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 a ddressed using a rat liver model. Male Fischer 344 rats, 6 weeks of ag e, 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 P H with i.p. administration of 500 mg/kg body weight of colchicine on d ays 1 and 3, A selection procedure was performed between weeks 2 and 4 , and the initiating activity of DEN was assessed in terms of developm ent of gamma-glutamyltransferase-positive foci at week 5, The 8-OHG le vels in the fiver 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 f oci 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 developmen t of foci at the termination, These results indicate that 8-OHG format ion in the liver DNA may be involved in DEN initiation of hepatocarcin ogenesis 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.