DNA-methylation by nitrosocimetidine and N-methyl-N-nitro-N-nitrosoguanidine in the intact rat

The ability of the nitroso derivative of the drug cimetidine to interact with cellular macromolecules in the intact rat was investigated. Radio-labelled nitrosocimetidine (NC) was shown to methylate DNA in a variety of tissues in the rat after oral administration. Radioactivity was also detected in the RNA and protein extracted from these same tissues. Methylation of DNA by the parent compound, cimetidine, was not detected in any of the tissues studied. For comparison, the DNA methylation produced by the carcinogen N-methyl-N-nitro-N-nitrosoguanidine (MNNG) dosed orally was measured. DNA alkylation by MNNG was found to be approx. 2-36 times greater than that produced by NC, varying with the tissues studied. The highest yield of DNA alkylation was found in the stomach for MNNG and the small intestine for nitrosocimetidine suggesting pharmacokinetic differences.