Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine.
The question of whether 8-hydroxyguanine (8-OHG) formation is involved in initiation by low dose levels of N-nitrosodiethylamine (DEN) was addressed using a rat liver model. Male Fischer 344 rats, 6 weeks of age, were administered single i.p. doses of DEN between 0.001 and 100 mg/kg body weight. The 8-OHG levels in liver DNA were measured within 72 h thereafter in randomly selected rats. The remaining rats were given either no further treatment, partial hepatectomy (PH) at hour 4, or PH with i.p. administration of 500 mg/kg body weight of colchicine on days 1 and 3. A selection procedure was performed between weeks 2 and 4, and the initiating activity of DEN was assessed in terms of development of gamma-glutamyltransferase-positive foci at week 5. The 8-OHG levels in the liver DNA were significantly elevated between hours 6 and 72 in a manner dependent on the DEN dose. Dose-dependent induction of foci was similarly noted with doses of 1-100 and 0.001-100 mg/kg body weight in the non-PH and the PH rats, respectively. The sizes of the foci were also significantly increased in a manner dependent on the DEN doses of 1-100 and 0.001-100 mg/kg body weight in the non-colchicine-treated and the colchicine-treated rats, respectively. Statistically, linear trends of 8-OHG formation due to DEN were different at 0.001-0.1 and 1-100 mg/kg body weight, but the total adducts formed within 72 h of the administration proved to be closely related to the development of foci at the termination. These results indicate that 8-OHG formation in the liver DNA may be involved in DEN initiation of hepatocarcinogenesis even at low dose levels, and that single i.p. doses of 0.001-0.1 and 1-100 mg/kg body weight might exert different effects.
Nakae
D
D
Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Japan.
Kobayashi
Y
Y
Akai
H
H
Andoh
N
N
Satoh
H
H
Ohashi
K
K
Tsutsumi
M
M
Konishi
Y
Y
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D004052:Diethylnitrosamine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D016014:Linear Models; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism* / Q000628:therapy; D008168:Lung / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D004052:Diethylnitrosamine; C024829:8-hydroxyguanine; D006147:Guanine; D015073:2-Acetylaminofluorene; D002251:Carbon Tetrachloride; D005723:gamma-Glutamyltransferase; D003078:Colchicine