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W Lijinsky

Publications and source records attributed to W Lijinsky.

At least 145 records · Page 8Linked to original sources
PubMed1982

Dose-response studies with nitroso-1,2,3,6-tetrahydropyridine and dinitrosohomopiperazine in F344 rats.

Dose-response studies were carried out on female F344 rats with two carcinogenic cyclic nitrosamines, nitroso-1,2,3,6-tetrahydropyridine (NTHP) and dinitrosohomopiperazine (DNHP). Groups of 20 rats were given the nitrosamines in drinking water solution, at concentrations ranging from 100 to 1 mg/liter of the former and 110 to 1.1 mg/liter of the latter, each lower dose being 40% of the dose above it. The lengths of treatment were 25 or 30 weeks at the higher concentrations, and were extended to most of the lifespan at the lower concentrations. The mortality rate of the animals with induced tumors of the upper gastrointestinal tract (and liver in the case of the highest dose of NTHP), decreased with lower doses at the higher concentrations. At the lower concentrations there was little effect on mortality rate, compared with untreated controls, but there were a number of rats with induced tumors of the upper GI tract and the incidence of these tumors increased with increasing dose of nitrosamine. Of the doses given, only the lowest dose of DNHP given for the shortest time was without significant carcinogenic effect. The relationship between dose of nitrosamine and carcinogenic potency, as measured by mortality rate, was linear over part of the range, but not at lower doses. The slopes of these dose responses differed between NTHP- and DNHP-treated animals, suggesting that the mechanisms of carcinogenesis by these two compounds are not identical.

Animals↗
PubMed1982

Studies of a deuterium isotope effect in carcinogenesis by N-nitroso-N-alkylurethanes in rats.

Nitroso-N-methylurethane and nitroso-N-ethylurethane were administered to groups of 20 female F344 rats in corn oil solution by gavage. Each rat received once a week 0.2 ml of solution containing 7 mg/ml or 1.75 mg/ml of the methyl compound or 8 mg/ml or 2 mg/ml of the ethyl compound for 20 weeks. In parallel with these treatments additional groups of rats were given equimolar dose of nitrosomethylurethane and nitrosoethylurethane fully labeled with deuterium in the N-alkyl groups. All animals were allowed to die naturally. The total doses received by the rats were 0.2 mmol at the higher concentration and 0.05 mmol at the lower concentration. Almost all of the treated rats died with papillomas and carcinomas of the forestomach (non-glandular stomach), and the other induced tumors of significance were carcinomas and papillomas of the esophagus in rats given the 7 mg/ml dose of nitrosomethylurethane, both labeled and unlabeled. There was no significant difference in tumor incidence or rate of mortality from tumors that would indicate a difference in carcinogenic effectiveness between the nitrosoalkylurethanes and their deuterium-labeled counterparts. Apart from the esophageal tumors induced only by nitrosomethylurethane at the higher dose, there was no significant difference in carcinogenic effectiveness between the methyl and ethyl nitrosourethanes.

Animals↗
PubMed1982

Contrasting carcinogenic effects of nitroso-2,6-dimethylmorpholine given by gavage to F344 rats and Syrian golden hamsters.

Nitroso-2,6-dimethylmorpholine (Me2NM) has been given by gavage to F344 rats of both sexes and to male Syrian hamsters at similar doses. The rats died more rapidly from the tumors induced than did the hamsters, the males being more susceptible than the females. The rats developed mainly carcinomas and papillomas of the esophagus, whereas the hamsters died with angiosarcomas of the liver, ductal adenocarcinomas of the pancreas, adenocarcinomas of the lung and olfactory adenocarcinomas of the nasal cavity. It was notable that, with the exception of a few lung tumors in the rat, none of the tumors found in the hamster were induced by Me2NM in the rat, and no esophageal tumors were seen in the hamsters.

Animals↗
PubMed1982

Dose-response studies in carcinogenesis by nitroso-N-methyl-N-(2-phenyl)ethylamine in rats and the effects of deuterium substitution.

A dose-response study of the carcinogenicity of nitroso-N-methyl-N-(2-phenyl)ethylamine was carried out in male Fischer 344 rats. The compound was given in drinking water at concentrations of 115, 28, 9.5, 3.2, 1.1 and 0.4 mg/litre. The highest concentration proved toxic leading to the early death of several animals; the remainder of this group were treated for 21 wk. All of the other concentrations were given for 33 wk, except the 28 mg/litre treatment which ceased at 30 wk. An additional group of rats was given 0.4 mg/litre for 104 wk. In all groups of animals, except those in the high-dose group that died early and those given 0.4 mg/litre for 33 wk, 50% or more of the animals had tumours of the oesophagus or forestomach or both when they died. In several groups the number of rats with these tumours approached 100%. The total dose of carcinogen received by the rats in the lowest dose group was 1.3 mg and 45% of them had tumours of the upper gastro-intestinal tract. The effect on carcinogenicity of labelling the nitrosamine with deuterium in either the methyl group or the alpha-methylene of the phenylethyl group was determined by treating groups of rats with equimolar concentrations of the deuterium-labelled and unlabelled nitrosamine. A very significant increase in carcinogenic effectiveness was observed with the compound containing deuterium in the alpha-methylene of the phenylethyl group, suggesting that methylation might not be the important event in carcinogenesis by this compound in rats.

Animals↗
PubMed1982

Comparison of the carcinogenic effectiveness in mouse skin of methyl- and ethylnitrosourea, nitrosourethane and nitrosonitro-guanidine and the effect of deuterium labeling.

The carcinogenic activities of a number of directly acting methylating and ethylating agents have been compared by mouse skin painting in acetone solution. Nitrosomethylurethane and nitrosoethylurethane failed to induce tumors after greater than 60 weeks treatment. Nitrosomethylurea was somewhat more effective than nitrosoethylurea, as measured by the longer latent period than nitrosoethylurea, as measured Nitrosomethylnitroguanidine, by the same measure, was a weaker carcinogen than nitrosoethylnitroguanidine at both dose levels used (0.02 M and 0.008 M); the latter compound was the most potent skin carcinogen of those examined. There was no significant difference in carcinogenic effectiveness when the alkyl group of the nitrosoureas or the nitronitrosoguanidines contained deuterium instead of hydrogen, which supports the concept that alkylation of cellular macromolecules by the intact alkyl group is responsible for carcinogenesis by these compounds.

Administration, Topical↗
PubMed1982

Comparative carcinogenesis by nitrosomorpholines, nitrosooxazolidines and nitrosotetrahydrooxazine in rats.

A comparison was made of the carcinogenic effectiveness of some cyclic nitrosamines containing oxygen in the ring. The compounds were administered to F344 rats at approximately equimolar concentrations in drinking water. Nitrosomorpholine, nitroso-1,3-oxazolidine and nitrosotetrahydro-1,3-oxazine were of similar potency and gave rise to hepatocellular carcinomas and angiosarcomas of the liver in almost 100% of treated rats. Methyl substitution at the beta position of nitrosomorpholine increased the potency, but retained the main target organ as the liver, while methyl substitution at both beta positions resulted in a further increase in potency, but elimination of the liver as a target and with the main site of tumor induction the upper gastrointestinal tract. In contrast, methyl substitution in the beta position of nitrosooxazolidine resulted in a decrease in carcinogenic potency, but with 100% incidence of liver tumors, but relatively few angiosarcomas. A methyl group at the 2-position of nitrosooxazolidine also reduced carcinogenic potency, all of the animals dying with liver tumors, but few angiosarcomas, but the change was no larger than that produced by the presence of methyl at the 5-position (beta).

Animals↗
PubMed1982

Structure activity studies with N-nitrosamines using Salmonella typhimurium and Escherichia coli.

Mutagenic activities of a large number of nitrosamines were determined using Salmonella histidine reversion and Escherichia coli arginine reversion assays. The cyclic nitrosamines exhibited a close correlation between their mutagenic and carcinogenic properties, while no such relationship was evident with the aliphatic nitrosamines. Substitution of cyclic nitrosamines with methyl, hydroxy and oxy groups did not alter the mutagenic activities. However, when positions alpha to the N-nitroso groups were substituted with methyl groups, the biological activity was eliminated. Substitution with halogens enhanced, whereas carboxyl substitution eliminated the biological activity. The E. coli assay not only substantiated the observations made with Salmonella, but also demonstrated mutagenic activity in the case of certain carcinogenic nitrosamines which were not mutagenic in the Salmonella assay.

Animals↗
PubMed1982

Esophageal carcinogenesis in F344 rats by nitrosomethylethylamines substituted in the ethyl group.

The carcinogenic activity in male F344 rats of five nitrosomethylalkylamines related to nitrosomethylethylamine has been examined. All rats were tested by administration of controlled doses of the compounds in the drinking water. Nitrosomethylbenzylamine was the most potent carcinogen of the five, causing death of most animals with tumors of the upper gastrointestinal tract (mainly the esophagus) within 6 months after a total dose of 0.2 mmol. The remaining compounds, all of which can be considered true derivatives of nitrosomethylethylamine, were less potent than nitrosomethylbenzylamine but also induced a high incidence of tumors of the esophagus. Nitrosomethyl-2-phenylethylamine and nitrosomethylneopentylamine were of comparable potency, while nitrosomethyltrifluoroethylamine was considerably less potent, as measured by the time to death with esophageal tumors. Deuterium-labeled nitrosomethylethylamine, in which deuterium replaces hydrogen on the beta-carbon atom of nitrosomethylethylamine, induced a high incidence of esophageal tumors as well as liver tumors after administration of identical doses. Reactions on the beta-carbon atom of nitrosomethylethylamine might be important as well as oxidation at the alpha-carbon atoms in determining carcinogenic effects.

Animals↗
PubMed1982

Carcinogenesis by isomers of N-nitroso-3,5-dimethylpiperidine.

The cis- and trans-isomers of N-nitroso-3,5-dimethylpiperidine were administered separately in drinking water solution to groups of 20 female F344 rats for 50 weeks. The concentrations of the solutions were 0.72 m M for the cis-isomer and 0.14 mM for the trans-isomer. In both groups the animals died with tumors of the upper gastrointestinal (GI) tract, mainly carcinomas of the esophagus, at about the same time. A third group of animals was given a mixture of the two isomers in the ratio of 5 cis:1 trans, and these animals died more rapidly with the same upper GI tumors. The trans-isomer appeared to be a more potent carcinogen than the cis-isomer. The 3,5-dimethyl derivative is a less potent carcinogen than nitrosopiperidine.

Animals↗
PubMed1982

Dose-response studies with nitrosoheptamethyleneimine and its alpha-deuterium-labeled derivative in F344 rats.

A dose-response study of the carcinogenicity of nitrosoheptamethyleneimine (N-HEP) in inbred F344 male and female rats was performed by administration of the nitrosamine at several concentrations in drinking water to groups of 20 rats. The concentrations differed by a factor of nearly 2.5 and ranged from 1.0 to 100 mg/liter. The duration of treatment was 13, 25, 50, or 100 weeks, after which the animals were allowed to die naturally of tumors induced. In most treated groups the incidence of tumors of the upper gastrointestinal tract approached 100%. However, at the higher doses there was an inverse relationship between total dose and survival time of the rats. Matched treatment of groups of rat with N-HEP labeled with deuterium in the alpha positions resulted in longer survival. The slower action of the deuterium-labeled compound, as measured by a lower rate of death from tumors, suggests that cleavage of a carbon-hydrogen bond at an alpha position is a rate-limiting step in carcinogenesis by N-HEP in rats.

Animals↗
PubMed1982

Comparative metabolism of 2,6-dimethylnitrosomorpholine in rats, hamsters, and guinea pigs.

The metabolism of N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) was studied in female Sprague-Dawley rats. Syrian golden hamsters, and guinea pigs. NDMM induces tumors in the esophagus in rats, pancreatic cancer in hamsters, and hemangioendothelial tumors of the liver in guinea pigs. An intragastric dose of NDMM (2 mg, 2 muCi/animal) was rapidly distributed throughout the tissues of both the rat and hamster, with no apparent accumulation of radioactivity in any one tissue. At low dose levels, NDMM was metabolized rapidly by both species. The hamster appeared to metabolize the compound faster than did the rat or guinea pig. At appreciable amount of radioactivity was excreted in the urine in all three species after 8 hr: approximately 54% in the hamster, 39% in the rat; and 30% in the guinea pig. During the first 24 hr, only a small percentage of the radioactivity excreted by the hamster, rat, and guinea pig was NDMM (0.8, 2, and 0.5%, respectively). High-pressure liquid chromatography analysis of urine collected 24 hr after administration revealed 12 metabolites. Although the urinary metabolites appeared to be similar in all three species, one large difference was the presence of a major urinary metabolite in hamster urine, which was absent or present in only small quantities in the rat and guinea pig. The guinea pig urine also had relatively more radioactivity present in one major fraction than did the hamster or rat.

Animals↗
PubMed1982

Relationship between carcinogenicity and in vitro metabolism of nitrosomethylethylamine, nitrosomethyl-N-butylamine, and nitrosomethyl-(2-phenylethyl)amine labeled with deuterium in the methyl and alpha-methylene positions.

With the use of rat liver preparations, the in vitro microsomal metabolism of methylethylnitrosamine, methyl-n-butylnitrosamine, and methyl(2-phenylethyl)nitrosamine labeled with deuterium in the methyl and alpha-methylene positions has been compared with that of the parent (unlabeled) compounds. All three forms of the liver carcinogen methylethylnitrosamine are metabolized with two sets of kinetic constants. Examination of these kinetic constants suggests that both methylation and ethylation of cellular nucleophiles might be important in the carcinogenic action of these nitrosamines. The esophageal carcinogen, methyl(2-phenylethyl)nitrosamine, gave only one set of kinetic constants during metabolism. The metabolism of the three methylbutylnitrosamines gave results similar to that of the three methylethyl nitrosamines. Except for metabolism of d2-methylbutylnitrosamine to butyraldehyde, two sets of kinetic constants were found. Approximately equivalent amounts of methylating species were produced from d3-methylbutylnitrosamine and d0-methylbutylnitrosamine.

Animals↗
PubMed1982

Inability of methapyrilene to induce sister chromatid exchanges in vitro and in vivo.

The induction of sister chromatid exchanges (SCE) by the hepatocarcinogen methapyrilene hydrochloride was investigated using appropriate in vitro and in vivo mammalian cell systems. Methapyrilene, even at the maximum tolerated dose, did not induce SCE in Chinese hamster ovary cells (CHO) or when CHO cells or hamster lung fibroblasts, V-79, were cocultivated with early cultures of rat liver epithelial cells, which are known to metabolize different classes of chemical carcinogens to active forms. Moreover, a hybrid clone of cells (formed by fusion of CHO cells with rat liver epithelial cells), which is highly sensitive to SCE formation by a number of xenobiotics, failed to produce SCE after treatment with methapyrilene. Experiments in vivo with bone marrow cells and in vitro with CHO cells cocultivated with primary hepatocytes from rats also confirmed the inability of methapyrilene to induce SCE in the indicator cells. Since aflatoxin B1 induced SCE in the in vitro and in vivo models, it may be concluded that methapyrilene does not induce SCE at a concentration which is not cytotoxic to the indicator cells in the different systems described. Autoradiographic studies in cultured rat liver cells with tritiated methapyrilene showed that the label was localized in the cytoplasm but not in the interphase nuclei or in the metaphase chromosomes, indicating a lack of interaction of methapyrilene with the nuclear macromolecules of the putative target cells for methapyrilene.

Aminopyridines↗
PubMed1982

Metabolism of nitrosomethyl-n-alkylamines in Fischer rats.

To investigate a possible connection between the pattern of the excreted metabolites of a series of nitrosomethylalkylamines and their tumour spectrum in rats, the urinary metabolites of nitrosomethylalkylamines with alkyl chain lengths from C4 (n-butyl) to C14 (n-tetradecyl) have been studied, using male Fischer rats. All of these compounds induced a high incidence of tumours in the rats, but only those with chain lengths of 8, 10, 12 or 14 carbons induced bladder tumours. The principal metabolite from the nitrosamines with an odd number of carbons in the alkyl chain was nitrosomethyl-2-carboxyethylamine. Nitrososarcosine and nitrosomethyl-3-carboxypropylamine were the principal metabolites from those compounds with even-numbered chains. No trend was discernible between the pattern or yields of these acids and the carcinogenic effectiveness. The principal component in the neutral fractions was nitrosomethyl-2-oxopropylamine (less than or equal to 1% of the dose administered). Very small amounts were obtained from the odd-numbered chain compounds, but serially increasing amounts from the even-numbered chain compounds.

Animals↗
PubMed1982

Chemical structural effects in carcinogenesis by nitrosamines.

The effects of changes on chemical structure among groups of closely related nitrosamines on their carcinogenic effectiveness, including both potency and target organ specificity, have been examined by chronic oral administration of the nitrosamines to rats. The effects of deuterium substitution for hydrogen at various positions supports the concept that oxidation at the alpha position to the nitroso function is usually a key step in activation of carcinogenic nitrosamines. Methyl substituents at the alpha position reduce carcinogenic potency, supporting the same idea. A large number of derivatives of nitrosopiperidine have shown a large variation in carcinogenicity, not simply explained by differences in the relative rates of alpha oxidation. The effects of methyl substitution on the carcinogenicity of nitrosomorpholine and nitrosooxazolidine were opposite, although the unsubstituted compounds were of almost identical carcinogenic activity. The variations in the response of rats to a large series of nitrosodialkylamines indicated that they might be metabolized similarly, giving one or more common products which are the proximate carcinogens, and these biological effects can be related to the results of studies of the metabolism of these compounds in rats.

Animals↗
PubMed1982

Transnitrosation by nitrosamines in vivo.

The significance of in vivo transnitrosation in carcinogenesis by the nitrosamines formed was studied by feeding mixtures of morpholine and nitrosamines to rats for most of their lifespan. In some groups, a transnitrosation catalyst (sodium thiocyanate) was fed simultaneously. None of the four nitrosamines induced a significant number of liver tumours when fed singly, although nitrosophenylbenzylamine induced tumours of the spleen and upper gastrointestinal tract and nitroso-N-methylpiperazine induced tumours of the nasal cavity. Nitrosoproline taken with morpholine did not give rise to tumours, except when given in combination with sodium thiocyanate, which gave rise to an even higher frequency of hepatic tumours when given alone. Nitrosohydroxyproline with morpholine induced liver carcinomas in 3 of 20 rats and in 9 of 20 rats in the presence of sodium thiocyanate. Rats given nitrosophenylbenzylamine plus morpholine lived less than 2 years and 4 of them had liver tumours. Most rats treated with nitrosomethylpiperazine died within a year, because of the tumours induced; the combination with morpholine hydrochloride led to the formation of liver carcinomas in 2 of 20 rats and in 5 of 20 when thiocyanate was given.

Animals↗