Effect of Chronic Treatment of Ratswith Dimethylnitrosamineon the Removalof 06-Methylguaninefrom DNA1

Rats were treated chronically for up to 6 weeks with unla beled dimethylnitrosamineat daily doses of 0.2 to 2 mg/kg! day. The effect of this pretreatment on the persistence of Q6.. methylguanmne, 7-methylguanine,and 3-methyladeninein DNA from liver, lung, and kidney wasdeterminedafter administration of a single 2-mg/kg dose of [‘4Cjdimethylnitrosamine. Pretreat ment did not affect the formation or the rate of loss of 3methyladenineor 7-methyguaninein any organ but resulted in a lower initial amount of 06-methylguaninein hepatic DNA as measured at 1 or 2 hr. The decrease in the initial amount of 06-methylguaninewas dependenton the dose of dimethylnitro samine used for pretreatment, with 2 mg/kg/day giving a maximal effect, although a significant decrease could still be observed when 0.2 mg/kg/day was used. It was also related to the time of pretreatment, requiring at least 2 weeks of exposure to 2 mg/kg/day for a maximalresponse.There was no effect of 06-methylguanineremoval from DNAof kidney or lung at any dose used. Pretreatmentwith dimethylnitrosammne led to an increased activity of an enzymeremoving 06-methyl guanine from methylatedDNAin vitro which could be detected ‘ in liver extracts but had no effect on a similar activity in kidney extracts. These results suggest that the lower amount of Q6@ methylguanine found in hepatic DNA of rats pretreated with dimethylnitrosamine was due to an increased activity of the enzyme system responsible for this reaction. This increase could be the result of an induction onactivation of the enzyme in response to the chronic administration of the carcinogen. The results are discussed in relation to the carcinogenicity of dimethylnitrosaminefor rat liver and to the observation of an inducible enzymesystem in Escherichia coli, which carries out an analogous reaction and protects against mutagenesis by alkylating agents.