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PubMed1993

N-nitroso compounds in fresh gastric juice and their relation to intragastric pH and nitrite employing an improved analytical method.

In order to examine further the relationship between intragastric N-nitrosation, gastric pH and nitrite, 457 fresh, fasting gastric juice samples were analysed for total N-nitroso compounds (NOC) and nitrite concentrations using a recently described improved assay method. Nitrite in log values was linearly related to intragastric pH (r = 0.887, P < 0.01) with a regression equation log[nitrite] (mumol/l) = 0.489 x pH - 2.209. Significantly higher NOC concentrations were found at intragastric pH ranges of 1.13-2.99 (mean +/- SE: 1.45 +/- 0.17 mumol/l, P < 0.05) and 6.00-8.42 (3.57 +/- 0.33 mumol/l, P < 0.01) compared with that at pH 3.00-5.99 (1.02 +/- 0.12 mumol/l). NOC concentration was significantly related to log nitrite concentration at both the low pH range 1.13-4.99 (r = 0.169, P < 0.01) and the high pH range 5.00-8.42 (r = 0.450, P < 0.01). The results in the present study confirm that both acid-catalysed N-nitrosation and biologically-catalysed N-nitrosation occur in the human stomach. However, great variations in nitrite and NOC concentrations were observed in both low and high pH samples, indicating that, as expected, both the acid-catalysed N-nitrosation and biologically-catalysed N-nitrosation processes are markedly affected by factors other than intragastric pH and nitrite.

Gastric Juice↗
PubMed2001

Sulfur-to-nitrogen transnitrosation: transfer of nitric oxide from S-nitroso compounds to diethanolamine and the role of intermediate sulfur-to-sulfur transnitrosation.

S-Nitrosothiols are formed in vivo and are involved in NO signaling. We investigated the sulfur-to-nitrogen transnitrosation activity of S-nitrosocysteine, S-nitrosoglutathione, S-nitrosohomocysteine, S-nitrosocysteinylglycine and S-nitroso-N-acetylcysteine in their reaction with the secondary amine diethanolamine in vitro. The resulting N-nitrosodiethanolamine, a strong carcinogen, was formed in yields of up to 11% from S-nitrosocysteine and S-nitrosocysteinylglycine, whereas the transnitrosation activity of the other S-nitroso compounds was weak. However, the addition of L-cysteine to a solution of S-nitrosohomocysteine and diethanolamine accelerated the decomposition of S-nitrosohomocysteine and resulted in a significant formation of N-nitrosodiethanolamine accompanied by the intermediate generation of S-nitrosocysteine. Thus, reactive nitrosothiols can be formed from less reactive analogs via sulfur-to-sulfur transnitrosation. We suggest that this affects regulation of NO trafficking in vivo. The reaction provides an alternative mechanism for the generation of carcinogenic N-nitroso derivatives.

Chromatography, High Pressure Liquid↗
PubMed1981

An assessment of carcinogenicity of N-nitroso compounds by the SIMCA method of pattern recognition.

The ability to predict the toxic responses of potential environmental pollutants on the basis of their physiochemical properties has many advantages. Pattern recognition methods can be used to predict such pharmacological properties. In this report the SIMCA method of pattern recognition is used to predict the carcinogenicity of N-nitroso compounds, and the advantages of this method of pattern recognition in such applications are discussed.

Carcinogens↗
PubMed1992

Mutational specificities of N-nitrosamines in a host-mediated assay: comparison with direct-acting N-nitroso compounds in vitro and an approach to deducing the nature of ultimate mutagens in vivo.

The mutational activities and specificities of several N-nitrosamines in Salmonella recovered from mouse liver in the host-mediated assay (HMA) were compared with the specificities of related direct-acting N-nitroso compounds in vitro. The specificities of the direct-acting methyl, ethyl, propyl, and 2-hydroxypropyl compounds were all different and presumably are attributable to the DNA adducts resulting from the corresponding alkyldiazonium or carbonium ions. Introduction of a 2-hydroxyl group greatly influenced the mutational specificity. The 2-oxopropyl compound showed the same specificity as the methyl compound. This result is consistent with one of the known breakdown pathways of the oxopropyl diazonium ion (or related reactive species), which leads to a methyl diazonium ion. The N-nitrosodialkylnitrosamines N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosodipropylamine (NDPA), which all require metabolic activation, showed specificities in the HMA similar to those of their direct-acting counterparts. The cyclic nitrosamine N-nitrosopyrrolidine was weakly active in the HMA, although its direct-acting derivative was a potent mutagen in vitro. The results for NDMA and NDEA were consistent with most previous studies of the metabolism of these compounds in vivo. However, NDPA can yield methylating, and probably hydroxypropylating, species in addition to propyldiazonium ion. As the specificity of NDPA was similar to that of a propylating agent, NDPA appears to lead to genotoxic products in the mouse liver mainly by direct alpha-hydroxylation. The initial results described here indicate that mutational specificity in the HMA can be used to deduce metabolic pathways leading to genotoxic products when the appropriate proximate mutagens are available as standards. Furthermore, we observed a reasonable correlation between potency in the HMA and hepatocarcinogenesis.

Animals↗
PubMed1978

Recent studies in Canada on the analysis and occurrence of volatile and non-volatile N-nitroso compounds in foods.

The present paper briefly summarizes the research activities of the Food Research Laboratories, Canadian Health Protection Branch, during the past two years. Data presented indicate that traces of nitrosamines, mainly nitrosodimethylamine and nitrosodiethylamine, can occur in cheese. Several new analytical methods are presented for the determination of non-volatile nitroso compounds, such as nitrosohydroxypyrrolidine, nitrosodiethanolamine, nitrosoproline, nitrosohydroxyproline and nitrosoglyphosphate (a nitrosated herbicide). It is shown that all of the above compounds, even the very polar nitrosoglyphosphate, can be converted to volatile derivatives and then analysed by GLC-MS or by conventional GLC using a specific (such as P-photometric) detector. Traces of nitrosohydroxypyrrolidine have been detected in a few samples of cooked bacon. Contrary to previously reported findings, no significant levels of nitrosoproline were detected in the 6 samples of raw bacon analysed.

Animals↗
PubMed1991

Gliomas and meningiomas in men in Los Angeles County: investigation of exposures to N-nitroso compounds.

We conducted a case-control study of primary tumours of the brain and cranial meninges in Los Angeles County to investigate the hypothesis that these tumours are related to occupational exposures. We also collected limited data on diet and personal habits that are likely to involve exposure to N-nitroso compounds (NOC), NOC precursors and modulators of NOC metabolism. Interviews were conducted with 272 men with a brain tumour diagnosed in 1980-84 and with 272 individually matched neighbourhood controls. The study was of sufficient size to allow for separate analyses of the 202 pairs of glioma patients and of the 70 patients of meningioma. Six glioma cases and one control had worked in the rubber industry, in which excesses of brain tumour have been shown in previous studies and where there are high levels of volatile NOC at various work sites. Ten meningioma patients and five controls had used cooling, cutting or lubricating oils, and most had used these daily (eight cases; four controls). Cases and controls were not different, however, with respect to other occupations known to involve exposures to NOC. Cases and controls also did not differ in their consumption of alcoholic beverages or cigarettes or in their passive exposure to cigarette smoke. The most striking dietary finding was a significant protective effect among glioma pairs of use of vitamin supplements, which increased with increasing frequency of use (p for trend = 0.04; odds ratio for use at least twice a day = 0.4 (95% confidence interval = 0.24-0.77)).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

N-nitroso compounds as a cause of human cancer.

Simultaneous consideration of epidemiological and experimental findings leads to the conclusion that the tobacco-specific nitrosamines (TSNA) 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) probably cause oral and respiratory cancers in humans. The role of other N-nitroso compounds (NOC) in the etiology of human cancer may best be defined by the study of known human carcinogens, such as certain foods eaten exclusively by populations with exceptionally high incidences and mortality rates for certain cancers. The evidence that NOC may be responsible for these elevated rates is reviewed in relation to two such high-risk populations: (i) residents of Lin-xian county in northern China, who have a striking excess of cancer of the oesophagus, and (ii) Cantonese people who have high rates of nasopharyngeal carcinoma (NPC). More studies are needed to define clearly the relationship between various types of cancers and prenatal or lifetime exposures to passive smoking. If passive smoking is found to increase the risk of developing various childhood and adult cancers, the NOC in tobacco are likely to be among the relevant carcinogens. Carcinogenesis models for studying the effects of prenatal exposure to NNK and NNN and other NOC seem particularly promising for the study of low-dose effects and modifying factors.

Adult↗
PubMed1996

N-nitroso compounds induce changes in carcinogen-metabolizing enzymes.

The bioactivation of N-nitrosoamines and polycyclic aromatic hydrocarbons (PAH) is mediated by the mixed function oxidase system, which includes dimethylnitrosamine N-demethylase I (DMN-dI), arylhydrocarbon hydroxylase (AHH), cytochrome P-450, cytochrome b5 and NADPH-cytochrome c reductase of liver microsomes. The present study shows the influence of N-nitroso compounds on the activities of the above-mentioned enzymes. Single-dose treatment (20 mg/kg body weight) of male mice with ethylbutylnitrosamine, propylbutylnitrosamine, or dibutylnitrosamine: increased (1) the activity of DMN-dI by 108%, 104%, 51%, respectively; (2) the cytochrome P-450 content by 106%, 72%, 51%, respectively; (3) the activity of AHH by 95%, 106%, 80% respectively; (4) the cytochrome b5 content by 164%, 97%, 94% respectively; and (5) decreased the activity of NADPH-cytochrome c reductase by 55%, 50% and 45%, respectively. Methylpropylnitrosamine decreased the activity of DMN-dI by 44% and the P-450 content by 50%. Diphenylnitrosamine also decreased cytochrome P-450 by 54%, AHH activity by 64% but increased the activity of DMN-dI by 42%, the cytochrome b5 content by 159% and NADPH-cytochrome c reductase activity by 57%. It seems from this study that the activity of AHH is dependent on P-450 content but DMN-dI is not since the compounds that increased or decreased the activity of AHH had parallel effects on P-450 content. Also, the extent to which the altered activities of DMN-dI, P-450, AHH, cytochrome b5 and NADPH-cytochrome c reductase depends on the type of alkyl groups linked to the nitroso group.

Animals↗
PubMed1994

Biological reduction of aromatic nitroso compounds: evidence for the involvement of superoxide anions.

The in vitro formation of phenylhydronitroxide and 2-methylphenylhydronitroxide free radicals from nitrosobenzene (NB) and 2-nitrosotoluene (NT), respectively, in either red blood cells (RBC) or RBC hemolysates, was confirmed by electron spin resonance spectroscopy (ESR). Free radicals were generated nonenzymatically from reaction of the respective nitroso compounds with a number of biological reducing agents as corroborated by model studies of NB or NT with NAD(P)H. Under aerobic conditions, phenylhydronitroxide and 2-methylphenylhydronitroxide underwent a subsequent one-electron transfer to oxygen, which then resulted in the formation of superoxide anion (O2-). The latter product was confirmed by the superoxide dismutase (SOD)-inhibitable reduction of cytochrome c (cyt c). Apparently, oxygen is needed for continuous formation of the hydronitroxide radical derivatives. On the other hand, under anaerobic conditions, no phenylhydronitroxide radical was generated from NB in the presence of NADH, but the formation of phenylhydroxylamine from NB was detected by the absorption spectrometry. These results suggest that oxygen is a preferential electron acceptor for hydronitroxide radical derivatives.

Blood↗
PubMed1987

Biochemical and molecular effects of N-nitroso compounds in human cultured cells: an overview.

In-vitro models using human tissues and cells provide a bridge between studies of humans and of laboratory animals. Cultured human cells activate N-nitrosamines to DNA-damaging metabolites, including alkyldiazonium ions and aldehydes; these metabolites can also inactivate DNA repair processes, such as O6-alkylguanine DNA-alkyltransferase (AAT) activity, and are mutagenic in human cells. Both human epithelial and mesenchymal cells have been transformed in vitro by N-nitroso compounds.

Cell Transformation, Neoplastic↗
PubMed1991

Levels of nitrite, nitrate, N-nitroso compounds, ascorbic acid and total bile acids in gastric juice of patients with and without precancerous conditions of the stomach.

To determine the relevance of gastric juice factors to gastric carcinogenesis, 56 patients with unoperated stomachs undergoing endoscopy for dyspepsia had gastric juice aspirated and analysed for pH, ascorbic acid, total bile acids, nitrite, nitrate and total nitroso compounds (NOCs). Plasma was obtained for vitamin C estimation. Antral and body biopsies were assessed for gastritis, Helicobacter pylori, atrophy and intestinal metaplasia (IM). Patients with chronic atrophic gastritis (n = 17) had lower gastric juice ascorbic acid concentrations (P less than 0.001), higher pH (P less than 0.05) and higher incidence of H. pylori infection (P less than 0.001) than normal subjects (n = 12). Patients with reflux gastritis (n = 9) had higher total bile acids (P less than 0.01). Patients with chronic gastritis and IM (n = 11) had higher gastric juice pH (P less than 0.01) and total bile acid concentrations (P less than 0.05), and lower gastric ascorbic acid concentrations (P less than 0.01) than those with chronic gastritis and no IM (n = 24). In chronic gastritis, high nitrite concentrations were associated with high pH (P less than 0.01). However, there were no significant differences in plasma vitamin C or gastric nitrite, nitrate or total NOC concentrations in relation to gastric histology. We conclude that the premalignant condition IM is associated with H. pylori infection, low gastric ascorbic acid levels and elevated total bile acids, but not to elevation in nitrite or total NOCs in fasting gastric juice.

Adult↗
PubMed1992

Levels of direct-acting mutagens, total N-nitroso compounds in nitrosated fermented fish products, consumed in a high-risk area for gastric cancer in southern China.

A high gastric cancer mortality in Fujian province (Peoples Republic of China) has been associated with the consumption of certain salted fermented fish products such as fish sauce (FS). We have investigated the levels and nature of N-nitroso compounds (NOC) and genotoxins present, before and after nitrosation, in 49 FS samples collected from villages in this high-risk area, pooled into six samples. The concentrations of total NOC before nitrosation ranged from 0.2 to 16 mumoles/l, and after nitrosation at pH 2 and pH 7, they rose by up to 4800- and 100-fold, respectively. In nitrosated samples, 40-50% of total NOC was not extractable into organic solvents; volatile N nitrosamines accounted for 1-2% and N-nitrosamino acids for 8-16% of total NOC. None of the FS samples exhibited genotoxic activity, but after nitrosation all were weakly active in the SOS chromotest. The highest SOS-inducing potency was observed with nitrosated ethyl acetate extracts of most samples. The formation of methylating agents was measured by incubation of nitrosated FS with DNA and subsequent analysis of 7-methylguanine adduct. 2 of the 6 nitrosated FS samples caused a slight increase in DNA methylation. 1 pooled home-made FS sample (the only one tested) contained tumour promoter-like substances, as measured by expression of certain EBV genes in Raji cells. HPLC fractionation of ethyl acetate extracts of FS samples allowed identification of three UV-absorbing peaks that, upon nitrosation, produced direct-acting genotoxins. This genotoxicity was partly ascribed to the formation of nitrite-derived arene diazonium cations that were characterized by a coupling reaction with N-ethyl-1-naphthylamine and thin-layer chromatography.

China↗
PubMed1993

Nitroxyl analogs as inhibitors of aldehyde dehydrogenase. C-nitroso compounds.

We previously postulated that the catalase-mediated oxidation of cyanamide leads to the formation of the unstable intermediate, N-hydroxycyanamide, which spontaneously decomposes to nitroxyl, the putative inhibitor of aldehyde dehydrogenase (EC 1.2.1.3; AlDH). Since it was not possible to provide direct evidence for the inhibition of AlDH by nitroxyl, we examined the activity of three representative substituted nitroxyls (C-nitroso compounds), viz. nitrosobenzene (NB), 1-nitrosoadamantane (NA), and 2-methyl-2-nitrosopropane (MNP), as direct inhibitors of yeast AlDH in vitro. While NB and NA were highly effective inhibitors in this system exhibiting IC50 values of 2.5 and 8.6 microM, respectively, MNP was considerably less effective with an IC50 of 0.15 mM. When tested in vivo, NA did not show any inhibitory activity on the hepatic AlDH, possibly due to the lack of site-specific delivery of the active monomeric form of this compound. However, NB at a low dose did inhibit hepatic AlDH as reflected by an increase in blood acetaldehyde levels. These results attest to the abilities of NB and NA to act as direct inhibitors of AlDH analogous to nitroxyl itself.

Adamantane↗
PubMedDate not supplied

Review of the occurrence and formation of non-volatile N-nitroso compounds in foods.

A review of the literature published prior to July 1991 covers the occurrence and formation of non-volatile N-nitrosamines occurring in foods and beverages. The presence of identified volatile and non-volatile N-nitrosamines accounts for less than 10% of the total apparent N-nitrosamine concentration. N-Nitrosoproline and N-nitrosothiazolidine-4-carboxylic acid are the most commonly identified non-volatile N-nitrosamines in the diet. Non-volatile N-nitrosamines account for 12 of the 21 currently identified N-nitroso compounds in foods and beverages.

Beverages↗
PubMed1979

Formation of carcinogenic N-nitroso compounds in corn-bread inoculated with fungi.

DMNA, DENA and MBNA are formed in corn-bread which has been inoculated with the most common species of fungi found in foodstuffs of Lin Xian County, Henan Province, such as F. moniliforme, A. flavus and others, and then, added with small amount of NaNO2 after a few days of incubation. These carcinogenic N-nitroso compounds can induce cancer of the liver or/and esophagus in experimental animals. Results of the present study show the capability of some fungi to produce chemical carcinogens as well as mycotoxins in contaminated food, and thus, open a new field of research in cancer etiology.

Aspergillus flavus↗
PubMed1979

A new N-nitroso compound, N-3-methylbutyl-N-1-methylacetonylnitrosamine, in corn-bread inoculated with fungi.

A new N--nitroso compound, N--1--methylacetonyl--N--3--methylbutylnitrosamine (MAMBNA) is found in corn-bread inoculated with the common fungi, such as Fusarium moniliforme, Geotrichun candidum, Aspergillus terreus or A. flavipes, encountered in food of Lin Xian County, Henan Province. The preliminary identification of this compound with TLC has been confirmed by GC-MS analysis. Furthermore, we have synthesized the MAMBNA and the chemical analysis shows that it is identical with the MAMBNA isolated from the corn-bread extract. In addition to the MAMBNA, dimethylnitrosamine, diethylnitrosamine and methylbenzylnitrosamine are formed also in the fungus-inoculated corn-bread after 8-day incubation and an addition of a small amount of sodium nitrite. The presence of precursor compounds for the formation of nitrosamine in the mouldy maize flour and their significance in respect to the etiology of esophageal cancer in high-risk areas have been discussed.

Aspergillus flavus↗
PubMed1983

[Endogenous synthesis of carcinogenic N-nitroso compounds: bacterial flora and nitrite formation in the healthy human stomach].

The endogenous synthesis of cancerogenic N-nitroso compounds: Bacterial flora and nitrite formation in the human stomach. In the discussion of the endogenous nitrosamine synthesis, nitrites play a decisive role. Since in a healthy stomach the acidity important for the nitrosamine formation is present, but since this acid environment is hostile to the bacterial growth and thus counteracts bacterial endogenous nitrite formation, the oral cavity has so far been regarded as the main site of endogenous nitrite formation. An analysis of 130 gastric secretions taken from empty stomachs has demonstrated that also in a healthy stomach considerable germ counts may be obtained in part when acidity is lowered physiologically (e.g. at night). Nitrite concentrations, which are six times as high as the quantities supplied with the saliva at the same time, are also produced in the acid pH range from 4 to 6. Consequently, in a healthy stomach as well the quantity of nitrite available for an endogenous nitrosamine synthesis is by far higher than has been assumed previously. This physiological risk should be allowed for in evaluating the pathophysiological or therapeutic changes in the gastric environment.

Bacteria↗
PubMed1996

Does increased endogenous formation of N-nitroso compounds in the human colon explain the association between red meat and colon cancer?

High red meat diets have been linked with risk of sporadic colorectal cancer; but their effects on mutations which occur in this cancer are unknown. G-->A transitions in K-ras occur in colorectal cancer and are characteristic of the effects of alkylating agents such as N-nitroso compounds (NOC). We studied th effect of red meat consumption on faecal NOC levels in eight male volunteers who consumed diets low or high in meat (60 or 600 g/day), as beef, lamb or pork, whilst living in a metabolic suite. Increased intake of red meat induced a significant (P<0.024) 3-fold increase from 40 + or - 7 to ab average of 113 + or - 25 microgram/day NOC, a range of exposure in faeces similar to that from tobacco-specific NOC in cigarette smoke. THe diets were isoenergetic and contained equal amounts of fat, but concentrations of heterocyclic amines were low. Faecal excretion of the promotor ammonia was significantly increased to 6.5 + or - 1.08 mmol/day. When the high red meat diets were supplemented with 20 g phytate-free wheat bran in six volunteers there was no reduction in NOC levels (mean 138 + or - 41 microgram/day NOC), but faecal weight increased. Higher starch and non-starch polysaccharide intakes reduced intraluminal cross-linking in microcapsules (r=-0.77) and reduced faecal pH (r=-0.64). In two volunteers there was no effect of 600 g white meat and fish o faecal NOC (mean low white meat diet 68 + or - 10 microgram/day, high white meat 56 + or -6 microgram/day nor on faecal nitrate, nitrite and iron. Faecal nitrite levels increased on changing from a white to red meat diet (mean high white meat diet 46 + or - 7 mg/day, high red meat diet mean 80 + or - 7 mg/day.) Increased endogenous production of NOC and precursors from increased red meat, but not white meat and fish, consumption may be relevant to the aetiology of colorectal cancer.

Adult↗