Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a more potent hepatocarcinogen in female than in male or ovariectomized rats. A possible mechanism for this increased sensitivity is through enhanced metabolic activation of estrogens by TCDD-induced enzymes leading to oxidative damage in the cell. As a marker for oxidative DNA damage, 8-oxo-deoxyguanosine (8-oxo-dG) was quantitated in livers of intact and ovariectomized Sprague-Dawley rats chronically treated with TCDD (125 ng/kg per day) with and without diethylnitrosamine as initiator. Elevated levels of 8-oxo-dG were detected in a significantly greater number of the intact compared to ovariectomized TCDD-treated rats. Expression of CYP1B1 mRNA, a newly identified cytochrome P450 with proposed estrogen hydroxylase activity, was highly induced by TCDD. The results are consistent with the hypothesis that increased metabolism of endogenous estrogens to catechols by TCDD-induced enzymes may lead to increased oxidative DNA damage and hence contribute to TCDD-mediated hepatocarcinogenicity in female rats.
Tritscher
A M
AM
Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Seacat
A M
AM
Yager
J D
JD
Groopman
J D
JD
Miller
B D
BD
Bell
D
D
Sutter
T R
TR
Lucier
G W
GW
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D003043:Cocarcinogenesis; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004958:Estradiol / Q000502:physiology; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology*; D010084:Oxidation-Reduction; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D004052:Diethylnitrosamine; D004958:Estradiol; D004247:DNA; D003849:Deoxyguanosine