Microsome-mediated 8-hydroxylation of guanine bases of DNA by steroid estrogens: correlation of DNA damage by free radicals with metabolic activation to quinones.
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.
Han
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Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
Liehr
J G
JG
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*
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