Enhanced O6-methylguanine-DNA alkyltransferase activity in rat liver nodules.
The progression of chemical carcinogen induced hepatic lesions in the rat from altered enzyme foci to hepatocyte nodules and ultimately to hepatocellular carcinoma appears to be related to the evolution of new cell populations within these hepatic lesions. Initiator-promoter-initiator experiments in rat liver models using alkylating agents as the second genotoxic compound suggest accelerated progression toward malignancy could be the result of mutations caused by O6-alkylguanine formation in the DNA of preneoplastic liver cells. Since mutation frequency is believed to be related not only to the extent of O6-alkylguanine formation in DNA, but also to the rate of O6-alkylguanine repair, we measured the activity of the enzyme which repairs O6-alkylguanine, O6-alkylguanine-DNA alkyltransferase, in rat liver nodules. The activity of O6-methylguanine-DNA alkyltransferase in extracts of rat liver nodules 15 and 25 weeks post-initiation was approximately 1.4- and 1.8-fold greater, respectively, than comparable extracts from untreated-control and promoter only-treated rat liver tissues. Thus, the enhanced progression toward malignancy caused by treatment of rats bearing carcinogen-induced preneoplastic hepatic lesions with alkylating agents cannot be explained by a generalized deficiency of O6-alkylguanine-DNA alkyltransferase in hepatic preneoplastic lesions as a whole. These studies show that the distinctive xenobiotic resistant phenotype of rat hepatocyte nodules includes, in addition to the previously documented alterations in xenobiotic activation and detoxification enzyme activities, enhanced activity of a specific DNA repair system.
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D004260:DNA Repair; D005260:Female; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011230:Precancerous Conditions / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344
D015073:2-Acetylaminofluorene; D002251:Carbon Tetrachloride; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase