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W Lijinsky

Publications and source records attributed to W Lijinsky.

At least 181 records · Page 10Linked to original sources
PubMed1981

Carcinogenesis by derivatives of 1-nitroso-3,5-dimethylpiperazine in rats.

Four mononitrosopiperazines were administered to groups of 20 female Fischer 344 rats to compare their effectiveness as carcinogens. The four, 1-nitroso-3,5-dimethylpiperazine, its 4-acetyl derivative, its 4-benzoyl derivative, and 1-nitroso-3,4,5-trimethylpiperazine, were given as 0.7 mM solutions in drinking water, 100 ml to each rat per week. The length of treatment varied from 26 weeks for nitrosotrimethylpiperazine to 50 weeks for 1-nitroso-3,5-dimethyl-4-benzoylpiperazine. Dimethyl- and trimethylnitrosopiperazine gave rise to virtually 100% incidence of undifferentiated lymphomas of the thymus and leukemias within 30 weeks (in contrast to the non-C-methylated analogs which are noncarcinogenic or only weakly so). Acetyldimethylnitrosopiperazine was also a potent carcinogen, all of the rats treated with it dying within 30 weeks with tumors of the esophagus. In contrast, benzoyldimethylnitrosopiperazine was weakly carcinogenic, inducing only a small number of tumors of the forestomach and reducing the normal life span of the rats very little.

Animals↗
PubMed1980

Potent carcinogenicity of nitrosodiethanolamine in rats.

Nitrosodiethanolamine is found in synthetic cutting oils and in many cosmetic preparations and is probably the N-nitroso compound to which human exposure is greatest. It is formed by reaction of the commonly used amines diethanolamine and triethanolamine with nitrosating agents. An assessment of the possible risk in human exposure to nitrosodiethanolamine must be based on sound chronic toxicity data. A previously published chronic test of this compound in rats has shown it to induce liver tumours after very high oral doses, and tumours of the nasal cavity after administration of high repeated doses to Syrian hamsters by subcutaneous injection. To improve our understanding of the carcinogenic potency of nitrosodiethanolamine, we undertook a more extensive study, in which the compound was administered at concentrations ranging from 3,900 to 31,250 parts per million (p.p.m.) in drinking water, to groups of rats for about 6 months. We report here that when the animals were killed, all bore hepatocellular carcinomas, many of which metastasized at the higher doses, indicating that nitrosodiethanolamine is a carcinogen of considerable potency in the rat. However, it is inactive or very weakly active in short-term tests, such as the Salmonella mutagenesis test developed by Ames.

Animals↗
PubMed1980

Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride.

The antihistaminic over-the-counter drug methapyrilene hydrochloride, mixed with food at a concentration of 0.1 percent, was administered to 50 male and 50 female Fischer rats. A second group of 50 male and 50 female rats was given the same treatment together with 0.2 percent of sodium nitrite added to the food. Almost all of the rats in both groups developed liver neoplasms, mainly hepatocellular carcinomas and cholangiocarcinomas. The first rat died with a liver neoplasm at the 43rd week. Over 50 percent of the rats in both groups had metastases from the carcinomas of the liver to distant organs. Control rats treated with nitrite only, or untreated, did not develop liver neoplasms. There was no discernible effect of nitrite on the carcinogenicity of methapyrilene hydrochloride.

Aminopyridines↗
PubMed1980

Mutagenicity of vinyl compounds in Salmonella typhimurium.

Eighteen compounds structurally related to the mutagenic carcinogen vinyl chloride have been tested for mutagenicity in five strains of Salmonella typhimurium. Acrolein, acrolein diethylacetal, acrylonitrile, allyl alcohol, allyl bromide, crotonaldehyde, crotyl alcohol, and vinyl bromide were mutagenic with one or more strains; acrolein bisulfite, acrolein oxime, acrylamide, acrylic acid, allylamine, trans-cinnamaldehyde, trans-cinnamic acid, crotonic acid, methyl methacrylate, and vinyl acetate were not mutagenic. The mutagenicity tests were performed both without and with activation by rat and hamster liver microsomal preparations (S9). All compounds were tested in the plate incorporation and/or liquid preincubation tests except vinyl bromide, which was tested as a gas.

Animals↗
PubMed1980

The mutagenicity of 45 nitrosamines in the Salmonella typhimurium.

The correlation between mutagenicity in the rat liver microsome--mediated Salmonella Mutagenicity Assay of Ames and carcinogenicity in rats was examined with three groups of nitrosamines. Qualitatively the correlation was good, but there was poor correlation between mutagenic potency and carcinogenic potency. Of 23 cyclic nitrosamines, 19 were carcinogenic and mutagenic, and two were carcinogenic but not mutagenic, and the carcinogenicity studies of the remaining two are not complete. Of six symmetrical aliphatic nitrosamines, five were carcinogenic and mutagenic while only one carcinogen was not mutagenic. The greatest discrepancy occurred among 16 asymmetric nitrosamines, where 11 were both carcinogenic and mutagenic, four were carcinogenic but nonmutagenic, and one carcinogenicity study is incomplete.

Animals↗
PubMed1980

Effects of methylation and ring size on mutagenicity of cyclic nitrosamines in Drosophila melanogaster.

The mutagenic activity of 7 nitrosopiperazines, 2 nitropyrrolidines, and 3 nitrosomorpholines was examined in the X-linked recessive-lethal assay of Drosophila melanogaster. Mutagenicity is also reported for a series of cyclic nitrosamines that differ in structure only in the number of carbon atoms in the ring. Of the 18 compounds tested, 6 (nitrosopiperazine; 2,3,5,6-tetramethyldinitrosopiperazine; nitrosoproline; 2,5-dimethylnitrosopyrrolidine; nitrosothiomorpholine; and nitrosooctamethyleneimine) were nonmutagenic. As we reported earlier in investigations with the nitrosopiperidines, substitutions with methyl groups at all of the alpha-carbon atoms reduce or eliminate the mutagenic activity of dinitrosopiperazine and nitrosopyrrolidine.

Animals↗
PubMed1980

Mutagenicity of N-nitrosopiperazine derivatives in Saccharomyces cerevisiae.

The mutagenic properties of 8 N-nitrosopiperazines were examined in Saccharomyces cerevisiae. Forward mutations to canavanine resistance and reversions of his1-7 were induced by N'-methyl-N-nitrosopiperazine, dinitrosopiperazine, 2-methyldinitrosopiperazine, 2,5-dimethyldinitrosopiperazine, and 2,6-dimethyldinitrosopiperazine, in the presence of rat-liver homogenate. N-nitrosopiperazine, 2,3,5,6-tetramethyldinitrosopiperazine, and 4-benzoyl-3,5-dimethyldinitrosopiperazine were non-mutagenic.

Canavanine↗
PubMed1980

Lack of metabolism of 2,6-dimethyldinitrosopiperazine by microsomes and postmicrosomal supernatant prepared from the rat esophagus and non-glandular stomach.

Microsomes and postmicrosomal supernatant were prepared from the esophagus and non-grandular stomach of rats. Using these fractions, we could not demonstrate in vitro metabolism of 2,6-dimethyldinitrosopiperazine (DMDNP), a potent esophageal and non-grandular stomach carcinogen in rats. The esophageal and non-grandular stomach fractions did metabolize N-nitrosopyrrolidine (NPYR) to a small extent, and liver microsomes and postmicrosomal supernatant metabolized both nitrosamines to a similar extent. Therefore, we advise caution in the interpretation of metabolic studies using 'target' and 'non-target' organs as indicative of activation of compounds to proximate carcinogens.

Animals↗
PubMed1980

The effect of deuterium labeling on the carcinogenicity of nitroso-2,6-dimethylmorpholine in rats.

Nitroso-2,6-dimethylmorpholine (Me2NMOR) was labeled with deuterium in either the alpha or beta positions. Both the deuterium-labeled, and the unlabeled, compounds were administered to female Fischer 344 rats at equimolar concentrations in drinking water. The animals were then allowed to die naturally with tumors. The parent compound and the alpha-d4-labeled derivative were given at 50 mg/liter and 20 mg/liter, while, because of a shortage of the compound, the beta-d2-labeled derivative was given only at 20 mg/liter. Almost all of the animals died with basal cell carcinomas and papillomas of the esophagus; many animals fed the lower doses also had tumors of the nasal cavity and tongue. The rate of death from induced tumors was lower in the alpha-d4-treated group than in those treated with the unlabeled compound (at both dose levels), but was higher in the rats treated with the beta-d2 compound. It appears that deuterium in the alpha positions decreases carcinogenic potency, while deuterium in the beta positions increases it. This suggests that oxidation at the beta carbon atoms is less likely to be involved in esophageal carcinogenesis in the rat by Me2NMOR than is oxidation at the alpha carbon atoms.

Animals↗
PubMed1980

Comparison of carcinogenesis by two isomers of nitroso-2,6-dimethylmorpholine.

The cis and trans isomers of nitroso-2,6-dimethylmorpholine (Me2NMOR) have been separated and administered to Fischer 344 rats at doses corresponding to their proportion in the mixture prepared from the commercial amine (approximately 2 cis to 1 trans). The mixture of isomers was given at 2 doses, 50 mg per liter of drinking water and 20 mg per liter. A standard volume of each solution was given (20 ml per day per rat) on 5 days of each week and the animals were treated for the same time at either higher or lower dose levels. Almost all of the animals died with basal cell carcinomas and/or papillomas of the upper gastrointestinal tract. The time at which the rats died with the tumors was used as a measure of carcinogenic potency. Survival of the treated animals was consistently longer at the lower dose of each isomer. It was concluded that the trans isomer of Me2NMOR is a more potent carcinogen in rats than the cis isomer.

Animals↗
PubMed1980

Carcinogenicity of the isomeric, N-nitroso-delta3-and N-nitroso-delta2-piperidines in rats and the in vivo isomerization of the delta3-to the delta2-isomer.

N-Nitroso-1,2,3,6-tetrahydropyridine (N-nitroso-delta3-piperidine), N-nitroso-1,2,3,4-tetrahydropyridine (N-nitroso-delta2-piperidine) and N-nitroso-3,4-epoxypiperidine were tested for carcinogenicity in Fischer 344 rats. The unsaturated nitrosamines were administered in drinking water (100 mg/l). The epoxide was administered by gavage in corn oil (11.5 mg/ml, 0.2 ml twice a week). Both of the unsaturated nitrosamines were potent carcinogens (most of the animals died by the 35th week), and both produced many esophageal tumors, a property which they have in common with the parent compound, N-nitrosopiperidine. The spectrum of the other tumors formed, however, was different. The delta3-isomer produced hemangioendothelial sarcomas in the liver, which were absent in the tumor spectrum of the delta2-isomer and N-nitrosopiperidine. The delta2-isomer, on the other hand, produced tumors of the forestomach and the oropharynx, which were essentially absent in the rats treated with the delta3-isomer. N-nitroso-3,4-epoxypiperidine was a toxic compound (8 deaths in the first 5 weeks), but most of the remaining animals survived to 40 weeks. Of these, 8 animals died of induced tumors (esophagus and liver). The delta2- and the delta3-isomers were administered by gavage to groups of rats and the blood of these animals was withdrawn at timed intervals. Analysis of the serum revealed that both of the nitrosamines were cleared rapidly from circulation but that at the same time the delta3-isomer was being isomerized to the delta2. The reverse transformation did not occur in vivo.

Animals↗
PubMed1980

Carcinogenicity of deuterium-labeled N-nitroso-N-methylcyclohexylamine in rats.

F344 rats were treated with both unlabeled N-nitroso-N-methylcyclohexylamine (NMC) and deuterium-labeled NMC (NMC-d3) in the methyl group. Both compounds were administered in the drinking water at concentrations of 50 and 12.5 mg/liter. The NMC-d3 was not less carcinogenic than the unlabeled NMC, which suggested that oxidation of the methyl group is not a rate-limiting step in the induction of esophageal tumors.

Animals↗
PubMed1980

Significance of in vivo formation of N-nitroso compounds.

Formation of N-nitroso compounds from amines and nitrite has been demonstrated in chemical systems and in the stomach of animals in vivo. The amines differ in the extent to which they give rise to N-nitroso compounds. Many amines are common in the environment. Other amines are ingested as drugs, food additives or as trace contaminants of food with agricultural chemicals. At least 20 such amines have been given chronically to rats together with sodium nitrite and the incidence of tumors compared with that in rats given the amine or nitrite alone. Until now 13 of these amines have given rise to a significant incidence of tumors under these conditions, indicating that ingestion of these amines when nitrite is present could provide a source of carcinogenic nitrosamines for man. some of the amines were more effective in this respect than others. These were aminopyrine, morpholine, disulfiram, methylbenzylamine and heptamethyleneimine.

Amines↗
PubMed1980

N-nitroso-2,6-dimethylmorpholine-induced hemangiosarcomas in the livers of randombred guinea pigs.

The carcinogenic effect of N-nitroso-2,6-dimethylmorpholine (DMNM) was studied in randombred guinea pigs after repeated administration of this compound by gavage. DMNM was administered at two dose levels (14 and 28 mg/kg body wt) weekly for 23 weeks. All animals were observed until their death or termination of the experiment at 54 and 37 weeks for the 14- and 28-mg dose levels, respectively. At 14 mg, 67% of the animals developed hemangiosarcomas of the liver and 60% developed cholangiomas between 36 and 54 weeks. In addition, a poorly differentiated malignant mesenchymal tumor was observed in 1 animal. At 28 mg, liver hemangiosarcomas were observed in 82% of the animals between 26 and 37 weeks. In addition, in 18% of the animals, bronchioalveolar adenoma (1 animal), hepatocellular carcinoma (1 animal), and malignant lymphoma (1 animal) were also induced. Metastases of hemangiosarcomas to lungs, mesenteries, and lymph nodes were observed in 3 animals of each group.

Animals↗
PubMed1980

Carcinogenicity of nitrosotrialkylureas in Fischer 344 rats.

Three nitrosotrialkylureas were administered to female F344 rats as approximately 1-mM solutions in drinking water. Nitrosotrimethylurea, given for 47 weeks, gave rise to astrocytomas of the brain and tumors of the forestomach; nitrosotriethylurea induced a high incidence of adenocarcinomas of the breast and uterus and tumors of the forestomach. Nitrosomethyldiethylurea induced almost exclusively a high incidence of both astrocytomas of the brain and tumors of the spinal cord.

Animals↗
PubMed1980

Electron microscopic autoradiography of the pancreas in the hamster treated with tritiated N-nitroso-2,6-dimethylmorpholine.

Syrian golden hamsters were given a single dose of [3H]-N-nitroso-2,6-dimethylmorpholine and killed 8 hr later. The pancreas was processed for electron microscopic autoradiography to detect binding of radioactivity to cellular constituents. The pancreatic acinar cells and duct epithelia were found to be labeled, while islet cells, centroacinar cells, and all nonepithelial elements were not. Acinar cells active in secreting zymogen had a high concentration of grains over the zymogen granules and the rough endoplasmic reticulum. Their nonsecreting counterparts contained abundant bound material in the nuclei and rough endoplasmic reticulum. Labeling was lower in the duct epithelia than in acinar cells, with the majority of grains associated with the heterochromatin. Our findings suggest that the acinar cells are the principle site of metabolic activation in this organ.

Animals↗