O6-methylguanine levels and histopathological changes in the rat esophagus and liver following single and repeated administration of N-nitrosomethylbenzylamine.

Abstract

In this study we investigated the time course of O6-methylguanine (O6-meGua) levels and concomitant histopathological effects in the rat esophagus and liver following single and repeated s.c. administration of the esophagus-specific carcinogen N-nitrosomethylbenzylamine (NMBA). The primary purpose of this study was to determine if differences in the induction and/or persistence of O6-meGua might account for differences in the tumorigenicity of NMBA observed with treatment regimens of 0.5 mg/kg/dose, 3 doses/week for 5 weeks (a proven tumorigenic regimen) and 1.67 mg/kg/dose, 3 doses/week for 2 weeks (an essentially non-tumorigenic regimen). Results of the single dose experiment indicated that enzymatic activation of NMBA in the rat esophagus was not dose limited, at least at doses up to and including 5.0 mg/kg. Results of the repeated dose experiment demonstrated that the non-tumorigenic NMBA regimen produced significantly higher levels of esophageal O6-meGua compared with the tumorigenic NMBA regimen. During the 2 week treatment period of the non-tumorigenic regimen esophageal O6-meGua levels decreased progressively, but remained significantly higher than in the tumorigenic regimen. In contrast, the relatively lower O6-meGua levels of the tumorigenic regimen remained essentially unchanged during the course of treatment. At 72 h following conclusion of dosing no O6-meGua was detected in the esophagi of rats treated with either regimen. Microscopic examinations revealed that the non-tumorigenic NMBA regimen produced a marked cytotoxic effect on the esophageal epithelium, while microscopic esophageal changes observed with the tumorigenic regimen were generally less severe. In the liver O6-meGua was detected in only a few rats and no remarkable microscopic pathology was observed in this organ. Together these findings indicate that: (i) abbreviated NMBA treatment induces tumors in the rat esophagus only at levels that induce DNA damage without causing extensive cytotoxicity; (ii) the lack of NMBA tumorigenicity in the rat liver may be due, at least in part, to the rapid and efficient repair of O6-meGua adducts, coupled with the lack of necrosis and compensatory cell division in this organ.