title: The ability of four catechol estrogens of 17beta-estradiol and estrone to induce DNA adducts in Syrian hamster embryo fibroblasts.
abstract: Catechol estrogens are considered critical intermediates in estrogen-induced carcinogenesis. We demonstrated previously that 17beta-estradiol (E(2)), estrone (E(1)) and four of their catechol estrogens, 2- and 4-hydroxyestradiols (2- and 4-OHE(2)), and 2- and 4-hydroxyestrones (2- and 4-OHE(1)) induce morphological transformation in Syrian hamster embryo (SHE) fibroblasts, and the transforming abilities vary as follows: 4-OHE(1) > 2-OHE(1) > 4-OHE(2) > 2-OHE(2) vertical line E(2), E(1). To examine the involvement of catechol estrogens in the initiation of hormonal carcinogenesis, we studied the ability of E(2), E(1) and their catechol estrogens to induce DNA adducts in SHE cells by using a (32)P-post-labeling assay. DNA adducts were detected in cells treated with each of all the catechol estrogens at concentrations of 10 microg/ml for 1 h and more. 2- or 4-OHE(2) formed a single DNA adduct, which was chromatographically distinct from each other. In contrast, 2- or 4-OHE(1) produced one major and one minor adduct, and the two adducts formed by each catechol estrogen exhibited identical mobilities on the chromatograms. Neither E(2) nor E(1) at concentrations up to 30 microg/ml induced DNA adducts. The abilities of the estrogens to induce DNA adducts were ranked as follows: 4-OHE(1) > 2-OHE(1) > 4-OHE(2) > 2-OHE(2) > > E(2), E(1), which corresponds well to the transforming and carcinogenic abilities of the estrogens. In addition, the level of DNA adducts induced by the catechol estrogens was markedly decreased by co-treatment of cells with the antioxidant L-ascorbic acid. The results indicate the possible involvement of oxidative metabolites of catechol estrogens of E(2) and E(1) in the initiation of endogenous estrogen-induced carcinogenesis.
authors.affiliation: Department of Pharmacology, The Nippon Dental University, School of Dentistry at Tokyo, Tokyo 102-8159, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Yagi
authors.forename: J C
authors.initials: JC
authors.lastname: Barrett
authors.forename: T
authors.initials: T
authors.lastname: Tsutsui
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006224:Cricetinae; D018736:DNA Adducts / Q000096:biosynthesis*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D002393:Estrogens, Catechol / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006894:Hydroxyestrones / Q000633:toxicity; D008647:Mesocricetus
chemical_list: D000975:Antioxidants; D018736:DNA Adducts; D002393:Estrogens, Catechol; D006894:Hydroxyestrones; C026418:4-hydroxyestrone; D004958:Estradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D001205:Ascorbic Acid; C024980:2-hydroxyestrone