Cell-specific differences in O6-alkylguanine DNA repair activity during continuous exposure to carcinogen.
The activity of the alkyl acceptor protein (AAP) responsible for repair of DNA containing the promutagenic lesion O6-alkylguanine was determined in hepatocytes and nonparenchymal cells (NPC) obtained from livers of control rats and rats exposed to hepatocarcinogens that primarily induce vascular or hepatocellular neoplasms. Basal levels of AAP activity were found to be 4-5 times higher in hepatocytes than in NPC. Exposure to 1,2-dimethylhydrazine or diethylnitrosamine produced a 2- to 3-fold enhancement of this activity in hepatocytes after exposure for as little as 3 days. The enhanced hepatocyte activity persisted throughout a 28-day exposure to 1,2-dimethylhydrazine. In contrast, AAP activity in NPC was decreased during the first week of exposure to 1,2-dimethylhydrazine and subsequently returned to control levels. No enhancement of AAP was apparent in the NPC. These and related data suggest that enhancement of this activity in rat hepatocytes is a response to cell proliferation. In contrast, the data clearly demonstrate that neither increased cell replication nor the presence of O6-alkylguanine was capable of enhancing AAP activity in NPC. Cellular differences in the repair of O6-alkylguanine appear to be a critical mechanism responsible for cell specificity in chemical carcinogenesis by alkylating agents.
D019813:1,2-Dimethylhydrazine; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002469:Cell Separation; D004260:DNA Repair; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004127:Dimethylhydrazines / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D009602:Nitrosamines / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002273:Carcinogens; D004127:Dimethylhydrazines; D008763:Methylhydrazines; D009602:Nitrosamines; D011506:Proteins; D004052:Diethylnitrosamine; D006147:Guanine; D019813:1,2-Dimethylhydrazine