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Alkylation of Nucleic Acids and Metabolism of Small Doses of DimethyInitrosamine in the Rat¹

Department of Physiology [A. E. P.] and Specialized Cancer Research Center [W. P.], The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033

Small doses (<100 µg/kg) of dimethylnitrosamine were metabolized very rapidly in the rat so that production of 7-methylguanine in liver DNA was virtually complete within 15 min. The amount of O⁶-methylguanine found in DNA at this time was only 40% of that expected from the amount of 7-methylguanine found and declined rapidly over a further 3 hr, indicating that it was removed very rapidly from liver DNA. Dimethyl- and diethylnitrosamine were absorbed very rapidly from the upper part of the small intestine (t, <3 min) but quite slowly (t, >60 min) from the stomach. Since the latter was slower than the rate of metabolism after p.o. administration, the majority of uptake appears to be via the intestine. When the nitrosamine was administered p.o. in a mixture with a high fat content, the rate of reaction with liver DNA decreased, but the final extent of production of 7-methylguanine was the same, consistent with a reduction in the rate of absorption due to a decrease in the rate of gastric emptying.

The amount of 7-methylguanine formed in kidney DNA following administration of dimethylnitrosamine by i.v. injection was about 10 times less than the amount formed in liver DNA, irrespective of the dose over a range of 1 µg/kg to 10 mg/kg. A similar ratio was found after p.o. administration of doses of 5 to 10 mg/kg, but at doses of 1 mg/kg or below, there was much less production of 7-methylguanine in the kidney. These results suggest that, at the lower doses, the dimethylnitrosamine absorbed from the intestine into the portal blood supply is metabolized sufficiently rapidly by the liver that little becomes available for metabolism in the kidney. Removal of O⁶-methylguanine from the renal DNA was slower than from the liver DNA, so that shortly after i.v. administration, the amount present in the kidney was more than half that in liver. Very little O⁶-methylguanine was formed in the kidney DNA when doses of less than 50 µg/kg were given by p.o. administration. These results indicate the importance of the route of administration in determining the interaction of dimethylnitrosamine with various organs and suggest that the formation of alkylated bases in extrahepatic tissues may depend on the dose and on the rate of absorption of the carcinogen. The very high activity of the liver in removing O⁶-methylguanine from DNA may provide a protective mechanism against tumor initiation.

¹ Supported by Grants CA18137 and 1P30 CA18450 from the National Cancer Institute, Department of Health, Education, and Welfare.

² To whom requests for reprints should be addressed.

Received 3/ 2/81. Accepted 5/11/81.