Decreased dimethylnitrosamine-induced O6- and N7-methyldeoxyguanosine levels correlate with development and progression of lesions in rat hepatocarcinogenesis

Abstract

Formation and repair of O6-medG and N7-medG (O6- and N7-methyldeoxyguanosine) in glutathione S-transferase-P form (GST-P)-positive liver cell foci, nodules, primary hepatocellular carcinoma (HCC) and transplanted hepatocellular carcinoma (TRP) induced by N-ethyl-N-hydroxyethylnitrosamine (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 weight dose of DMN was administered intraperitoneally. Nude rats (NIH rnu/rnu) bearing TRP were similarly treated. Sequential killing 6, 12, 24, 48 and 72 h thereafter revealed significantly decreased indices of cells binding antibodies to O6-medG and N7-medG adducts in GST-P-positive foci and nodules, and particularly HCC and TRP, as compared to background 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 of DNA adduct repair in foci and nodules subsequent to the peak found at the 12 h time-point did not appear to be significantly different from that in the surrounding tissue at the dose of DMN studied. The results indicate decreased formation of DMN-associated DNA damage, in line with the known metabolic profile of carcinogen-induced focal liver lesions.