DECREASED DIMETHYLNITROSAMINE-INDUCED O(6)-METHYLDEOXYGUANOSINE AND N7-METHYLDEOXYGUANOSINE LEVELS CORRELATE WITH DEVELOPMENT AND PROGRESSION OF LESIONS IN RAT HEPATOCARCINOGENESIS

Formation and repair of O6-medG and N7-medG (O6- and N7-methyldeoxygua nosine) in glutathione S-transferase-P form (GST-P)-positive liver cel l foci, nodules, primary hepatocellular carcinoma (HCC) and transplant ed hepatocellular carcinoma (TRP) induced by N-ethyl-N-hydroxyethylnit rosamine (EHEN) were immunohistochemically assessed following a single exposure to dimethylnitrosamine (DMN). Male Fischer 344 rats received a 0.1% solution of EHEN as their drinking water for 4 weeks and were maintained on basal diet until week 40, when a single 50 mg/kg body we ight dose of DMN was administered intraperitoneally. Nude rats (NIH rn u/rnu) bearing TRP were similarly treated. Sequential killing 6, 12, 2 4, 48 and 72 h thereafter revealed significantly decreased indices of cells binding antibodies to O6-medG and N7-medG adducts in GST-P-posit ive foci and nodules, and particularly HCC and TRP, as compared to bac kground parenchyma values. Similarly, differences between foci/nodules and HCC/TRP were also significant, indicating that decrease in adduct formation is associated with further malignant conversion. The rate o f DNA adduct repair in foci and nodules subsequent to the peak found a t the 12 h time-point did not appear to be significantly different fro m that in the surrounding tissue at the dose of DMN studied. The resul ts indicate decreased formation of DMN-associated DNA damage, in line with the known metabolic profile of carcinogen-induced focal liver les ions.