Structure-activity relations in carcinogenesis by N-nitroso compounds

Abstract

For a large number of N-nitroso compounds a comparison of their carcinogenic effects in rats and Syrian golden hamsters has been made. Nitrosamines, which require metabolic activation, and nitrosoalkylamides, which do not, produce quite different tumor responses. There are also large differences in the types of tumor induced in rats and in hamsters. In all the studies doses of the various compounds, equimolar to the extent that was possible, are administered orally. Continuous doses (in drinking water or food) often produce a response different from that after administration of the same compound in pulsed doses (by gavage), even though the same total dose is delivered. Continuous doses of nitrosamines are usually more effective than pulsed doses, but with the nitrosoalkylureas, the reverse is more generally the case. Rat and hamster liver is a common target of many nitrosamines, but rarely of nitrosamides. The most common site of tumor induction in rats by N-nitroso compounds is the esophagus, but the hamster esophagus never responds. The pancreas duct of the hamster is a common target of nitrosamines containing a beta-oxygenated propyl group, but pancreas duct tumors are never seen in rats. Nitrosomethyl-n-alkylamines (with an even numbered carbon chain) induce bladder tumors in rats and hamsters. Many nitrosoalkylureas induce tumors of the nervous system in rats, as well as a great variety of other tumors. In hamsters, nitrosoalkylureas give rise only to tumors of the forestomach and spleen, but no tumors of the nervous system. The similar carcinogenic actions of certain groups of N-nitroso compounds can be related to their generation, directly or by metabolism, of similar simple moieties having certain organs as their target.

DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine

“…The present data ( Figure 3) show a considerable extent of oesophageal DNA methylation (7-methylguanine/guanine) by the next higher homologues, with oesophagus/liver ratios increasing from 0.069 (C3) to 1.28 (C4) and 0.98 (C5). These three compounds are powerful oesophageal carcinogens, producing highly malignant squamous carcinomas after an induction time of only 4-6 months (3,6,10). The other compounds studied produce neither oesophageal tumours nor extensive oesophageal DNA methylation, except for A/-nitrosomethylhexylamine (C6) which is a fairly potent carcinogen in this organ (10) even though its capacity to methylate target organ DNA was found to be low (Figure 3).…”

“…Compounds Cl -C4 and C6-C12 were given to Fischer 344 rats, and C5 to nus of the Donryu strain. Data were compiled from refs (3,6,10,28). lower extent (ethylation, hydroxyethylation) than did DNA methylation.…”

“…Subsequent work by Lijinsky and co-workers on A/-nitrosomethylalkylamines containing an alkyl group with more than five carbon atoms showed a striking alternating pattern, with nitrosamines containing an even-numbered carbon chain (C8, CIO, C12) producing urinary bladder tumours and those with an odd-numbered carbon chain (C7, C9, Cl 1) inducing liver and lung tumours (2,3). Investigations into the biological basis of this correlation between chemical structure and organ-specific carcinogenicity (Figure 1) have in the past focused on AZ-nitrosomethylbenzylamine (4), A/-nitrosomethylethylamine (5) and JV-nitrosomethylpentylamine (6), and have led to the assumption that the induction of oesophageal carcinomas is related to a preferential bioactivation of these nitrosamines by a P-450 isozyme in die oesophageal mucosa with high substrate specificity for asymmetric nitrosamines (4,5,7).…”

Qualitative Thin-Layer and High-Performance Liquid Chromatographic Analysis of 1-Substituted Diazen- 1-ium-1,2-diolates on Aminopropyl-Bonded Silica Gel

“…Perhaps most worrisome, the oxidative degradation of diazeniumdiolates can produce congener nitrosamines ( Fig. 1), many of which are potent carcinogens (10). Thus, if used in biological experiments, even a slightly degraded diazeniumdiolate product can pose a significant future health hazard.…”

LACK OF COMBINATION HEPATOCARCINOGENICITY OF HARMAN, NORHARMAN AND AMITROLE WHEN GIVEN WITH NaNO2 IN THE RAT

“…Another compound of interest is 2-amino-1,3,4-triazole (amitrole), a pesticide whose use is now limited to non-crop applications because of its induction of thyroid tumors in mice and rats by a non-genotoxic mechanism which involves interference with the functioning of thyroid peroxidase (IARC, 2001). NNitroso compounds are known to induce tumors in various organs, and the rat liver is a common target of many nitrosamines (Lijinsky, 1987). Therefore, investigation of carcinogenicity of NaNO 2 , in combination with amino compounds (harman, norharman and amitrole) is of interest and importance.…”