Comparative carcinogenesis by some aliphatic nitrosamines in Fischer rats

Lijinsky, William; Reuber, Melvin D.

doi:10.1016/0304-3835(81)90158-0

Cited by 34 publications

(32 citation statements)

References 5 publications

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“…dose, concentrations of 7-methylguanine in rat liver are 100 times higher than in the oesophagus (5). Nevertheless, N-nitrosomethylethylamine does produce a low incidence of oesophageal carcinomas in addition to hepatic neoplasms when administered in the drinking water (9). 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).…”

Section: Discussionmentioning

confidence: 45%

“…If this were true, one would expect bladder tumours also after administration of A/-nitrosornethylhexylamine and A/-nitrosomethylbutylamine (C4), which should similarly be oxidized to form A/-nitrosomethylcaiboxypropylamine. The low incidence of bladder tumours produced by C6 (9) and the lack of a carcinogenic response of this organ to C4 is probably due to the very rapid and fatal induction of oesophageal carcinomas.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1987

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Aliphatic iV-nitrosomethylalkylamines exhibit a remarkable organ specificity in rats, the principal targets for tumour induction being liver, oesophagus, urinary bladder and lung. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6 h survival) of each of 12 homologues, ranging from N-nitrosodimethyiamlne (Cl) to A4utrosomethyldodecylamine (C12). Methylpurines (7-and O*-methylguanine) were determined by cation exchange HPLC with fluorescence detection. Highest levels of hepatic DNA methylation were found with A'-nkrosodimethjiainine (Cl) and A'-nitrosornethylethylamine (C2), the most potent bepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length for C1-C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenkity, the butyl and pentyl derivatives (C4, C5) being most effective. In rat lung, the extent of DNA methylation was generally lower and there was no apparent correlation with carcinogenicity. Methylation of kidney DNA also decreased with increasing chain length and was only detectable for C1-C5. In urinary bladder DNA, methylpurines were below or close to the limit of detection. It is concluded that the initiation of malignant transformation by DNA methylation alone (through hydroxylation at the methylene a-carbon) could be operative for Cl in kidney and lung, for Cl and C2 in liver, and C3-C5 in oesophagus. For the higher homologues, the extent of DNA methylation seems insufficient to explain the complex pattern of tissue specificity, suggesting that DNA modification other than, or in addition to, methylation may be responsible. IntroductionEarly investigations by Druckrey and co-workers (1) on the carcinogenicity of asymmetric nitrosamines in rats revealed a high degree of organ-specificity. Short-chain N-nitrosomethylalkylamines (Cl, C2*) induced predominantly rumours of liver and lung whereas the higher asymmetric homologues (C3-C6) produced exclusively or preferentially oesophageal neoplasms.

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Section: Discussionmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 99%

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

et al. 1987

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“…Nitrosomcthylhydroxyethylamine, the product expected from ~-oxidation of the ethyl group in 7, induces liver tumors, but not esophageal tumors in rats [27]. The metabolism of 7 leading to induction of tumors of the esophagus in rats must be assumed to be a minor pathway, since 7 itself induces esophageal tumors only at high dose rates [28]. This implies that pharmacokinetics play a most important role in determining tile sites of induction of tumors by 7: indeed, as will be shown later, in carcinogenesis by nitrosamines in general.…”

Section: Deuterium-containing N-nitroso Compoundsmentioning

confidence: 99%

Structure-activity relations in carcinogenesis by N-nitroso compounds

Lijinsky

1987

Cancer Metast Rev

111

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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.

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“…The vascular lining cells of mice (34,35), rats (36), and dogs (37) appear to be highly sensitive to hepatocarcinogens that are methylating agents, whereas hepatocytes of rats (36,38), hamsters (39,40), and primates (41,42) are more susceptible to ethylating agents. m6G is the principal promutagenic lesion induced in DNA by methylating hepatocarcinogens.…”

mentioning

confidence: 99%

Cell-specific differences in O6-alkylguanine DNA repair activity during continuous exposure to carcinogen.

Swenberg¹,

Bedell²,

Billings³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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The activity of the alkyl acceptor protein (AAP) responsible for repair of DNA containing the promutagenic lesion O6-alkylguanine was determined in hepatocytes and nonparenchymal cells (NPC) obtained from livers of control rats and rats exposed to hepatocarcinogens that primarily induce vascular or hepatocellular neoplasms. Basal levels of AAP activity were found to be 4-5 times higher in hepatocytes than in NPC. Exposure to 1,2-dimethylhydrazine or diethylnitrosamine produced a 2- to 3-fold enhancement of this activity in hepatocytes after exposure for as little as 3 days. The enhanced hepatocyte activity persisted throughout a 28-day exposure to 1,2-dimethylhydrazine. In contrast, AAP activity in NPC was decreased during the first week of exposure to 1,2-dimethylhydrazine and subsequently returned to control levels. No enhancement of AAP was apparent in the NPC. These and related data suggest that enhancement of this activity in rat hepatocytes is a response to cell proliferation. In contrast, the data clearly demonstrate that neither increased cell replication nor the presence of O6-alkylguanine was capable of enhancing AAP activity in NPC. Cellular differences in the repair of O6-alkylguanine appear to be a critical mechanism responsible for cell specificity in chemical carcinogenesis by alkylating agents.

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Comparative carcinogenesis by some aliphatic nitrosamines in Fischer rats

Cited by 34 publications

References 5 publications

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

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

Structure-activity relations in carcinogenesis by N-nitroso compounds

Cell-specific differences in O6-alkylguanine DNA repair activity during continuous exposure to carcinogen.

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