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- W2100049945 abstract "Several clinical reports have implied that the administration of cimetidine, a widely used and very effective drug for the treatment of gastric disorders, is related to the occurrence of stomach tumors. Furthermore, it has been noted that in vitro nitrosation of cimetidine produces a compound similar in chemical structure to N -methyl- N ′-nitro- N -nitrosoguanidine (MNNG), a potent laboratory animal carcinogen, and suggested that such nitrosation might be occurring in vivo . This remains to be shown. We have studied the in vitro reaction of nitrosocimetidine (NC) and MNNG with DNA and present evidence which indicates that, in the presence of activating nucleophile, these compounds methylate DNA with comparable effectiveness. Using high-pressure liquid chromatographic techniques to resolve and quantitate some of the methylated DNA purines, we have found that the relative yields of the major purine modification products produced by the two compounds are essentially the same. We take this as evidence that MNNG and NC generate the same methylating species upon decomposition. The decomposition rates of NC and MNNG have been observed as a function of pH, and it has been found that, at all pH values tested, NC is the much more stable compound. For example, in pH 7.4 phosphate buffer, NC has an estimated half-life of 135 hr compared to 5.6 hr for MNNG. It has been shown previously that the decomposition of MNNG is accelerated by nucleophilic compounds. Utilizing assays which monitor the decay of nitroso-group absorbance and of methylating capacity, we corroborate these findings. The NC decomposition rate is not detectably accelerated by excess nitrogen nucleophile (lysine) but is accelerated by sulfur nucleophiles (reduced glutathione and cysteine). These accelerated rates, however, are somewhat less than those observed in parallel MNNG experiments. In accord with previous reports, we find that about one-half of the MNNG decomposition in excess cysteine is via a denitrosation pathway; our evidence suggests that an even greater fraction of NC is denitrosated by cysteine. Finally, in NC DNA modification experiments run in the absence of cysteine, we observed only a trace of methylation over a 34-hr incubation period. No indication of DNA modification by the parent compound, cimetidine, with or without cysteine has been detected." @default.
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- W2100049945 date "1981-01-01" @default.
- W2100049945 modified "2023-09-26" @default.
- W2100049945 title "Methylation of DNA by nitrosocimetidine in vitro." @default.
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