Biomedical subjects

W Lijinsky

Publications and source records attributed to W Lijinsky.

At least 163 records · Page 9Linked to original sources

PubMed1981

Morphology of early changes in liver carcinogenesis induced by methapyrilene.

Two weeks of treatment with the liver carcinogen methapyrilene induced a significant increase in mitochondria of periportal hepatocytes in F344 rats. Administration of [3H]-methapyrilene hydrochloride resulted in a pronounced concentration of bound radioactivity in the periportal hepatocytes, with mitochondria being the principal site of intracellular binding. The nuclei of the liver cells were unlabeled.

Aminopyridines↗

PubMed1981

Skin tumors induced by painting nitrosoalkylureas on mouse skin.

The carcinogenic action of nitrosamides has been investigated by applying a 0.04 M solution in acetone of 17 nitrosoalkylureas and one nitrosoalkylcarbamate to the shaved interscapular skin of female Swiss mice. Each of a group of 20 mice received 25 microliter of solution twice a week for 40 or 50 weeks, after which the animals were observed until death or 100 weeks. The appearance and progression of skin tumors within the painted area was charted for each animal. Nitroso-2-fluoroethylurea was toxic to the skin and was retested using a 0.01 M solution in acetone. No tumors was seen with nitrosoallylurea, nitroso-iso-butylurea, nitrosobenzylurea, and nitroso-2-phenylethylurea. The most potent compounds were nitrosomethylurea, nitrosoethylurea, and nitroso-2-fluoroethylurea. Nitroso-n-amylurea and nitroso-n-hexylurea were somewhat less potent, each inducing tumors in 11 of 20 mice. Nitrosocarbaryl gave rise to skin tumors in eight mice. The remaining compounds, nitroso-n-propylurea, nitroso-iso-propylurea, nitroso-n-butylurea, nictroso-sec-butylurea, nitroso-n-undecylurea, nitroso-n-tridecylurea, nitrosophenylurea, and nitrosocyclohexylurea were much less effective skin carcinogens, yielding tumors in from one to five mice. No good correlation was apparent between the relative stability of the compounds, their mutagenicity to Salmonella and their carcinogenicity to mouse skin.

Animals↗

PubMed1981

Mutagenicity of N-nitrosopyrrolidine derivatives in Salmonella (Ames) and Escherichia coli K-12 (343/113) assays.

The mutagenicity of nitrosopyrrolidine (NPYR) and its derivatives was determined by use of the Ames Salmonella assay. A clear specificity to revert the missense stain of TA1535 and a requirement for the phenobarbital-induced rat-liver activation system (S9 mix) were noted. 3,4-Dichloronitrosopyrrolidine was more mutagenic than NPYR, whereas 3-hydroxynitrosopyrrolidine was weakly mutagenic. The carcinogenic nitroso-3-pyrrolidine was not mutagenic under the test conditions. The noncarcinogenic derivatives (2,5-dimethylnitrosopyrrolidine, nitrosoproline and 4-hydroxynitrosoproline) were not mutagenic. Liquid preincubation assays were not any more effective than the pour-plate assays. Selected derivatives of NPYR were tested in the Escherichia coli K-12 (343/113) assay A specificity to revert the missense mutation at the arg locus and a dependence on phenobarbital-induced rat-liver S9 mix were noted with NPYR and its derivatives. 3,4-Dibromonitrosopyrrolidine, which was not mutagenic in Salmonella, was effective in E. coli, and the weakly carcinogenic NPRL was a weak mutagen resulting in a 2-fold enhancement in the E. coli arginine reversion assay.

Animals↗

PubMed1981

Nitrosamine-induced mutagenesis in Escherichia coli K12 (343/113). 1. Mutagenic properties of certain aliphatic nitrosamines.

The Escherichia coli K12 (343/113) test system developed by G. Mohn was used to detect the mutagenic activity induced by a group of aliphatic nitrosamines. Metabolic activation was incorporated into the assay by the addition of liver homogenates induced in either Sprague-Dawley rats or C3H mice with the addition of 0.1% phenobarbital to the drinking water. Nitrosodiethylamine (NDEA) was mutagenic upon metabolic activation and exhibited a preference to revert the missense mutation at the arginine locus. NDEA was also capable of inducing the forward mutation, selected as an ability to utilize galactose. NDEA was converted effectively into a mutagen in a time period of 30 min to 2 h. Metabolic activation with the mouse and rat liver preparations did not result in quantitative differences. Aliphatic nitrosamines that gave unexpected results with the Salmonella assay [4-10] were examined in the E. coli system. Nitrosodipropylamine (NDPA) and nitrosodiallylamine (NDAA) were mutagenic in both E. coli and Salmonella. Nitrosomethylethylamine (NMEA) was not mutagenic in Salmonella but was mutagenic in E. coli, and a strong carcinogen, nitrosomethylneopentylamine (NMNA), was not mutagenic in either assay. These results indicate the use of multiple genetic assays for the detection of genotoxic chemicals in our environment.

Escherichia coli↗

PubMed1981

Comparative carcinogenicity of two isomers of nitroso-2,6-dimethylmorpholine in guinea pigs.

The cis and trans isomers of nitroso-2,6-dimethylmorpholine (Me2NMOR) were administered by gavage to male Strain-2 guinea pigs as solutions in oil twice weekly for 30 weeks. Those animals treated with the cis isomer developed almost 100% incidence of liver tumors, together with tumors of the lung and adrenal cortex. In contrast, almost none of the animals treated with the trans isomer died with tumors. In rats, the trans isomer was considerably more potent than the cis, whereas this is not the result in guinea pigs, in which the cis is possibly more potent than the trans. This suggests that the mechanisms of activation in the 2 species might be different.

Adrenal Cortex Neoplasms↗

PubMed1981

Carcinogenic effect of nitrosopyrrolidine, nitrosopiperidine and nitrosohexamethyleneimine in Fischer rats.

Three homologous cyclic nitrosamines, nitrosopyrrolidine, nitrosopiperidine and nitrosohexamethyleneimine, were administered to groups of 20 female F344 rats in drinking water, as 0.9 mM solutions. Treatment with the latter 2 compounds lasted 28 weeks, at which time several animals had died with esophageal tumors. All of the animals in these 2 groups were dead by the 36th week of the experiment. Most of the animals given nitrosohexamethyleneimine also had angiosarcomas of the liver, and a few hepatocellular carcinomas were seen. Treatment with nitrosopyrrolidine lasted 50 weeks and the first animal in the group died at the 63rd week with an hepatocellular carcinoma. By the 110th week, almost all of these animals had died with the same type of tumor, and the 2 survivors were then killed. Many of the hepatocellular carcinomas had metastasized. There were no tumors of the liver in the rats treated with nitrosopiperidine.

Animals↗

PubMed1981

The carcinogenic effect of nitrosomethyldodecylamine in European hamsters.

Laboratory-bred European hamsters received nitrosomethyldodecylamine (NMDA) subcutaneously in olive oil once weekly for life. The animals showed mainly mucoepidermoid carcinomas of the lung, carcinomas of the urinary bladder and squamous cell carcinomas and sarcomas at the injection site. The tumour incidence was 90% in males and 70% in females, while the average tumour latency was 32 +/- 6 weeks for both sexes. Males had an average survival time of 29 +/- 17 weeks and females 24 +/- 19 weeks.

Animals↗

PubMed1981

Comparative carcinogenesis by some aliphatic nitrosamines in Fischer rats.

The carcinogenic effectiveness of 5 simple aliphatic nitrosamines was compared by feeding to groups of 20 Fischer rats in drinking water. Nitrosodi-isobutylamine was by far the weakest carcinogen, giving rise after comparatively high doses to tumors of the nasal cavity and trachea. Nitrosodimethylamine (NDMA) induced almost exclusively hemangiosarcomas of the liver, whereas nitrosodiethylamine (NDEA) gave rise to a high incidence of hepatocellular carcinomas, after administration of approximately the equivalent dose; all of the animals also developed tumors of the esophagus. Nitrosomethylethylamine (NMEA) induced both hemangiosarcomas and hepatocellular carcinomas, together with some esophageal tumors, but must be considered a weaker carcinogen than the dimethyl or diethyl analogs, since a much higher dose was needed to achieve a comparable effect. Nitrosodi-n-propylamine (NDPA) was of comparable potency with NDMA and NDEA, but gave rise under these conditions only to tumors of the esophagus and forestomach, and induced no liver tumors.

Animals↗

PubMed1981

The carcinogenic effect of 1,1-diethyl-3-methyl-3-nitrosourea in European hamsters.

Laboratory-bred European hamsters received subcutaneous injections of 1,1-diethyl-3-methyl-3-nitrosourea once weekly for life. The animals developed mainly squamous cell carcinomas of the nasal and oral cavities and malignant sarcomas (schwannomas) of the glandular stomach. The average tumour latency was shorter in females (24 weeks) than in males (28 weeks), while tumour incidence was 80% for both sexes.

Animals↗

PubMed1981

The effect of 4-substitution on the carcinogenicity of nitrosopiperidine.

Nitrosopiperidine and three derivatives substitute in the 4-position were fed to female F 344 rats in drinking water at equimolar concentration. The substituents were phenyl, cyclohexyl and tertiary-butyl. Like nitroso-piperidine, the t-butyl-and phenyl-derivatives induced tumors of the upper gastrointestinal tract (esophagus, forestomach and tongue), but the animals given nitroso-piperidine died earlier and after a smaller total dose. The rats given 4-phenylnitrosopiperidine also had a high incidence of tumors of the liver, both hepatocellular carcinomas and angiosarcomas. These tumors were absent from untreated animals of this strain. In contrast, no induced tumors were observed in rats treated with 4-cyclohexylnitrosopiperidine.

Animals↗

PubMed1981

The relationship between the carcinogenicity and mutagenicity of nitrosamines in a hepatocyte-mediated mutagenicity assay.

A quantitative relationship was established for 26 nitrosamines between their carcinogenic effectiveness in experimental animals and their mutagenic activity in a mammalian cell-mediated assay. Mutagenesis was measured in Chinese hamster V79 cells co-cultivated with primary rat hepatocytes, which are capable of activating nitrosamines. Resistance to ouabain and to 6-thioguanine served as the genetic markers.

Animals↗

PubMed1981

Carcinogenesis in Syrian hamsters by N-nitroso-2,6-dimethylmorpholine, its cis and trans isomers, and the effect of deuterium labeling.

Groups of 20 Syrian male golden hamsters were treated by gavage with solutions of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine in olive oil. Two doses of each isomer were given for the same time and the ratios of the concentrations corresponded with the ratio in the normally prepared mixture, 2 parts cis to 1 part trans. The cis isomer was more potent in inducing tumors of the liver and pancreas than the trans isomer. The effect of replacement of hydrogen with deuterium at the positions alpha and beta to the nitroso function on carcinogenic potency was examined by administering by gavage the respective isotopically labeled compounds to groups of 20 male hamsters. Each labeled sample constituted a mixture of cis and trans isomers in the ratio of approximately 2 to 1, and the dose was identical with that of the unlabeled sample of the nitrosamine. The beta deuterium labeled compound was less carcinogenic and the alpha deuterium labeled compound was more carcinogenic than the unlabeled material. There was not significant difference between the isomers in activation to a bacterial mutagen by pancreas microsomes or in binding to DNA of the pancreas.

Animals↗

PubMed1981

Fluoro-substituted N-nitrosamines. 1. Inactivity of N-nitrosobis(2,2,2-trifluoroethyl)amine in carcinogenicity and mutagenicity tests.

N-Nitroso-bis(2,2,2-trifluoroethyl)amine (hexafluorodiethylnitrosamine, 6-F-DEN) was synthesized as a derivative of diethylnitrosamine (DEN) with blocked terminal C-atoms to avoid metabolic oxidation at this site. Chronic oral administration of 6-F-DEN in drinking water did not induce tumours in Sprague-Dawley and in Fischer 344 rats. On the other hand, equimolar doses of DEN or even much lower ones are clearly carcinogenic. Mutagenicity tests using Salmonella typhimurium strains TA 1535 and TA 100 and metabolic activation by rat liver S-9 fraction were equally negative with 6-F-DEn. The substitution of fluorine in the beta-position of DEn apparently inhibits the alpha-oxidation considered necessary for carcinogenesis and mutagenesis of dialkylnitrosamines.

Animals↗

PubMed1981

Induction of carcinogenesis in Fischer rats by methylalkylnitrosamines.

Five nitrosomethyl-n-alkylamines with long aliphatic chains were administered to male F344 rats by gavage for 30 weeks. The rats treated with nitrosomethyl-n-octylamine and nitrosomethyl-n-nonylamine died within one year, while a majority of those given nitrosomethyl-n-decylamine, nitrosomethyl-n-dodecylamine, and nitrosomethyl-n-tetradecylamine lived for more than 80 weeks. Apart from the spontaneous tumors found in untreated rats of this strain, the rats treated with all four compounds containing an even number of carbon atoms in the long chain developed a high incidence of transitional cell carcinoma of the bladder. In addition, the rats treated with nitrosomethyloctylamine developed tumors of the liver (hepatocellular carcinomas and some angiosarcomas), lung, and nasal cavity. Nitrosomethylnonylamine failed to induce tumors in the bladder but induced tumors of the liver (hepatocellular carcinomas and cholangiocarcinomas), lung tumors, and some tumors of the nasal cavity.

Adenocarcinoma↗

PubMed1981

Penetration of rat skin by N-nitrosodiethanolamine and N-nitrosomorpholine.

N-Nitrosomorpholine (NMOR) and N-nitrosodiethanolamine (NDELA) were painted on the clipped upper dorsal skin of male F344 rats. NDELA was applied undiluted, dissolved in water, and dissolved in cutting oil; NMOR was applied dissolved in water and in ethyl acetate. Aqueous solutions of the nitrosamines were used for gavage. Rats were housed individually. Blood and urine samples were analyzed for nitrosamines by chromatography combined with a Thermal Energy Analyzer. Maximum penetration of NMOR was approximately equal to 34% 2 hours after application of 5 mg to the skin or by gavage; less than 1% appeared in the urine in 24 hours. Skin painting with NDELA in water (20 mg/100 microliters) and in cutting oil (25 mg/25 microliters) yielded small concentrations of NDELA (always < 25 micrograms/ml blood). When 50 mg of undiluted NDELA was painted on the skin, 130 to 220 micrograms/ml of blood was recovered after 1 hour. Administering 50 mg NDELA in water by gavage yielded similar blood concentrations. Maximum skin penetration observed with NDELA was 78% 1 hour after application of 50 mg. From 20 to 30% of the NDELA applied undiluted and by gavage appeared in the urine in 24 hours. Although animals and humans differ, skin exposure to NMOR or NDELA represents a risk due to absorption.

Administration, Topical↗

PubMed1981

Greater effectiveness of hepatocyte and liver S9 preparations from hamsters than rat preparations in activating N-nitroso compounds to metabolites mutagenic to Salmonella.

A comparison was made of the ability of liver S9 and hepatocyte preparations from noninbred Syrian golden hamsters and noninbred Sprague-Dawley rats to metabolically activate a number of nitroso compounds in the Salmonella mutagenesis assay. The liver S9 and hepatocyte preparations from hamsters were consistently more effective than were preparations from rats in metabolizing nitrosodimethylamine (NDM), nitrosodiethylamine, nitrosodiallylamine, nitrosopyrrolidine (NP), nitrosomorpholine (NM), nitrosodiethylmethylurea (NDEMU), and nitrosodimethyl-ethylurea (NDMEU) to mutagenic forms. The use of hamster S9 preparations with NP and NM resulted in up to 14 times the number of revertant colonies obtained with rat preparations; in the presence of hamster hepatocytes, up to 32 times the number of revertants were obtained. The S9 preparations from male hamsters not treated with the enzyme inducers phenobarbital and Aroclor 1254 were more effective than were those from female hamsters for activating NP, NM, and NDM, NDEMU and NDMEU, which have been reported to be carcinogens but not mutagens, were mutagenic in the presence of induced liver S9 or hepatocyte preparations from hamsters but not from rats. When tested with any of the S9 or hepatocyte preparations, nitrosodiphenylamine and nitrosomethylaniline, also reported to be carcinogens but not mutagens, gave no mutagenic responses. Nitrosodioctyl-amine, which has been reported to be noncarcinogenic, was also not mutagenic.

Animals↗

PubMed1981

Relationship of rat urinary metabolites of N-nitrosomethyl-N-alkylamine to bladder carcinogenesis.

Nitrosomethylalkylamines with chain lengths from C4 (n-butyl-) to C14 (n-tetradecyl-) were each administered in three rats at doses equimolar with 12 mg of the butyl compound. All of the compounds administered to rats at this dose, twice a week for 30 weeks, induced tumors in 100% of the animals. Some of the compounds with even-numbered alkyl chains induced bladder tumors, and a connection was sought with the metabolites of these excreted in urine. The pooled 24-hr urine was extracted with ethyl acetate before and after acidification to provide a neutral fraction and a fraction containing nitrosoamino acids. The fraction containing the acids was analyzed by capillary gas chromatography and by gas chromatography-mass spectrometry after esterification with diazomethane; the neutral fraction was analyzed similarly. The principal metabolite of the nitrosoamines with odd-numbered chains was found in the acidic fraction and was identified as nitrosomethyl-2-carboxy-ethylamine. There were several acids in the mixtures derived from the nitrosamines with even-numbered chains, nitrososarcosine and nitrosomethyl-3-carboxypropylamine being the major components. There was no trend in the yields of the nitrosamino acids that could be correlated with the differences in carcinogenic potency between the nitrosamines; the maximum yield of acids was more than 30% (from the tetradecyl compound). The principal component of the neutral fraction (less than or equal to 1% of the nitrosomethylalkylamine administered) was nitrosomethyl-2-oxopropylamine. The yield of this compound increased with length of the even-numbered chain nitrosamines.

Animals↗

PubMed1981

Dose response studies of carcinogenesis in rats by nitrosodiethylamine.

A dose-response study was conducted in Fischer rats with nitrosodiethylamine, which was administered in regulated amounts as a solution in drinking water. Groups of 20 female rats each received a different treatment, one group consisted of 12 animals; one of the groups was untreated. The concentrations of the solutions fed ranged from 113 to 0.45 mg/liter at six successive concentrations differing from a factor of 2.5. The treatment times were 17 weeks at the highest concentration; 22 weeks with 45 mg/liter; and 30 weeks with 18, 7, 2.8, 1.1 and 0.45 mg/liter. The two lowest dose levels were also given for 60 weeks, and the 0.45-mg/liter dose was given for 104 weeks. Animals were allowed to die naturally with tumors, and the time to death with tumors was an index of the potency of treatment. In the top four treatment groups, the potency measured in this way was proportional to the total dose of carcinogen administered. At all other doses, survival time was much less dependent on the dose administered, whether or not tumors were induced by the treatment. The principal tumors found were in the upper gastrointestinal tract, mainly the esophagus, at all doses. In the two highest dose groups, there was a high incidence of liver tumors also. There were few liver tumors in the lower dose groups, but there was a dose-related incidence of tumors of the upper gastrointestinal tract. It was remarkable that a nitrosodiethylamine concentration of 0.45 mg/liter (0.45 ppm) administered for 104 weeks induced tumors of the upper gastrointestinal tract in 70% of the treated rats.

Animals↗