Differential repair of O(6)-methylguanine in DNA of rat hepatocytes and nonparenchymal cells.
Chronic administration of several chemical carcinogens to laboratory animals induces a variety of tumours which arise from specific cell populations within the liver. In the rat, diethylnitrosamine induces hepatocellular carcinomas, dimethylnitrosamine induces both angiosarcomas and hepatocellular carcinomas, vinyl chloride primarily induces angiosarcomas, and 1,2-dimethylhydrazine induces malignant haemangioendotheliomas. One of the principal mechanisms thought to be involved in initiating carcinogenesis is the alkylation of specific sites on DNA, such as the O(6) position of guanine. Previous investigations of alkylation and repair have, however, analysed DNA prepared from whole liver. This approach does not localize alkylation or repair capacity in the different cell types which give rise to neoplasia. Furthermore, although hepatocytes account for more than 90% of the liver's mass, they only comprise 60-70% of its cells. The nonparenchymal cell (NPC) population, which consists almost entirely of endothelial and Kupffer cells, accounts for the remaining 30-40% and contains 10-20% of the DNA. Therefore, we decided to investigate the alkylation and repair of O(6)-and 7-methylguanine in the target and non-target cells following oral administration of 1,2-dimethylhydrazine. We report here that although initial alkylation was slightly less in NPCs, removal of O(6)-methylguanine was significantly slower. This led to a preferential accumulation of O(6)-methylguanine in NPC 24 h after administering a second daily dose. In contrast, 7-methylguanine decreased at similar rates, resulting in a 28-fold greater O(6)-methylguanine/7-methylguanine ratio in the target cell population.
D000818:Animals; D004260:DNA Repair; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D004127:Dimethylhydrazines; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008297:Male; D008745:Methylation; D051381:Rats
D003848:Deoxyguanine Nucleotides; D004127:Dimethylhydrazines