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At least 19 recordsLinked to original sources
PubMed1990

Several known indole compounds are not important precursors of direct mutagenic N-nitroso compounds in green cabbage.

In this study we investigated the role of indole-3-acetonitrile, indole-3-carbinol, indole and tryptophan in the formation of N-nitroso compounds in green cabbage extracts. Green cabbage extracts were separated by gel permeation chromatography. Fractions were treated with nitrite, tested for mutagenicity and analysed for total N-nitroso content. Fractions in which spiked indole-3-acetonitrile, indole-3-carbinol, indole and tryptophan eluted appeared to be low in mutagenic activity and contained relatively small amounts of N-nitroso compounds. To detect indole compounds other than the ones used in the gel permeation chromatography experiments, high-performance liquid chromatography and gas chromatography-mass spectrometry analyses were performed of green cabbage extracts. Indole-3-carboxaldehyde was found to be the most commonly occurring indole compound, but it did not show direct mutagenic activity upon nitrite treatment. Indole-3-acetonitrile was the second most common compound; although it was mutagenic after nitrite treatment, its contribution to the mutagenicity of nitrite-treated green cabbage was roughly estimated to be only 2%. No other indole compounds were detected. From this study we conclude that neither the tested indole compounds nor indole-3-carboxaldehyde play a significant role in the formation of direct mutagenic N-nitroso compounds in nitrite-treated green cabbage extracts.

Brassica↗
PubMed1989

N-nitroso compound formation in human gastric juice.

The gastric formation of N-nitroso compounds probably constitutes a major source of human exposure to this important class of environmental carcinogens. Following reduction of nitrate to nitrite by oral or gastric bacteria, reaction with nitrogenous constituents of gastric juice can occur leading to the in situ formation of N-nitroso compounds, probably primarily derived from amides, ureas or aromatic amines. While gastric nitrite concentrations are raised in the achlorhydric relative to the normal stomach, the latter, owing to its acidity, offers a particularly favourable environment for the formation of N-nitroso compounds, as indicated by the finding of greatly increased gastric concentrations of N-nitroso compounds following an oral dose of nitrate. This illustrates the importance of the dynamic nature of the relationships between the various parameters involved in the formation of N-nitroso compounds. While in principle the same is true of the process of inhibition of nitrosation by reducing agents such as ascorbic acid (since, depending on the relative concentrations of reducing agent, nitrite and oxygen, inhibition or catalysis of nitrosation can occur), ingestion of 1 g ascorbic acid brings about a significant reduction in the gastric concentration of N-nitroso compounds.

Animals↗
PubMed1989

Environmental exposure to preformed nitroso compounds.

In the human environment, nitrosatable amine precursors to N-nitroso compounds and nitrosating species such as nitrite and oxides of nitrogen are abundant. As a result, the formation of N-nitroso compounds and human exposure to these compounds show a rather complex pattern. The largest known human exposures to exogenous N-nitrosamines occur in the work place. This is particularly evident in the rubber and tyre manufacturing industry and in metal cutting and grinding shops. Nearly all industries which are concerned with the production and/or use of amines have a related nitrosamine problem. Outside the industrial environment, commodities such as cosmetics, pharmaceuticals, rubber and household products, which are either prepared from amines or contain high concentrations of amino compounds, may be subject to contamination by low concentrations of N-nitroso compounds. This contamination may result from the use of contaminated starting materials, in particular amines, or from the formation of N-nitroso compounds during manufacturing processes. A similar problem exists with agricultural chemicals. As our knowledge of the occurrence and formation of N-nitroso compounds in the environment increases, preventive measures can be introduced, particularly in manufacturing industries, to reduce the levels of human exposure to nitrosamines in the work place and to protect the consumer from nitrosamine exposure from household commodities.

Air Pollution↗
PubMed1988

Intestinal cancer induced by N-nitroso compounds.

Several N-nitroso compounds induce tumors of the colon, and some induce tumors in other parts of the intestinal tract as well. The nitrosamines that induce colon tumors are beta oxidized n-propyl-nitrosamines. These require metabolic activation, as do 1,2-dimethylhydrazine, azomethane, and azoxymethane, another group of colon carcinogens. Several nitrosoalkylureas induce tumors in rat colons after oral administration, although the monoalkylnitrosoureas are fairly unstable and might not be expected to reach the colon. However, monoalkylnitrosoureas are equally effective with the much more stable dialkylnitrosoureas. Although nitrosomethylurea did not induce colon tumors under these conditions, nitrosoethylurea did, together with nitrosodiethylurea and other nitrosoethylalkylureas. Nitroso-n-butyl-, n-amyl-, n-hexyl-urea, and nitrosohydroxyethylurea also induced colon tumors, but the last, like nitrosoethylurea, also induced tumors of the duodenum and ileum. In most of these experiments male rats were more susceptible to induction of intestinal tumors than female rats. An explanation for the differences between these compounds of similar structure might be found in variations in their ability to alkylate DNA in intestinal cells, or in differences in stability of the alkylated product between the compounds. The physical properties of the compounds might also modulate the process of carcinogenesis, however.

Alkylation↗
PubMed1976

[N-nitroso compounds. Analysis and possible carcinogenicity in man].

Much work has been carried out on N-nitroso compounds but their role in human pathology has still to be elucidated. We cannot extrapolate experimental data to the human situation but we do have indirect evidence that nitroso compounds can be carcinogens in man. Although some nitrosamines are organ-specific, the nitroso group induces the development of many different types of cancer in animals It is probable that the same phenomenon occurs in human pathology, and we cannot therefore expect to have special case reports on their carcinogenicity in man. Therefore, an alternative approach to the study of the role of nitrosamines in human pathology would be to establish a correlation between cancer morbidity in some regions and amounts of N-nitroso compounds in the environment. In view of the complexity of the problem of in vivo nitrosamine formation, it is more realistic nowadays to measure exogenous nitrosamines. Many laboratories are currently engaged on studies on N-nitroso compounds, although systematic information on their presence in the environment is scant. Furthermore, the data acquired by different laboratories has been obtained using a variety of methods for sampling, storage, clean-up and identification and estimation, with the result that it is not known to what extent these results are comparable.Therefore, the standardization and determination of comparability of methods for the identification of N-nitroso compounds is the first step towards their quantitation in the environment. Adequate methods are now available for the determination of volatile nitrosamines, down to the mug/dg level, but methods for non-volatile nitrosamines are still in the development stages. In order to avail all interested laboratories of information on analytical methods for volatile nitrosamines, IARC's analytical chemistry laboratory has organized a three part collaborative study using samples of canned luncheon meat. The results of this study were encouraging, and the European Sub-Committee for the Guidance of Collaborative Studies, at its last meeting, recommended that such studies be continued and extendedto include non-volatile nitrosamines. In parallel with the perfection of analytical techniques, IARC has initiated studies on the measurement of volatile nitrosamines in the environment in conjuction with the epidemiological studies on oesophageal cancer at present being carried out. The data collected up to now is far from being complete but it is important in that it represents the first step towards the evaluation of the risk to health of N-nitroso compounds, which constitute a part of the total carcinogenic load in the human environment.

Animals↗
PubMed1991

Occurrence of and exposure to N-nitroso compounds in tobacco.

The concentrations of 21 N-nitroso compounds in smokeless tobaccos are presented. Tobacco-specific nitrosamines accounted for 70-90% of the total identified N-nitroso compounds. Daily exposure of smokeless tobacco users to preformed N-nitroso compounds may exceed 200 micrograms/day in certain populations.

Humans↗
PubMed1979

Computer assisted structure-activity studies of chemical carcinogens. An N-nitroso compound data set.

N-nitroso compounds, consisting of nitrosamines and nitrosamides, are potentially important in the etiology of human cancer. An attempt to study the molecular structure-carcinogenicity relations of these compounds is reported. A pattern-recognition approach was used to develop predictive ability for carcinogenic potential. A set of 15 calculated molecular structure descriptors that supported a linear discriminant function able to successfully separate 116 carcinogens from 28 noncarcinogens was identified. Predictive ability of an overall of 91%--93% for carcinogens and 85% for noncarcinogens--was obtained in the randomized testing. This relatively high predictability demonstrates that pattern-recognition methods can be useful in analyzing these compounds for carcinogenic activity. The inclusion of two electronic descriptors implicitly supports the alpha-hydroxylation hypothesis. The relations of descriptors used and possible mechanism of action are discussed.

Amides↗
PubMed1991

Inhibition by fatty acids of direct mutagenicity of N-nitroso compounds.

Fatty acids inhibited the direct mutagenicity of N-nitroso compounds in Salmonella typhimurium TA1535, Escherichia coli WP2 and WPhcr-, and E. coli H/r30R (wild) and Hs30R (uvrA). This inhibitory activity was dependent on the concentration of fatty acids, and fatty acids with longer alkyl chain were more potent. Of the N-nitroso compounds tested, alpha-hydroxy nitrosamines underwent the strongest inhibitory effect. The rate of decomposition was not changed by addition of fatty acids. The partitioning property of the mutagens was altered but not to such a degree as to explain the amount of inhibition. No significant difference in alkylating activity of the N-nitroso compounds was observed in phosphate and acetate buffers. A stronger inhibition of mutagenicity by a butylating mutagen was detected in E. coli WP2 than in WP2hcr- and in E. coli H/r30R than in Hs30R, suggesting that excision repair was a possible mechanism of inhibition. The mutagenicity and cytotoxicity of alpha-hydroxy nitrosamines in Chinese hamster V79 cells were also inhibited by acetate.

Animals↗
PubMed1989

Reduction of aryl-nitroso compounds by pyridine and flavin coenzymes.

1. A systematic kinetic investigation of the reduction of aryl-nitroso compounds by pyridine and flavin coenzymes and their analogs, in enzymatic and nonenzymatic systems, has been reported. 2. Two main groups of nitroso compounds have been investigated, representatives nitroso-benzene and 1-nitroso-2-naphthol; in all enzymatic and nonenzymatic systems, the former was always reduced to phenyl-hydroxyl-amine and the latter to 1-amino-2-naphthol. 3. Pyridine compounds included NADH, APAD-4H2 and DBNA-4H2 in nonenzymatic systems, and liver alcohol dehydrogenase. Flavin compounds included 1,5-dihydrolumiflavin and various forms of reduced 5-ethyl-lumiflavin, in nonenzymatic systems, and the flavoenzymes glucose-oxidase and NADPH-cytochrome P450 reductase. 5. Pyridine coenzymes and their analogs reduced nitroso compounds by a direct hydride transfer, with a primary kinetic isotope of 9.5 +/- 2.2. 6. All flavin compounds (glucose-oxidase and its nonenzymatic analog 1,5-dihydrolumiflavin and NADPH-cytochrome P450 reductase and its analog 5-ethyl-1,5-dihydrolumiflavin) reduced aryl-nitroso compounds with high efficiency (k2 greater than 10(5)M(-1) min(-1)). 7. The flavin compounds have been shown to be much more efficient reductans of nitroso compounds, compared to pyridine coenzymes, both in enzymatic and nonenzymatic systems; the only exception to this rule presented the extremely efficient reduction of p-substituted aryl-nitroso compounds by liver alcohol dehydrogenase.

Anaerobiosis↗
PubMed1978

Comprehensive analytical procedures for the determination of volatile and non-volatile, polar and non-polar N-nitroso compounds.

The first comprehensive analytical procedures for the quantitative analysis of N-nitroso compounds are described. The scheme divides N-nitroso compounds into four major, overlapping categories: volatile (Class I), non-volatile, low polarity (Class II), non-volatile, non-ionic, high polarity (Class III) and non-volatile, ionic, high polarity (Class IV). Existing analytical techniques for each class of compound are integrated into an organized and logical sequence of analysis to allow all classes of compounds to be determined. TEA-GC is used for the volatile compounds and TEA-HPLC for the non-volatile. It is emphasized that the coincidence of retention time in either TEA-GC alone or TEA-HPLC alone cannot be taken as sufficient evidence for the identification of N-nitroso compounds, especially for samples from complex matrices. Independent techniques are required to confirm these results. The confirmatory techniques used frequently in our laboratory are: (1) spectroscopic analysis (IR, NMR, UV and MS), (2) formation and identification of derivatives, and (3) parallel TEA-GC/TEA-HPLC techniques. These procedures are now used at Thermo Electron for the comprehensive screening of environmental samples.

Chemical Phenomena↗
PubMed1976

The effects of some carcinogenic nitroso compounds on the rat liver nucleolus.

The hepatocyte nucleoli of rats undergo a variety of specific and nonspecific alterations after the administration of 8 nitroso compounds and 5 corresponding non-nitroso compounds. After the oral administration of dimethylnitrosamine and diethylnitrosamine, and unusual segregation of the nucleolus was encountered in the cells with karyorrhexis. Most characteristic of the segregation are the scattered ribosome-like granules at the outermost layer of the altered nucleolus. Frequently microspherules with halos 150 nm in diameter are found in all rats treated with nitroso compounds, which have been reported to be carcinogenic in the organs other than the liver. With the exception of butylurea and butylamine no such specific microspherules were found in the nucleoli after the administration of corresponding non-nitroso compounds.

Animals↗
PubMed1989

The occurrence of N-nitroso compounds in kiwam tobacco.

The concentrations of tobacco-specific nitrosamines (TSNA), volatile and non-volatile N-nitroso compounds in kiwam, a fermented Indian tobacco product are presented. Total identified N-nitroso compound concentrations in kiwam ranged from 6.19 to 25.4 mg/kg fresh weight tobacco, the concentration range of TSNA was 5.43-22.2 mg/kg tobacco which accounted for 67-87% of the total identified N-nitroso compound burden. The high concentrations of TSNA found in kiwam tobacco may present a considerable exposure source to carcinogenic N-nitroso compounds for people using this type of tobacco.

India↗
PubMedDate not supplied

Formation of mutagenic N-nitroso compounds in vegetable extracts upon nitrite treatment: a comparison with the glucosinolate content.

More than 30 vegetables were screened for their potential to form biologically active N-nitroso compounds upon treatment with nitrite under acidic conditions. The total N-nitroso content was determined in the nitrite-treated and untreated extracts of the vegetables according to a modified method of Walters et al. (Analyst, Lond. 1978, 103, 1127). All treated extracts contained N-nitroso compounds at levels ranging from 23 to 789 nmol/25 mg dry matter. In the same samples the mutagenic activity was determined using the Salmonella typhimurium assay. About half of the vegetables were found to be mutagenic upon nitrite treatment. (Nitrite-treated extracts were considered to be mutagenic if the number of induced revertants was at least twice as high as that induced by the corresponding untreated extract). The content of different glucosinolates in the dry matter of the vegetables was also determined. Glucosinolates could be detected only in cruciferous vegetables, at levels ranging from 1.8 to 26.0 mumol/g dry matter. Although the nitrite-treated extracts of brassica species contained more N-nitroso compounds and induced more revertants than did other vegetables, there was no significant correlation between these parameters. However, the amounts of N-nitroso compounds formed upon nitrite treatment (expressed per fresh weight) did correlate significantly (P less than 0.01) with the amounts of glucosinolates (r = 0.95). When the glucosinolates were divided into aryl/alkyl- and indolyl-glucosinolates, the significant correlation was maintained for both subgroups (r = 0.93 and 0.95, respectively). From this it can be concluded that glucosinolates are probably involved in the formation of N-nitroso compounds in certain nitrite-treated vegetables.

Glucosinolates↗
PubMedDate not supplied

Mutagenesis by N-nitroso compounds: relationships to DNA adducts, DNA repair, and mutational efficiencies.

The relationships between DNA alkylation, DNA repair and mutagenesis by N-nitroso compounds in Salmonella were examined. DNA adducts formed by treatment of the bacteria with N-nitroso compounds were monitored. Critical to the study was establishing which adducts led to mutations. Two methods were employed. In one, correlations in the dose-responses for adducts and mutagenesis were sought. For instance O6-methyl- and -ethyl-guanine, in contrast to other adducts, exhibited thresholds in their accumulation in Salmonella DNA, and mutagenesis at GC base pairs also exhibited the same threshold, suggesting a dependence of mutagenesis on the O6-alkylguanines. In the second method, mutagenesis induced by different mutagens with overlapping adduct spectra was compared. For example, EMS and ENU generate similar ratios of adenine adducts, but only ENU produces thymine adducts, and only ENU induced AT-GC and AT-CG base changes. These observations suggested that ethylthymines led to these mutations. Furthermore, it was found that these mutations were largely dependent on the presence of the plasmid, pKM101, indicating that error-prone repair activity contributes importantly in their processing to mutations. When DNA adducts by N-nitrosopyrrolidine were examined it was found that only one major adduct was detected in an excision-repair-deficient strain, and that this adduct was not present in a repair-proficient strain. Mutagenesis was also greatly reduced in the proficient strain, suggesting that mutagenesis was dependent on this adduct. From the relationships between premutagenic adduct levels and mutagenesis it was possible to calculate estimated values for the mutational efficiencies for several adducts. This calculation assumed an average distribution of adducts and mutations and required knowledge of the target size and the types of mutations that could lead to phenotypic changes. For the unrepaired O6-methyl- and -ethyl-guanines, and the O-ethylthymines the mutational efficiencies were high (ca. 30-70%), but for the N-nitrosopyrrolidine adduct it was low (ca. 1%). Initial studies were carried out on the mutational specificities of two higher homologue N-nitroso compounds (the N-nitroso-N-propyl- and N-butyl-nitroguanidines) in uvrB/pKM101 strains. This class of nitroso compounds is known to form similar DNA adducts as ENU. Their specificities were similar to that of N-nitroso-N-ethylurea at a high dose except the fraction of mutations at AT base pairs was reduced. The fraction of GC-CG transversions was although low, increased. The mutational specificities of N-nitroso-N-methylurea and N-nitrosopyrrolidine were significantly different from the specificity of E

Alkylation↗
PubMed1992

Carcinogenesis and mutagenesis by N-nitroso compounds having a basic center.

Two N-nitroso compounds that are derivatives of N,N-dimethylethylenediamine and are therefore strongly basic, were tested for carcinogenic activity. They were methylnitrosamino-N,N-dimethylethylamine (MNDMEA) and N,N-dimethylaminoethylnitrosoethylurea (DMENEU). Each was administered orally to male and female F344 rats by gavage. MNDMEA was also given by gavage to Syrian hamsters and to rats as a solution in drinking water. The response of rats treated with MNDMEA was almost the same by the two modes of treatment and all developed tumors of the esophagus and died in less than 40 weeks; many also had tumors of the nasal mucosa. Hamsters were less susceptible to the nitrosamine than rats, since they survived longer following a larger dose and the tumor incidence was small; several hamsters had tumors of the nasal mucosa, some males also had tumors of the liver and lung and one male and two females had a tumor of the colon. Although it is a strong directly acting mutagen, dimethylaminoethylnitrosoethylurea was weakly carcinogenic in rats, giving rise to tumors of the uterus and mammary gland in females, but having no particular target organ in male rats. The presence of a basic center in these N-nitroso compounds does not prevent their absorption nor their entry into cells, which they can transform to tumors.

Administration, Oral↗
PubMed1979

N-Nitroso compound contaminants in prescription and nonprescription drugs.

73 pharmaceutical products, consisteing of both prescription and over-the-counter drugs have been analyzed by gas chromatography-thermal energy analysis (GC-TEA) and high-pressure liquid chromatography-thermal energy analysis (HPLC-TEA) for the presence of N-nitroso compound contaminants. The methods used were designed to detect both volatile and non-volatile N-nitroso compounds at levels down to 1 ng/g (1 ppb). Results presented here indicate that N-nitroso compound impurities are absent from the majority of the products tested. However, for 3 of the drugs, our analysis suggests the possible presence of N-nitroso compounds at levels up to 81 ng/g (81 ppb). The identity of the suspect N-nitroso compounds have not yet been established. In the case of the over-the-counter drugs, two of these have been shown to contain TEA responsive materials (126 ppb, 406 ppb), that may appear to be O-nitroso compounds rather than N-nitroso.

Chemical Phenomena↗
PubMed1989

Mechanisms of action of N-nitroso compounds.

There is ample evidence from studies in experimental animals that N-nitroso compounds are carcinogenic because in the body they form potent electrophilic alkylating agents. These reactive intermediates are formed by spontaneous decomposition in the case of nitrosoureas and related compounds, or by metabolic activation in the case of N-nitrosamines. The electrophiles subsequently react with DNA of target tissues to form altered bases which leads to the initiation of carcinogenesis. There is now convincing evidence that the biological activity of N-nitroso compounds in humans does not differ substantially from that in experimental animals. We can therefore predict with a high degree of confidence that N-nitroso compounds including nitrosamines are carcinogenic in man.

Animals↗