Increased excision of O6-methylguanine from rat liver DNA after chronic administration of dimethylnitrosamine

Abstract

Male BDIV rats were given dimethylnitrosamine (2 mg/kg daily) by stomach tube on weekdays for a total of 9 weeks, the final dose being of 14C-labeled material. Control rats received only the labeled dimethylnitrosamine. Liver DNA was isolated at various times later (from 2 to 12 hr), and normal and alkylated purines were determined after hydrolysis in mild acid by chromatography on Sephadex G-10. The levels (measured as dpm/micronmol of parent base) of 7-methylguanine in the DNA of the pretreated rats were the same as or slightly higher than those of the control animals, and the persistence of this product was similar in both groups. This was also true for 3-methyladenine. In contrast, the initial amount of O6-methylguanine in the liver DNA of the pretreated rats was one-third of the amount found in the control rats, and the rate of loss of this product from DNA was higher in the pretreated animals. These differences were reflected in the alkylation product ratios: the 3-methyladenine:7-methylguanine ratios were closely similar in the two groups of animals at all times, whereas the O6-methylguanine:7-methylguanine ratio was initially 3 times higher in the control animals and fell more slowly. DNA synthesis (as measured by the incorporation of [3H]thymidine) was higher in the liver, kidney, and lung of rats receiving dimethylnitrosamine pretreatment. These findings are discussed with respect to the hepatocarcinogenicity of chronically administered dimethylnitrosamine.