DNA methylation by N-nitrosomethylbenzylamine in target and non-target tissues of laboratory rodents. Comparison with carcinogenicity.

Following oral or systemic (subcutaneous) administration to rats,N-nitroso -methylbenzylamine (NMBzA) causes a high incidence of oesophageal tumours. Methylation of DNA purines by a single oral dose of [14C-methyl]-NMBzA was most extensive in the oesophagus, followed by liver, forestomach and lung. After a single intravenous injection, alkylation levels were also highest in oesophageal DNA, followed by liver, lung and forestomach. These differences in the extent of alkylation were found to correlate with the autoradiographic distribution of tissue-bound 14C-radioactivity in in-situ preparations of the upper gastrointestinal tract following oral exposure to [14C-methyl]-NMBzA. In mice, systemic administration of NMBzA leads to the development of forestomach and lung tumours; in this species, DNA methylation after intraperitoneal injection of NMBzA is highest in liver, followed by lung and forestomach. Administration of [14C-methyl]-NMBzA to mice in the drinking-water led to very high concentrations of alkylated DNA bases in both oesophagus and forestomach. This finding is in good agreement with carcinogenicity studies, which showed 100% carcinoma incidence at these sites. Autoradiographic studies indicate that in rats and mice the metabolism of NMBzA in the oesophagus is largely restricted to the mucosa, whereas in lung, bioactivation occurs predominantly in the bronchial epithelium. In autoradiographs from liver, tissue-bound radioactivity showed a patchy distribution, with predominant reaction in the centrilobular region. In Mongolian gerbils, methylation of lung DNA by a similar subcutaneous dose of [14C-methyl]-NMBzA was greater than in rats and mice, whereas in the remaining tissues, levels of methylated purines were comparatively low. Chronic subcutaneous administration of NMBzA to gerbils caused no tumour within an observation period of two years.