Saturation of repair system for O6-methylguanine in rat liver DNA by pretreatment with cyclic nitrosamines.
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Animals↗
Biomedical subjects
W Lijinsky
Publications and source records attributed to W Lijinsky.
Mutagenicity of amine drugs and their products of nitrosation.
8 drugs that are amines or amides and that interact with nitrous acid to form potentially carcinogenic and mutagenic N-nitroso derivatives were tested for mutagenicity to Salmonella typhimurium. None of the compounds was mutagenic alone, with or without liver S9 activation. After reaction with nitrite in acetic acid solution, the products of 4 of the compounds were mutagenic. Diphenhydramine and hydrochlorothiazide gave products mutagenic with or without activation, but only to strain TA98. Methaphenilene gave products mutagenic to TA1538, TA98 and TA100 without microsomal activation. Dimethyldodecylamine-N-oxide after nitrosation was mutagenic with S9 activation to TA1535 indicating a response to the nitrosomethyldodecylamine formed. Allantoin, pyrilamine, chlorothen, methafurylene and thenyldiamine were not mutagenic alone or after nitrosation.
Amines↗
Dose-response study with N-nitrosodiethanolamine in F344 rats.
A dose-response study of the carcinogenicity of N-nitrosodiethanolamine was conducted in F344 rats. The nitrosamine was administered in drinking-water at a controlled rate (20 ml/rat/day, 5 days/wk) to groups of 16 or 20 rats of each sex. The doses administered were as follows: 2500 mg/litre drinking-water for 45-wk, 1000 mg/litre for 50 wk, 400 mg/litre for 50 wk and 400 mg/litre for 75 wk. Almost all of the treated animals died with hepatocellular carcinomas, of which 20-45% metastasized in each group. The females in each treatment group tended to die earlier, because they received a higher dose per unit body weight, but for each sex there was a dose-related decrease in survival as the carcinogen dose increased. There was a considerable incidence of tumours of the nasal cavity. The incidence of these tumours tended to be higher in males than in females and might be sex- or lifespan-related. A number of rats had cholangiocarcinomas in the liver and there were a few kidney tumours and tumours of the oesophagus in animals given the higher doses. None of these tumours was seen in the untreated controls of either sex, almost all of which outlived the treated animals. It is concluded that N-nitrosodiethanolamine is a carcinogen of considerable potency in rats.
Animals↗
Chronic toxicity tests of pyrilamine maleate and methapyrilene hydrochloride in F344 rats.
Methapyrilene hydrochloride was administered at levels of 125 or 250 ppm in the diet to groups of male and female F344 rats. The closely analogous antihistaminic drug pyrilamine, as the maleate, was given at 2000 ppm in the diet or at 2 g/litre drinking-water to groups of male and female F344 rats. Almost all of the rats given the higher dose of methapyrilene had either carcinomas or neoplastic nodules of the liver, whereas at 125 ppm 40% of the rats had neoplastic nodules in the liver. Among the 20 male and 20 female rats treated with pyrilamine maleate mixed into the diet, two males and two females had hepatocellular carcinomas and, in addition, five males and eight females had neoplastic nodules in the liver. The incidence of liver neoplasms in the rats given pyrilamine in the drinking-water did not differ from that in the untreated controls, of which five males and three females had neoplastic nodules in the liver.
Aminopyridines↗
Induction of tumours in rats by feeding nitrosatable amines together with sodium nitrite.
Feed containing 0.2% allantoin or diphenhydramine (as the hydrochloride) or 0.1% chlorpheniramine (as the maleate), with or without 0.2% sodium nitrite, was given ad lib. to groups of 20 or 24 male and 20 or 24 female F344 rats for 106 wk. Groups of 24 male and 24 female F344 rats were given drinking-water that contained N,N-dimethyldodecylamine-N-oxide at a concentration of 0.1%, with or without 0.2% sodium nitrite, for 93 wk. Control rats were given untreated feed or drinking-water and nitrite-treated controls were given sodium nitrite at a concentration of 0.2% in feed or drinking-water. At the end of the treatment period the rats were given untreated feed and water and observed until death. There was little or no life-shortening effect in any treatment group. None of the four amines administered alone induced an increase in the incidence of any tumour in comparison with the untreated control groups. In the male rats given diphenhydramine, chlorpheniramine or N,N-dimethyldodecylamine-N-oxide concurrently with nitrite there was a significant increase in the incidence of liver neoplasms (hepatocellular carcinomas and neoplastic nodules). In the groups given untreated feed or drinking-water there were, respectively, five and three male rats that had liver tumours. In contrast the number of male rats with liver tumours was ten in the group given dimethyldodecylamine-N-oxide plus nitrite, 11 in that given diphenhydramine plus nitrite and 14 (eight with carcinomas) in the group given chlorpheniramine plus nitrite. These results suggest that the ingestion of dimethyldodecylamine-N-oxide, diphenhydramine hydrochloride or chlorpheniramine under conditions when they could be nitrosated with nitrite in the stomach might present an increased carcinogenic risk.
Allantoin↗
Carcinogenesis by N-nitrosohexamethyleneimine in NZO inbred mice.
The carcinogenic response of NZO/BlGd inbred mice of both sexes to oral N-nitrosohexamethyleneimine (NHEX) was investigated at 2 differing dose rates, but equal cumulative doses. Mice received 52 mg NHEX (2 mg/g body wt) in drinking water over either an 8-week period (200 mg/l) or a 32-week period (50 mg/l), and were then kept for their natural lifespans. The main sites of tumorigenesis were upper alimentary tract (oropharynx, esophagus, squamous and glandular stomach) and liver. Lymphomas and biliary epithelial tumours were also induced, but lung carcinogenic response was of marginal statistical significance. In contrast to previous reports we found responses in mice very similar to the organ pattern of NHEX carcinogenesis in rats. A comparable previous study in rats found a more marked change in response pattern at the 2 NHEX dose rates but total doses differed by up to 1.6 times in that experiment. With equal total doses of NHEX the mouse tumour patterns at the same 2 dose rates were nearly the same, but there were higher incidences of liver and lung tumours and of lymphomas at the high dose rate, in agreement with the rat study. There were no significant sex differences in carcinogenic response.
Administration, Oral↗
The effect of deuterium substitution on carcinogenesis by azoxymethane.
Azoxymethane was synthesized labeled with deuterium in one or other of the two methyl groups. Groups of 20 male F344 rats were given either 4 mg or 1 mg per week of each of the labeled compounds or of unlabeled azoxymethane each week in drinking water, for 30 weeks, after which the animals were kept until they died. All in the high dose groups died earlier with tumors induced by the treatment than did those in the low dose groups. Azoxymethane itself led to earlier death than either of the deuterium-labeled compounds, and methylazoxymethane-d3 seemed to be the least potent compound. The incidence of liver tumors and of kidney tumors was similar in the groups receiving the same dose of all 3 compounds. However, there were fewer tumors of the colon in animals given methyl-d3-azoxymethane than with the other 2 compounds. These results are consistent with the concept that either methyl group of azoxymethane can be oxidized in the course of activation to a proximate carcinogenic agent for liver, kidney or colon of rats, but that oxidation of the methyl group next to the nitrogen bearing oxygen is more important in the induction of colon tumors.
Animals↗
Carcinogenesis in rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses.
Four nitrosomethylalkylamines were given to F344 rats in drinking water at concentrations of 0.22 mM or less. The total doses delivered to each animal were 0.5 and 0.2 mmol of nitrosodimethylamine (NDMA), 0.6 mmol of nitrosomethyl-2-oxopropylamine (NMOP) and nitrosomethyl-2-hydroxy-propylamine (NMHP) and 0.9 mmol of nitrosomethyl-2,3-dihydroxypropylamine (NMDHP). NDMA induced liver neoplasms in most of the animals, including 35% with hemangiosarcomas as well as hepatocellular tumors at the higher dose, but only hepatocellular tumors at the lower dose and the latter group of rats survived longer. NMOP induced a high incidence of esophageal tumors and NMHP induced a high incidence of both esophageal and nasal cavity tumors. NMDHP was the least potent of the 4 carcinogens, and induced lung tumors, neoplastic nodules in the liver, a few esophageal tumors and a few nasal cavity tumors, but after a long induction time.
Animals↗
The carcinogenic effect of 1,1-diethyl-3-methyl-3-nitrosourea in Syrian golden hamsters.
1,1-Diethyl-3-methyl-3-nitrosourea (Et2MNU) was subcutaneously injected in Syrian golden hamsters once weekly for 52 weeks. The animals developed mainly papillomas and squamous cell carcinomas of the nasal cavity and forestomach and hemangioendotheliomas of the spleen. Although survival time and tumour latency showed dose-dependency, tumour incidence did not.
Administration, Oral↗
Carcinogenesis in rats by asymmetric nitrosamines containing an allyl group.
Four asymmetric nitrosamines containing 1 allyl group were administered to rats in drinking water to aid in understanding the failure of nitrosodiallylamine ( NDAA ) to induce tumors in rats. Three of the compounds were given at equimolar doses, the fourth at somewhat lower dose. All four nitrosamines induced tumors of the esophagus and/or nasal cavity. Nitrosoallylethanolamine (NAE) induced a 30% incidence of hepatocellular carcinomas, while nitrosoallyl -2- hydroxypropylamine induced 70% hepatocellular carcinomas and a much lower dose of nitrosoallyl -2- oxopropylamine induced 80% of hepatocellular carcinomas, several of which metastasized. Nitrosoallyl -2,3- dihydroxypropylamine , which increased the mortality from tumors much more than the other compounds, failed to induce tumors in the liver, but induced a high incidence (85%) of tumors of the esophagus. The conclusion is that the allyl group is not metabolically inert, but that its presence in these molecules modifies their metabolism so as to give rise to tumors in a variety of organs. It does not seem that formation of an allylating agent is the common mechanism of carcinogenesis by these compounds.
Allyl Compounds↗
Induction of tumors of the nasal cavity in rats by concurrent feeding of thiram and sodium nitrite.
Simultaneous feeding to rats of thiram with sodium nitrite was carried out to assess the possibility of formation of carcinogenic N-nitroso derivatives in vivo. Following the administration of feed containing 500 ppm thiram plus 2000 ppm sodium nitrite for 104 w, a high incidence of tumors of the nasal cavity was found in both sexes, 18 of 24 males and 15 of 24 females. No nasal-cavity tumors were seen in untreated rats, or those given 500 ppm of thiram or 2000 ppm of sodium nitrite alone. A 20% incidence of papillomas of the forestomach was also seen in the rats of both sexes given the combined treatment. The other significant difference in incidence of tumors between the rats given thiram with or without nitrite was a decreased number of animals with monocytic leukemia, which is a common neoplasm in untreated F344 rats.
Animals↗
The effect of 3-methyl substitution on the carcinogenicity of nitroso-4-piperidone.
The carcinogenic activity of the 3-methyl derivative of nitroso-4-piperidone was compared with that of the compound without the methyl group, by chronic administration to rats at equimolar doses in drinking water. Nitrosopiperidone induced both liver and esophageal tumors, whereas the 3-methyl derivative induced only tumors of the esophagus in a much shorter time.
Animals↗
Carcinogenesis in rats by some hydroxylated acyclic nitrosamines.
A comparison was made of the carcinogenic effectiveness of five hydroxylated nitrosodialkylamines given to female F344 rats in drinking water. Nitroso-2,3-dihydroxypropyl-2-hydroxypropylamine was the most potent carcinogen among those examined, and induced almost exclusively tumors of the upper gastrointestinal tract. Considerably less potent was nitrosobis-(2-hydroxypropyl)amine, which also induced mainly tumors of the esophagus, although several animals also had tumors of the nasal cavity. Nitrosodiethanolamine was weaker again, and induced a high incidence of hepatocellular carcinomas. Nitroso-2-hydroxypropylethanolamine, which can be considered a hybrid of nitrosodiethanolamine, and the bis-hydroxypropyl compound, induced both esophageal tumors and hepatocellular carcinomas, together with some liver angiosarcomas; it appeared to lie in potency between the two symmetrical compounds. In contrast, nitroso-2,3-dihydroxypropylethanolamine was a very weak carcinogen, having little life-shortening effect; it induced hepatocellular carcinomas in only a small number of animals, together with some neoplastic nodules.
Animals↗
Carcinogenicity of nitrosododecamethyleneimine in NZR/Gd inbred rats.
Nitrosododecamethyleneimine (NDMI) was given to NZR/Gd rats by gavage in olive oil solution, confirming its hepatocarcinogenic activity. Twenty male and 20 female rats received 2.5 mg NDMI twice a week for 52 weeks; a further 10 male rats received 25.0 mg twice a week for 12 weeks. Two-thirds of the animals survived more than 2 years. Of the rats given the high dose of NDMI 50% died with hepatocellular carcinomas, as did 8% of the rats receiving the lower dose and 0.5% of untreated rats (p less than 0.001). In NDMI-treated animals the incidence of atriocaval tumours (p less than 0.001) and of lung tumours (p less than 0.025) was also significantly higher than in untreated controls.
Animals↗
Carcinogenesis by nitrosomorpholines, nitrosooxazolidines and nitrosoazetidine given by gavage to Syrian golden hamsters.
Five cyclic nitrosamines, four containing oxygen in the ring, were administered by gavage to groups of 20 male Syrian golden hamsters. After administration of very similar doses, nitrosomorpholine, nitroso-2-methylmorpholine and nitroso-5-methyl-1,3-oxazolidine caused the animals to die with tumors after similar times, but nitrosomorpholine induced mainly tumors of the nasal cavity (and a few of the trachea), whereas the 2-methyl derivative induced tumors of the nasal cavity and liver. While nitroso-1,3-oxazolidine and its 5-methyl derivative both induced liver tumors (but no tumors in the nasal cavity) those induced by the former compound took much longer to kill the animals. Nitrosoazetidine, a liver carcinogen in rats, but which had been reported to be inactive in hamsters, did induce tumors of the liver in 30% of hamsters after a much larger dose than the other cyclic nitrosamines.
Animals↗
The metabolism of nitrosodi-n-propylamine, nitrosodiallylamine and nitrosodiethanolamine.
Nitrosodiallylamine has been reported to be non-carcinogenic in rats while nitrosodipropylamine and nitrosodiethanolamine are liver carcinogens. That nitrosodipropylamine is metabolized at the alpha-position by liver microsomes from Fischer-344 rats supports the widely held contention that such metabolism is responsible for the carcinogenicity of nitrosamines. Nitrosodiallylamine is also metabolized at the alpha-position by the same microsomal preparations. Thus, although alpha-oxidation may be responsible for the carcinogenicity of some nitrosamines, this mechanism alone cannot account for tumorigenicity. Nitrosodiethanolamine is not metabolized by rat liver microsomes, but is metabolized by hepatocytes for Fischer-344 rats. In this case, a mechanism other than the oxidation at the alpha-position may be responsible for the carcinogenic action.
Animals↗
Contrasting responses of rats and Syrian hamsters to orally administered N-nitroso compounds.
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Administration, Oral↗
Comparison of the carcinogenic effectiveness of N-nitrosobis(2-hydroxypropyl)amine, N-nitrosobis(2-oxopropyl)amine, N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, and N-nitroso-2,6-dimethylmorpholine in Syrian hamsters.
For examination of metabolic interrelationships in carcinogenesis between N-nitroso-2,6-dimethylmorpholine, N-nitrosobis(2-oxopropyl)amine (CAS: 60599-38-4), N-nitrosobis(2-hydroxypropyl)amine (CAS: 53609-64-6), and N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine, each was given to a separate group of 20 female Syrian golden hamsters by gavage. All four compounds induced tumors of the pancreatic duct and lung tumors, but the incidences varied from one compound to another. In addition, N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine induced many hepatocellular and cholangiocellular neoplasms, which the other two compounds did not. On the basis of short time to death with tumors and the relatively low total dose administered, N-nitrosobis(2-oxopropyl) amine appeared to be the most potent carcinogen in the hamster among the four. N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine was next in potency but was considerably weaker than N-nitrosobis(2-oxopropyl)amine. N-Nitroso-2,6-dimethylmorpholine, which was similar in potency to N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine, however, did not induce a significant incidence of liver tumors of any type; and N-nitrosobis(2-hydroxypropyl) amine was considerably less potent than the other three compounds. These results did not support the opinion of N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine as the proximate carcinogenic metabolite of all three compounds in the Syrian hamster but instead suggested that these compounds might have acted through formation of different and yet unknown carcinogenic intermediates.
Animals↗