Cell specificity in hepatocarcinogenesis: preferential accumulation of O6-methylguanine in target cell DNA during continuous exposure to rats to 1,2-dimethylhydrazine.
Concentrations of the major methylated DNA purines were determined in two liver cell cell populations of Fischer 344 rats during administration of 30 ppm 1,2-dimethylhydrazine (SDMH) in the drinking water for periods of up to 4 weeks. Quantitation of 7-methylguanine and O6-methylguanine (O6MG) was achieved by highly sensitive optical methods following separation of DNA bases by high-performance liquid chromatography. Overall alkylation as indicated by the concentration of 7-methylguanine was near maximum in both hepatocytes and liver nonparenchymal cells by the third day of SDMH administration. Similar amounts of 7-methylguanine were present in the two liver cell populations at seven of nine time points during 4 weeks of exposure. In contrast, dramatic differences in the cumulative concentrations of O6MG were seen in the two cell populations. Nonparenchymal cells accumulated O6MG during the first 8 days of exposure and had up to a 30-fold greater concentration of this product than did the corresponding hepatocytes. In the hepatocytes, a rapid decline in O6MG concentration was observed between 1 and 3 days of exposure to SDMH. Thereafter, only low levels of this promutagenic lesion were present in hepatocytes. Exposure of rats to the same regimen of SDMH for up to 10 months caused angiosarcomas in the livers of over 90% of the animals, while hepatocellular carcinomas occurred in only 40%. Thus, a strong correlation exists between the inability to repair O6MG and cell specificity for carcinogenesis.
D019813:1,2-Dimethylhydrazine; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000302:isolation & purification / Q000378:metabolism*; D004127:Dimethylhydrazines / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008763:Methylhydrazines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004127:Dimethylhydrazines; D008763:Methylhydrazines; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D019813:1,2-Dimethylhydrazine