Possible Involvement of Adaptation Mechanisms in the Achievement of an Ineffective Dose Range for the Carcinogenicity of Genotoxic Carcinogens

Abstract

Recent findings have indicated that there may be a practical threshold or an ineffective dose range for the carcinogenicity of genotoxic carcinogens. In male Fischer 344 rats given a 16-week chronic feeding administration of 0.0001-1 ppm of N-nitrosodiethylamine (DEN), glutathione S-transferase placental form (GST-P)-positive liver preneoplasias developed at 0.1 ppm or higher, but hepatic level of 8-oxoguanine (8-oxoG), an oxidative DNA damage, was not elevated even at 1 ppm. In contrast, hepatic 8-oxoG level was elevated by a single intraperitoneal administration of 0.001-100 mg/kg body weight of DEN within 6 h and remained high within 72 h, in a clear dose-dependent manner without any ineffective doses, and GST-P-positive preneoplasias correspondingly developed through the selection procedure. The 8-oxoG level was elevated also in extrahepatic organs within 6 h but returned to the normal level within 72 h. In a separate experiment, hepatic 8-oxoG level remained high even 18 weeks after 2 weekly intraperitoneal administrations of 100 mg/kg body weight of DEN. The early prolonged elevation of 8-oxoG level in target organ DNA was similarly induced by heterocyclic amines and dimethylarsinic acid in association with the down-regulation of the Ogg1 gene encoding an 8-oxoG-specific repair enzyme. Taken together, it is suggested that adaptation mechanisms may be involved in the achievement of an ineffective dose range for the carcinogenicity of genotoxic carcinogens during their continuing exposure at sufficiently low level doses.