Oxidative DNA damage in XPC-knockout and its wild mice treated with equine estrogen.
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.
Okamoto
Yoshinori
Y
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
Chou
Pei-Hsin
PH
Kim
Sung Yeon
SY
Suzuki
Naomi
N
Laxmi
Y R Santosh
YR
Okamoto
Kanako
K
Liu
Xiaoping
X
Matsuda
Tomonari
T
Shibutani
Shinya
S
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
D004268:DNA-Binding Proteins; D004967:Estrogens; C501002:Xpc protein, mouse; C065250:4-hydroxy-equilenin; D004855:Equilenin