The accumulation of O6-methylguanine in the liver and kidney DNA of rats treated with dimethylnitrosamine for a short or a long period

Abstract

A large dose of dimethylnitrosamine was administered to rats by two different dosing regimens, one being eleven intraperitoneal injections of 5 mg/kg body wt. at 12-h intervals (a dosing regimen strongly carcinogenic for the kidney but not the liver), and the other being a continuous dosing over several weeks by adding 8.5 mg of dimethylnitrosamine to each litre of drinking water giving an approximate daily dose of 0.7 mg/kg body wt. This treatment is known to be strongly carcinogenic for the liver but not the kidney. The accumulation in DNA of liver and kidney of the methylated purines 7-methylguanine and O 6-methylguanine under each regimen were measured and compared. With the eleven-injection regimen there was a build up of O 6-methylguanine in the DNA of the susceptible organ, the kidney, whilst in the liver virtually no accumulation was detected. Under the prolonged, low concentration regimen the liver, in spite of its susceptibility to the carcinogen did not accumulate O 6-methylguanine. The results are discussed in terms of the hypothesis that production of O 6-methylguanine and its persistence in the DNA of the target organ are responsible for the carcinogenic action of dimethylnitrosamine.