O-6-METHYLGUANINE LEVELS AND HISTOPATHOLOGICAL CHANGES IN THE RAT ESOPHAGUS AND LIVER FOLLOWING SINGLE AND REPEATED ADMINISTRATION OF N-NITROSOMETHYLBENZYLAMINE

In this study we investigated the time course of O-6-methylguanine (O- 6-meGua) levels and concomitant histopathological effects in the rat e sophagus and liver following single and repeated s.c. administration o f the esophagus-specific carcinogen N-nitrosomethylbenzylamine (NMBA). The primary purpose of this study was to determine if differences hi the induction and/or persistence of O-6-meGua might account for differ ences in the tumorigenicity of NMBA observed with treatment regimens o f 0.5 mg/kg/dose, 3 doses/week for 5 weeks (a proven tumorigenic regim en) 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 li mited, at least at doses up to and including 5.0 mg/kg. Results of the repeated dose experiment demonstrated that the non-tumorigenic NMBA r egimen produced significantly higher levels of esophageal O-6-meGua co mpared with the tumorigenic NMBA regimen, During the 2 week treatment period of the non-tumorigenic regimen esophageal O-6-meGua levels decr eased progressively, but remained significantly higher than in the tum origenic regimen, In contrast, the relatively lower O-6-meGua Levels o f the tumorigenic regimen remained essentially unchanged during the co urse of treatment, At 72 h following conclusion of dosing no O-6-meGua was detected in the esophagi of rats treated with either regimen, Mic roscopic examinations revealed that the non-tumorigenic NMBA regimen p roduced a marked cytotoxic effect on the esophageal epithelium, while microscopic esophageal changes observed with the tumorigenic regimen w ere generally less severe, In the liver O-6-meGua was detected in only a few rats and no remarkable microscopic pathology was observed in th is organ, Together these findings indicate that: (i) abbreviated NMBA treatment induces tumors in the rat esophagus only at levels that indu ce 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 O-6-meGua adducts, coupled with the lack of necrosis and compensatory cell division in this orgam.