DNA single-strand breaks in kidneys of Syrian hamsters treated with steroidal estrogens: hormone-induced free radical damage preceding renal malignancy.
The chronic administration of estradiol by subcutaneous (s.c.) implantation into male Syrian hamsters induces kidney tumors. Free radicals generated by redox cycling between catecholestrogens and their quinones have been proposed to damage DNA and to thus mediate renal hormone-induced carcinogenesis. As part of an examination of this postulate, we assayed by a filter elution technique DNA single-strand breaks in livers and kidneys of male hamsters treated with estrogen by single intraperitoneal (i.p.) injection, by s.c. implant or by continuous infusion and compared values to those in untreated controls. The DNAs of hamster liver and kidney were not affected by one i.p. injection of 5, 15 or 150 mg/kg estradiol. However, treatment of hamsters with one 25 mg estradiol implant/animal for 2 weeks elevated by 10% the levels of DNA single-strand breaks in kidney, but only to a minor extent in liver, which is not a target of estrogen-induced carcinogenesis. An infusion of 250 micrograms/day/animal of estradiol or 4-hydroxyestradiol for one week by osmotic pumps into hamsters resulted in a comparable increase of single-strand breaks in kidney DNA, whereas 2-hydroxyestradiol under these conditions had a negligible effect. It is concluded that the induction of DNA single-strand breakage by either estradiol or 4-hydroxyestradiol in hamster kidney supports a mechanism of estrogen-induced carcinogenesis by free radical generation via redox cycling between 4-hydroxyestradiol and its corresponding quinone.
Han
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Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Liehr
J G
JG
D000818:Animals; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D002393:Estrogens, Catechol; D005609:Free Radicals / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008297:Male; D008647:Mesocricetus
D004277:DNA, Single-Stranded; D004967:Estrogens; D002393:Estrogens, Catechol; D005609:Free Radicals; D004958:Estradiol; D004247:DNA; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol