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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↗
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↗
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↗
PubMed1991

Specificity in the methylation of DNA by N-nitroso compounds.

A sequencing assay was used to determine the reactivity of N-nitroso compounds that are simple methylating agents with individual nucleotides in a defined DNA sequence. The maximal difference in reactivity between guanines is about five fold. DNA in the Z, cruciform and H conformations was shown to be methylated by N-methyl-N-nitrosourea in a manner which was indistinguishable from the reactivity of B-DNA. Electronic factors rather than steric factors appear to dominate the methylation reaction. Transcriptionally active genes were shown to be methylated by N-nitroso compounds in vivo more extensively than untranscribed genes. The results suggest that local sequence, secondary conformation and transcriptional activity may all influence the carcinogenic potential of N-nitroso compounds.

Base Sequence↗
PubMedDate not supplied

Volatile, non-volatile and total N-nitroso compounds in bacon.

Twenty-five smoked and unsmoked fried bacon samples have been analysed by a group selective procedure to measure the concentration of apparent total N-nitroso compounds (ATNC). The levels of a range of individual N-nitroso compounds, including simple volatile N-nitrosamines, N-nitrosothiazolidines, N-nitrosamino acids and N-nitrosothiazolidine carboxylic acids have also been examined. Concentrations of ATNC varied from 430 to 6800 micrograms(N-NO)/kg with a mean of 2700 micrograms(N-NO)/kg. Protein-bound N-nitrosoproline was the most abundant compound detected in unsmoked bacon, mean 260 micrograms/kg, and on average accounted for 4% of the ATNC concentration. For smoked bacon, bound N-nitrosoproline was detected in levels of up to 890 micrograms/kg and contributed 5% to the ATNC total. The most abundant compound present in smoked bacon was N-nitrosothiazolidine-4-carboxylic acid, mean 660 micrograms/kg, and this accounted for 6% of the ATNC. N-Nitrosothiazolidine, mean 340 micrograms/kg, and 2-(hydroxymethyl)-3-nitrosothiazolidine-4-carboxylic acid, mean 180 micrograms/kg, were the next most prominent compounds detected in smoked bacon. The combined sum of all the individual N-nitroso compounds measured accounted for, on average, 16% of the total ATNC. The identities of the N-nitroso compounds comprising the majority of the ATNC in bacon remain unknown.

Animals↗
PubMed1976

N-nitroso compounds: detection in ambient air.

By use of a new, highly selective detection technique for N-nitroso compounds, which is sensitive to picogram quantities and which is based on the catalytic cleavage of the N-NO bond and the subsequent detection of the nitrosyl radical, dimethylnitrosamine has been found in concentrations of 0.02 to 0.96 part per billion in three out of five air samples from Baltimore, Maryland, and 0.014 to 0.051 part per billion in five out of six air samples from Belle, West Virginia. The sensitivity of the analytical procedures used was 1 part in 10(12). The presence of dimethylnitrosamine has been confirmed by using the new detector in conjunction with both a gas-liquid chromatograph and a high-performance liquid chromatograph. In addition, between one and three as yet unidentified N-nitroso compounds were detected in both cities. N-Nitroso compounds were not found in air samples from Philadelphia, Pennsylvania; Wilmington, Delaware; and Waltham, Massachusetts.

Air Pollutants↗
PubMed1976

The relation between the determinable quantities of volatile N-nitroso compounds and the peroxide number in soya bean oil.

Comparative studies of soya bean oil with and without addition of N-nitroso compounds (NDMA and NDEA) at different hydroperoxide concentrations have shown that the determinable quantities of substances having the retention time of N-nitroso compounds in soya bean oil and of nitrosoamines added to the oil are dependent upon the peroxide number. The determination was carried out by gas chromatography (nitrogen detector, nitrogen-sensitive, flame-ionization detector) prior to and following irradiation with UV light (360 nm). When the peroxide number was above 4, the determinability and the recovery were reduced by more than 60 per cent. In advanced autoxidation and after reduced recoveries, large amounts of NMDA and NDEA may be encountered for a short time. A possible linkage between N-nitroso compounds and peroxide is discussed. Comparative investigations of soya beans, crude oil, intermediates and commercially available steamed oils have revealed that the concentrations of the compounds with NDMA and NDEA properties in crude oil (peroxide number about 3) is higher than in soya beans. The recovery of these compounds is very poor in intermediate products with high peroxide numbers (about 5 to 9). However, N-nitroso compounds can be demonstrated in commercially available oils treated with steam (peroxide number about 0.7), although to a lesser extent than in crude oil.

Chemical Phenomena↗
PubMed1991

Endogenous N-nitrosation in man assessed by measurement of apparent total N-nitroso compounds in faeces.

The faecal concentration of substances responding to the chemical test for N-nitroso compounds (apparent total N-nitroso compounds, ATNC) was investigated in human subjects consuming their normal free-choice diet. Concentrations ranged from 40 to 590 micrograms (N-NO)/kg faeces. To ascertain the likely relative contributions of endogenous ATNC formation and preformed, dietary ATNC, the subjects consumed a diet low in nitrate and ATNC for 8 days. At the end of this period, ATNC had decreased substantially with concentrations ranging from below the 40 micrograms (N-NO)/kg detection limit up to 143 micrograms (N-NO)/kg, mean 82 micrograms (N-NO)/kg. On supplementing this diet with 300 mg nitrate/day, faecal ATNC levels increased markedly. On the third day of this regime, values were in the range 73-714 micrograms (N-NO)/kg with a mean of 307 micrograms (N-NO)/kg. The results, together with the known limited occurrence of ATNC in the majority of foodstuffs so far tested, generally non-detectable or less than 100 micrograms (N-NO)/kg, suggest that endogenous formation via species derived from dietary nitrate is likely to be an important source of ATNC in human faeces.

Adult↗
PubMedDate not supplied

Determination of N-nitroso compounds by high-performance liquid chromatography with postcolumn reaction and a thermal energy analyzer.

Carcinogenic nonvolatile N-nitroso compounds have been difficult to determine in foods and other consumer products because of the incompatibility of aqueous high-performance liquid chromatography (HPLC) mobile phases with the thermal energy analyzer (TEA), a sensitive and selective detector for N-nitroso compounds. A postcolumn technique has been developed that permits the use of aqueous mobile phases with an interfaced liquid chromatograph/TEA. This system was linear from 3.5 to 900 ng of N-nitrosoproline injected. Coefficients of variation of 3.0 and 5.1%, respectively, were obtained when N-nitrosoproline and N-nitrosotrimethylurea were repeatedly injected at the 80- to 90-ng level. Mixtures of volatile and nonvolatile N-nitroso compounds as well as N-nitrosodipeptides were separated and quantitated by HPLC/TEA with a water/acetonitrile gradient.

Chemistry Techniques, Analytical↗