title: Oxidative DNA damage in XPC-knockout and its wild mice treated with equine estrogen.
abstract: Long-term hormone replacement therapy with equine estrogens is associated with a higher risk of breast, ovarian, and endometrial cancers. Reactive oxygen species generated through redox cycling of equine estrogen metabolites may damage cellular DNA. Such oxidative stress may be linked to the development of cancers in reproductive organs. Xeroderma pigmentosa complementation group C-knockout ( Xpc-KO) and wild-type mice were treated with equilenin (EN), and the formation of 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) was determined as a marker of typical oxidative DNA damage, using liquid chromatography electrospray tandem mass spectrometry. The level of hepatic 8-oxodG in wild-type mice treated with EN (5 or 50 mg/kg/day) was significantly increased by approximately 220% after 1 week, as compared with mice treated with vehicle. In the uterus also, the level of 8-oxodG was significantly increased by more than 150% after 2 weeks. Similar results were observed with Xpc-KO mice, indicating that Xpc does not significantly contribute to the repair of oxidative damage. Oxidative DNA damage generated by equine estrogens may be involved in equine estrogen carcinogenesis.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Pei-Hsin
authors.initials: PH
authors.lastname: Chou
authors.forename: Sung Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Y R Santosh
authors.initials: YR
authors.lastname: Laxmi
authors.forename: Kanako
authors.initials: K
authors.lastname: Okamoto
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D004855:Equilenin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006736:Horses; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010084:Oxidation-Reduction
chemical_list: D004268:DNA-Binding Proteins; D004967:Estrogens; C501002:Xpc protein, mouse; C065250:4-hydroxy-equilenin; D004855:Equilenin