Hydroxyestrone and 4-hydroxy-estradiol raised 8-OHdG contents significantly, to 1.61 +/- 0.79 and 1.27 +/- 0.31 8-OHdG/10(5) deoxyguanosine (dG) respectively over controls (0.68 +/- 0.25 8-OHdG/10(5) dG). The corresponding 2-hydroxylated estrogens and the parent hormones estrone, estradiol and equilenin did not affect 8-hydroxylation of guanine bases of DNA. In incubations of catechol estrogens with microsomes and cumene hydroperoxide the 4-hydroxyestrogens were oxidized to quinones more rapidly than the 2-hydroxyestrogens. Our data support a mechanism of hydroxyl radical generation from estrogens by redox cycling between 4-hydroxylated metabolites and their quinones. The rapid oxidation of 4-hydroxylated estrogens to quinones, their redox cycling and hydroxyl radical damage to DNA is consistent with the previously reported carcinogenic activities of 4-hydroxylated, but not of 2-hydroxylated, catechol estrogens.

Topics: Animals; Biotransformation; Cricetinae; DNA; DNA Damage; Equilenin; Estradiol; Estrogens, Catechol; Estrone; Free Radicals; Guanine; Hydroxyestrones; Hydroxylation; Liver; Male; Mesocricetus; Microsomes, Liver; Quinones