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PubMed1982

Induction of preneoplastic and neoplastic lesions in rats treated N-nitroso compounds.

Dose-related changes of incidences of pre-neoplastic and neoplastic lesions in the liver or urinary bladder were examined with N-nitroso-dimethylamine (NDMA) or N-nitrosobutyl-4-hydroxybutylamine (NBHA) respectively. The incidences of lesions by the two carcinogens were compared in short-term and long-term experiments. In a short-term experiment, rats were given a basal diet containing NDMA at concentrations of 10.0, 1.0 and 0.1 mg/kg for 6 weeks, after initiation by a single i.p. injection of N-nitrosodiethylamine (NDEA). Similar, long-term experiments (96 weeks) were also performed, but without NDEA pretreatment. A clear dose-related effect was found in the induction of pre-neoplastic lesions when the groups given 10.0 and 1.0 mg/kg NDMA were compared. This coincided with the results of a long-term experiment on the induction of hyperplastic nodules and hepatocellular carcinomas. Various concentrations of 0.05 to 0.005% of NBHA in the drinking water were given for different periods up to 12 weeks, in a short-term, and up to 40 weeks in a long-term experiment. Incidences of early preneoplastic lesions of the cell surface observed by scanning electron microscopy showed a tendency to increase with longer duration and higher dose (0.01 to 0.05%). A clear dose-dependent effect was found for the incidence of papilloma and carcinoma in the groups subjected to longer treatments.

Animals↗
PubMed1982

Mutagenicity of N-nitroso compounds formed by the reaction of sulpyrine with nitrite; effects of cysteine and its derivatives.

Cysteine and its derivatives were tested for their effect on the mutagenic activities of nitrosation products of sulpyrine, 1-diketo-butyryl-1-phenyl-2-methyl-2-nitrosohydrazide hydrate (DPMN) and 4-(N-methyl-N-nitroso)aminoantipyrine (MNAA), using Salmonella typhimurium TA100. The addition of cysteine, cysteamine, cysteine methyl ester, glutathione, 2-mercaptoethanol and homocysteine to the mixture of DPMN and bacteria before pre-incubation markedly increased the mutagenic activity of DPMN in the absence of rat-liver microsomal preparation (S9 mix). An approximately thirty-fold increase in the number of revertants was caused by the addition of cysteine at a concentration of 3 mmol/1. Studies of the structure-activity relationship suggest that a thiol group is necessary in order that the compounds exhibit the enhancing effect and that the thiol compounds having an amino group at the beta-position are more active than the others. Both cysteine and glutathione were rather inhibitory in the development of mutagenesis by MNAA in the presence of S9 mix.

Aminopyrine↗
PubMed1976

Mutagenic selectivity of carcinogenic nitroso compounds: III. N,alpha-acetoxymethyl-N-methylnitrosamine.

A comparative genetic study was undertaken on the testicular tissue of Drosophila with N-alpha-acetoxymethol-N-METHYLNITROSAMINE (AcODMN) and its unsubstituted parent N,N-dimethylnitrosamine (DMN), to assess the role of intracellular metabolism on their mutagenicities. The relative genetic potencies of the two compounds were deduced from regression studies of the dose effect on the metabolically inert sperm and the metabolizing early germ cells (spermatocytes and spermatogonia) with respect to the induction of the non-specific X-chromosome recessives (lethals and visibles) and the specific effects on representatives of the RNA genes, especially rDNA. Genetic activity per unit molar dose was invariably higher for the acetoxy derivative as compared to the parent amine, but the differential in this respect varied significantly for various mutational classes and as a function of the metabolic level in the target cells. The induction of point-mutations (X-recessives) increased with the level of intracellular metabolism with bothe compounds and this was more pronounced with the parent amine, which was in accordance with the DNA methylation mechanism. In contrast, the yield of the specific rDNA deletions was not markedly enhanced with the increased metabolic activity in the early germ cells, especially with the acetoxy derivative. The induction of these deletions could not, therefore, be explained on the basis of DNA methylation, but was reconcilable with the posible generation of a nitroso-aldehydic metabolite, which could effect DNA-protein cross-linkage within the genic nucleoproteins. The two test compounds gave comparable frequencies of mosaicism among corresponding mutations and the same rDNA selectivity index, which indicated identical molecular mechanisms of mutagenesis. The higher genetic potency of the acetoxy derivative as compared to the parent amine would thus be indicative of its greater yield of the same mutagenic metabolites. Carcinogenicity studies with the two compounds paralleled the mutagenicity results, which whould suggest that the same molecular mechanisms could well be responsible for the initiation of both phenomena.

Animals↗
PubMed1976

Comparative studies of neoplastic response to a single dose of nitroso compounds. 5. The effect of dimethylnitrosamine in Swiss, ASW/SN and A-strain mice.

The tumorigenic effect of dimethylnitrosamine given once at 5 different dose levels was compared in adult Swiss, ASW/SN and A-strain mice. Considering the overall tumour incidence, at the highest dose level an increase was found in Swiss and ASW/SN mice, but not in A-strain animals. However, the effect of treatment was unequivocal for lung neoplasms. The rate of carcinomas rose significantly in all 3 strains, although a clear dose response-relationship could be established only in Swiss and ASW/SN mice. A dose-dependent effect for adenomas was found solely in Swiss mice.

Adenoma↗
PubMed1978

[On the carcinogenetic action of N-nitroso compounds. 7th communication: methyl-, trideuteromethyl-, ethyl-, n-propyl-, n-butyl-, acetoxymethyl-nitrosamine, and methyl-butyroxymethyl-nitrosamine (author's transl)].

The homologons alkyl-acetoxymethyl-nitrosamines were tested for carcinogenicity in SD rats. All compounds were found to be carcinogenic and induced within the same time carcinomas of the forestomach. The total doses necessary for induction of tumors are related to the length of the alkyl chain and hence to the watersolubility. These results are discussed.

Alkylation↗
PubMed1979

[Comparative investigations on the organotropic carcinogenic effect of different N-nitroso compounds with rat after single and chronic treatment (author's transl)].

After the gavage of 200 mg N-nitrosodiethylamine per kg body weight only kidney tumors developed while long-term administration of 10 ppm N-nitrosodiethylamine induced esophageal tumors and hepatocellular carcinomas in female rats (SIV 50). This change of the organ-specific carcinogenic effect is not observed in experiments with N-methyl-N-nitrosobenzylamines substituted with a methyl group at the phenyl moiety. Both chronic treatment and single doses induced tumors of the esophagus and the pharynx.

Animals↗
PubMed1979

Comparative studies of neoplastic response to a single dose of nitroso compounds. 6. The effect of diethylnitrosamine in Syrian golden hamsters.

The effect of a single subcutaneous injection of different DEN doses was examined in adult Syrian hamsters observed for life. The minimal effective dose (threshold dose) for neoplastic response, reflected by induction of papillary polyps in the larynx and/or trachea, was 1.03 mg DEN/kg body weight. No tumors were found which could be related to treatment in other segments of the respiratory epithelium nor in other tissues.

Animals↗
PubMed1982

Comparative studies of neoplastic response to a single dose of nitroso compounds. The effect of N-nitrosobis (2-hydroxypropyl)amine in Syrian golden hamsters.

Single s.c. applications of N-nitrosobis(2-hydroxypropyl)amine (BHP) caused carcinogenic effects in adult Syrian golden hamsters at doses as low as 1/40 of the LD50. The tumor spectrum decreased at lower doses, which affected the pancreas more strongly than the liver, whereas higher doses exhibited a more pronounced hepatocarcinogenicity and also induced tumors in the respiratory tract, gallbladder, kidney, and vagina. These results demonstrated a potent pancreatic carcinogenic effect of BHP at the lowest dose level. Hence, the presence of BHP in the environment, even in small quantities, should be regarded as a potential hazard to human health.

Adenocarcinoma↗
PubMed1987

Two types of antimutagenic effects of gallic and tannic acids towards N-nitroso-compounds-induced mutagenicity in the Ames Salmonella assay.

The frequency of his+ revertants induced by N-methyl-N-nitrosourea (MNU) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the strain TA100 of Salmonella typhimurium was decreased by gallic and tannic acid. In weak buffer solutions, the inhibition effects of gallic acid towards MNU and MNNG mutagenicity was caused primarily by a decrease of pH in the incubation mixtures. At adjusted pH (pH 5.0 and 6.5), the antimutagenic effects are largely the result of an interaction between MNU or MNNG with phenolic acids outside the cells.

Gallic Acid↗
PubMed1975

Mutagenic selectivity of carcinogenic nitroso compounds. II. N,N-dimethylnitrosamine.

The genetic properties in the hepatocarcinogen N,N-dimethylnitrosamine (DMN) were examined in Drosophila for the assessment of the role of dose, cellular metabolism and genic target in its mutagenicity. Genetic activity was assayed with respect to the induction of the non-specific X-chromosome recessives (lethals and visibles) relative to the effects on specific genic sites, especially rDNA, which yields bobbed (bb) mutations. Dosses and germ cell types, which indicated that DMN induced at least some multiple-hit mutagenic events. The genetic activity of DMN was favoured by cellular metabolism for all mutational classes, as was indicated by the progressive increase in mutational classes, as was indicated by the progressive increase in mutation yield during spermatogenesis--from the metabolically inert mature sperm to the actively metabolizing spermatocyte and spermatogonia. The role of DNA methylation in the mutagenicity of DMN was deduced from quantitative assays for its genetic activity relative to the methylating nitrosamide--N-methyl-N-nitrosourethane (MNUr)--over the same dose range (1-10 mM) and on identical cell types and genic targets. In the metabolically inert cells (mature sperm), the two compounds were equally active with respect to the non-specific effects (X-recessives), but MNUr, but the two compounds were equally effective on rDNA. These results could not be entirely interpreted by the methylation hypothesis and indicated that a DMN aldehydic metabolite, structurally analogous to MNUr, might be responsible for the induction of the rDNA mutations. The rDNA selectivity index of DMN was significantly lower than for MNUr, which paralleled their relative carcinogenic verstilities. However, DMN was comparatively more effective on the tRNA genes, a feature which might be associated with its oncogenic specificity.

Animals↗
PubMed1980

Nitrosamine carcinogenicity: a quantitative relationship between molecular structure and organ selectivity for a series of acyclic N-nitroso compounds.

A mathematical model has been developed which describes the selectivity between liver and other target organs for a series of carcinogenic N-nitro-sodialkylamines. The relationship requires structural terms for the parent molecule as well as for the potential metabolites. This suggests that the nitrosamine metabolites are involved in tumor induction and that they participate directly in the mechanisms responsible for selecting the target organ.

Animals↗
PubMed1992

Formation of superoxide in the reaction of photolytically altered nifedipine--a nitroso compound--with unsaturated membrane lipids.

Nifedipine, which is unstable at light, is photolytically converted to the corresponding 4-[2'-nitrosophenyl]-pyridine (NTP). We reported earlier that NTP react with unsaturated lipids in a pseudo Diels-Alder reaction, thus forming stable nitroxide radicals. In this paper we report that superoxide is being generated in the latter reaction. Superoxide formation was evidenced by SOD-inhibitable cytochrome c reduction in the reaction of NTP with egg phosphatidylcholine at molar ratio 1:1, and 1:3. In this reaction an ESR-observable nitroxide radical was formed. Maximum nitroxide formation was observed after 90 min; the addition of SOD (93 units/ml) increased the concentration of nitroxide. This effect of SOD was reversed by catalase, indicating involvement of hydrogen peroxide in this effect. The nitroxide radical formation appears to be metal-independent, since neither iron salts, nor an iron chelator, desferal, influenced the nitroxide formation. Although production of superoxide in our system was only observed at high concentrations of NTP and of unsaturated lipids, this reaction may be of potential cytotoxic significance due to redox cycling of the nitroxide/hydroxylamine couple in cellular systems.

Chelating Agents↗