title: Microsome-mediated 8-hydroxylation of guanine bases of DNA by steroid estrogens: correlation of DNA damage by free radicals with metabolic activation to quinones.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.forename: J G
authors.initials: JG
authors.lastname: Liehr
mesh_terms: D000818:Animals; D001711:Biotransformation; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D004855:Equilenin / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D002393:Estrogens, Catechol / Q000378:metabolism / Q000494:pharmacology*; D004970:Estrone / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives; D006894:Hydroxyestrones / Q000494:pharmacology; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism*
chemical_list: D002393:Estrogens, Catechol; D005609:Free Radicals; D006894:Hydroxyestrones; D011809:Quinones; D004970:Estrone; C026418:4-hydroxyestrone; D004958:Estradiol; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; C014036:4-hydroxyestradiol; D004855:Equilenin