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Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation
Author(s) -
Hiraku Yusuke,
Yamashita Naruto,
Nishiguchi Meiko,
Kawanishi Shosuke
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1193
Subject(s) - dna damage , chemistry , catechol , catalase , cell growth , estrogen , carcinogenesis , dna , biochemistry , oxidative stress , dna oxidation , biology , endocrinology , gene
Estrogen‐induced carcinogenesis involves enhanced cell proliferation (promotion) and genotoxic effects (initiation). To investigate the contribution of estrogens and their metabolites to tumor initiation, we examined DNA damage induced by estradiol and its metabolites, the catechol estrogens 2‐hydroxyestradiol (2‐OHE 2 ) and 4‐hydroxyestradiol (4‐OHE 2 ). In the presence of Cu(II), catechol estrogens formed piperidine‐labile sites at thymine and cytosine residues in 32 P 5′‐end‐labeled DNA fragments and induced the formation of 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine. NADH markedly enhanced Cu(II)‐dependent DNA damage mediated by nanomolar concentrations of catechol estrogens. Catalase and bathocuproine inhibited the DNA damage, suggesting the involvement of H 2 O 2 and Cu(I). These results suggest that H 2 O 2 , generated during Cu(II)‐catalyzed autoxidation of catechol estrogens, reacts with Cu(I) to form the Cu(I)–peroxide complex, leading to oxidative DNA damage, and that NADH enhanced DNA damage through the formation of redox cycle. To investigate the role of estrogens and their metabolites in tumor promotion, we examined their effects on proliferation of estrogen‐dependent MCF‐7 cells. Estradiol enhanced the proliferation of MCF‐7 cells at much lower concentrations than catechol estrogens. These findings indicate that catechol estrogens play a role in tumor initiation through oxidative DNA damage, whereas estrogens themselves induce tumor promotion and/or progression by enhancing cell proliferation in estrogen‐induced carcinogenesis. © 2001 Wiley‐Liss, Inc.