Location of N-methyl-N′-nitro-N-nitrosoguanidine-induced gastrointestinal tumors correlates with thiol distribution

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Abstract
Chronic administration of N-methyl-N′-nitro-N-nltrosoguanidine (MNNG) in the drinking water causes a high incidence of carcinomas of the glandular stomach in rats. Following a single oral dose of [ 14 C-methyl]MNNG (80 p.p.m.; 2.5 mg/kg), the extent of DNA methylation in the glandular stomach was 9 and 20 times higher than that in the forestomach and oesophagus, respectively. The autoradiographic distribution of tissue-bound radioactivity within the glandular stomach of BONN/WIST rats coincides with strain-specific tumor location at the small curvature. Following intragastric administration of [ 14 C-methyl]MNNG, alkylation levels in forestomach and glandular stomach were twice as high as those observed after oral exposure via the drinking water, whereas duodenal DNA showed a much lower extent of methylation. The regional differences in DNA alkylation correlated with tissue-specific variations in the concentration of cellular thiols which are known to accelerate the heterolytic decomposition of MNNG. When [ 14 C-methyl]-MNNG was given intragastrically together with the thiolblocking agent, N-ethylmaleimide, covalent binding of the 14 C-radioactivity to forestomach, glandular stomach and duodenum was almost completely abolished. This indicates that the preferential induction of glandular stomach tumors by MNNG relies on high concentrations of cellular thiols in the target tissue.