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Involvement of 8-Hydroxyguanine Formation in the Initiation of Rat Liver Carcinogenesis by Low Dose Levels of N-Nitrosodiethylamine¹

Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634, Japan

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 -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.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research in Priority Areas, Cancer Research Grant 06280119 from the Ministry of Education, Science, Sports and Culture of Japan, as well as Grants-in-Aid for the Comprehensive 10-Year Cancer Control and for Scientific Research Expenses for Health and Welfare Programs from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed. Phone: 81-7442-2-3051, ext. 2576; Fax: 81-7442-5-7308.

Received 7/15/96. Accepted 1/31/97.

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