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PubMed1989

Quantitative pattern recognition for structure-carcinogenic activity relationship of N-nitroso compounds based upon Di-region theory.

In this paper, it is evidenced by the quantitative structure-carcinogenic activity relationship (QSCAR) and the pattern recognition treatment of N-nitroso compounds (NNC) that the key step of carcinogenesis induced by NNC is the cross-linking on the complementary base pair of DNA, through the bifunctional alkylation between alpha-carbon and another carbon within the same chain. The alkylation by the alpha-carbon atom is through the diazonium salt, but that by the atom other than the alpha-position is through the active ester formed from the hydroxylated metabolite of the chain. Therefore, the alkylation by the beta-position of NNC, or by its gamma-position, under suitable conditions, of which the distances from the alpha-position both approach 2.80-3.00 A, would be the most favourable positions along with the alpha-position for the cross-linking to occur between the complementary base pairs of DNA, which will yield the carcinogenic activity of NNC. The above conception of bifunctional alkylation can reduce the QSCAR of NNC to a reasonable structure-chemical reactivity relationship under the complex biological conditions, and is the successful extension of the Di-region theory to the carcinogenesis mechanism of the important NNC series. In the light of the above viewpoint, for 153 NNCs including the nitrosamines and nitrosamides which have been tested reliably with animals, the correct discrimination ratio by quantitative pattern recognition according to carcinogenic activity indexes divided into 5 degrees comes up to as high as 97%.

Alkylation↗
PubMed1991

N-nitroso compounds in cigarette tobacco and their occurrence in mainstream tobacco smoke.

The tobacco and mainstream smoke of 20 commercial brands of filter and non-filter cigarettes were analysed for N-nitroso compounds. The concentrations of N-nitrosodimethylamine (NDMA), N-nitrosoethylmethylamine (NEMA) and N-nitrosopyrrolidine (NPYR) in cigarette tobacco were very much lower than in mainstream smoke, where the levels were 6.3-76.4 ng/cig NDMA, less than 1.0-7.1 ng/cig NEMA and 3.9-41.2 ng/cig NPYR. N-Nitrosodiethylamine was not detected in mainstream smoke and N-nitrosopiperidine (less than 1.0 ng/cig) was detected in the smoke of four unfiltered cigarette brands. The five major non-volatile nitrosamines present in cigarette tobacco were 4-(N-nitroso-N-methylamino)butyric acid (not detected to 200 ng/cig), N-nitrosopipecolic acid (not detected to 670 ng/cig), N-nitrososarcosine (22-460 ng/cig), 3-(N-nitroso-N-methylamino)propionic acid (110-4990 ng/cig) and N-nitrosoproline (580-15000 ng/cig). The tobacco-specific nitrosamines N-nitrosoanabasine and N-nitrosoanatabine were found at levels of 270-2330 ng/cig and 18-205 ng/cig in cigarette tobacco and mainstream smoke respectively. N-Nitrosonornicotine was present at 400-5340 ng/cig and 19-855 ng/cig in cigarette tobacco and mainstream smoke respectively. 4-(N-Nitrosomethyl-amino)-1-(3-pyridyl)-1-butanone concentrations of 100-960 ng/cig and 21-470 ng/cig in cigarette tobacco and mainstream smoke were determined. 4-(N-Nitrosomethyl-amino)-4-(3-pyridyl)-1-butanol (iso-NNAL) was detected in four dark (French) tobacco unfiltered cigarettes at a concentration range of 140-240 ng/cig and 5-11 ng/cig in the corresponding mainstream smoke. For non-filter cigarettes, a transfer rate of 3.4-4.6% for iso-NNAL was calculated.

Germany, West↗
PubMed1995

Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC.

The questions of whether and how N-nitroso compounds (NOC) may be inducing cancer in humans are discussed. The principal subjects covered include nitrite-derived alkylating agents that are not NOC, reasons for the wide tissue specificity of carcinogenesis by NOC, the acute toxicity of nitrosamines in humans, mechanisms of in vivo formation of NOC by chemical and bacterial nitrosation in the stomach and via nitric oxide (NO) formation during inflammation, studies on nitrite esters, use of the nitrosoproline test to follow human gastric nitrosation, correlations of nitrate in food and water with in vivo nitrosation and the inhibition of gastric nitrosation by vitamin C and polyphenols. Evidence that specific cancers are caused by NOC is reviewed for cancer of the stomach, esophagus, nasopharynx, urinary bladder in bilharzia and colon. I review the occurrence of nitrosamines in tobacco products, nitrite-cured meat (which might be linked with childhood leukemia and brain cancer) and other foods, and in drugs and industrial situations. Finally, I discuss clues from mutations in ras and p53 genes in human tumors about whether NOC are etiologic agents and draw some general conclusions.

Animals↗
PubMed1996

Blocking the endogenous formation of N-nitroso compounds and related carcinogens.

Humans are exposed to a wide range of nitrogen-containing compounds and nitrosating agents, such as nitrite, nitrate and nitrogen oxides (NOx), that can react in vivo to form potentially carcinogenic N-nitroso compounds (NOCs), as well as several carcinogenic C-nitro(so) or reactive diazo compounds. Nitrosating agents can also be synthesized endogenously by bacteria and activated macrophages via the nitric oxide (NO) synthase pathway. Endogenous nitrosation can thus occur at many locations in the body, including sites of chronic infection or inflammation. Ascorbic acid, alpha-tocopherol, phenolic compounds, and fruit, vegetable and plant extracts inhibit NOC formation by destroying nitrosating agents. Fresh fruits and vegetables (sources of nitrosation inhibitors) exert a protective effect against various epithelial cancers. In addition to giving rise to nitrosating agents, overproduction of NO in chronic inflammatory conditions leads to the generation of peroxynitrite (a source of oxidative DNA damage and lipid peroxidation) and aldehydes and epoxides derived from lipid peroxidation that yield miscoding exocyclic DNA adducts. Inhibition of the inducible NO synthase and strengthening of the cellular defence system against oxidative stress should block NO-associated DNA damage. This chapter summarizes mechanistic, experimental and human studies that address the inhibition of endogenous formation of NOCs and related carcinogens as a method of chemoprevention.

Anticarcinogenic Agents↗
PubMed1982

Catalytic role of some phenolic substances in endogenous formation of N-nitroso compounds.

N-nitrosation can be catalysed or inhibited in vivo by different naturally-occurring polyphenolic compounds. The catalytic effect is particularly affected by pH. Thus, individual dietary habits can be expected to have marked effects on endogenous formation of N-nitroso compounds because of catalysis by polyphenols in foodstuffs, in addition to individual differences in pH.

Animals↗
PubMed1987

[Determination of N-nitroso compounds in the gastric juice for evaluation of the individual nitrosating capacity of the body].

The article deals with a comparison of the results of human body nitrosating ability determination by two methods: (a) nitroso compound (NC) assay in diurnal urine after oral administration of its precursors, and (b) assay of the same in gastric juice after in vitro addition of precursors. The data for the first part of the investigation were obtained from the literature, and for the second one--from the experiments by the authors. Both studies used essentially identical groups of patients, primarily those suffering gastrointestinal pathology. Since the results matched to a considerable degree, it was inferred that (1) gastric juice is a factor of body nitrosating ability, and (2) in vitro determinations of said ability in gastric juice are fully justified. Moreover, the latter procedure is sometimes more practicable, particularly, in view of the marked relationship between nitrosating ability, and, especially, the efficacy of inhibitors of NC endogenous synthesis, on the one hand, and the individual characteristics of the body, on the other.

Aminopyrine↗
PubMed1993

Mutagens, N-nitroso compounds and their precursors in gastric juice from patients with and without precancerous lesions of the stomach.

This study examined whether elevated risk of gastric cancer is associated with high levels of total N-nitroso compounds (NOC), their precursors and nitrosation-dependent genotoxins in gastric juice (GJ). An improved method for quantifying total NOC was used and genotoxicity was assayed in E. coli. Results from patients (n = 210) with or without precancerous lesions of the stomach and living in three areas with up to 8-fold variations in gastric cancer risk (U.K., France, Colombia) were compared. The level of nitrite (range < 1-472 mumol/l) was found to increase with the pH of GJ from the three countries and was dependent on country of collection. The levels of NOC (range: < or = 0.01-8.0 mumol/l) in GJ were not affected by stomach histology and country of collection. NOC levels increased linearly with nitrite concentrations, but the slope of the regression line was greater for acidic GJ (pH < or = 4). These data together suggest that chemical nitrosation contributes at least as much as other nitrosation pathways to the intragastric formation of NOC. Acid-catalysed nitrosation of GJ in vitro increased the NOC concentration (range: 7-1332 mumol/l) up to several 1000-fold but this increase was not predictive of gastric cancer risk either by country or by stomach histology. After acid-catalysed nitrosation, direct genotoxicity (SOS-inducing potency) was significantly higher in GJ with original pH > 4 and highest in samples from Colombia. The results (a) provide no support that intragastric total NOC levels are elevated in subjects with precancerous stomach lesions or living in a high risk area for stomach cancer; (b) confirm that a high nitrite level and elevated pH in GJ are strongly associated, the level of nitrite being associated with precancerous stomach conditions only in Colombia; (c) reveal the presence of precursor compounds in GJ, that after nitrosation yield direct mutagens that probably contain NOC and other substances. As their concentrations were significantly higher in achlorhydric subjects and highest in Colombian patients, these data together provide support for a role of intragastrically formed nitrite-derived direct mutagens in gastric cancer aetiology.

Adult↗
PubMed2005

Classification of the carcinogenicity of N-nitroso compounds based on support vector machines and linear discriminant analysis.

The support vector machine (SVM), as a novel type of learning machine, was used to develop a classification model of carcinogenic properties of 148 N-nitroso compounds. The seven descriptors calculated solely from the molecular structures of compounds selected by forward stepwise linear discriminant analysis (LDA) were used as inputs of the SVM model. The obtained results confirmed the discriminative capacity of the calculated descriptors. The result of SVM (total accuracy of 95.2%) is better than that of LDA (total accuracy of 89.8%).

Artificial Intelligence↗
PubMed1983

Effect of plasma and carboxylesterase on the stability, mutagenicity, and DNA cross-linking activity of some direct-acting N-nitroso compounds.

The effects of mouse plasma, human plasma, and purified porcine liver carboxylesterase on nitrosourea, nitrosamide, and nitrosocarbamate chemical stability, mutagenicity, and DNA cross-linking activity were compared. These three classes of N-nitroso compounds are chemically similar but displayed different biological activities and were affected differently by plasma and carboxylesterase. Nitrosourea stability as well as mutagenicity and DNA cross-linking activity were affected negligibly by esterase or plasma. In contrast, nitrosamide and nitrosocarbamate stability, mutagenicity, and DNA cross-linking activity were rapidly decreased in the presence of plasma or carboxylesterase. For example, chemical half-lives were from 10- to 20-fold shorter for the nitrosamides and nitrosocarbamates in the presence of 5% mouse plasma. Similar decreases were seen for mutagenicity and DNA cross-linking activity. Preliminary studies indicated one active plasma component to be an enzyme, possibly an esterase. Additional factors such as sulfhydryls may also participate. Whereas some nitrosoureas are active antitumor agents, the lack of antitumor activity for analogous nitrosamides and nitrosocarbamates may reside predominantly in their rapid in vivo inactivation. These results may help to account for the high in vitro mutagenicity as compared with the low in vivo activities of nitrosamides and nitrosocarbamates.

Animals↗
PubMed1981

Greater effectiveness of hepatocyte and liver S9 preparations from hamsters than rat preparations in activating N-nitroso compounds to metabolites mutagenic to Salmonella.

A comparison was made of the ability of liver S9 and hepatocyte preparations from noninbred Syrian golden hamsters and noninbred Sprague-Dawley rats to metabolically activate a number of nitroso compounds in the Salmonella mutagenesis assay. The liver S9 and hepatocyte preparations from hamsters were consistently more effective than were preparations from rats in metabolizing nitrosodimethylamine (NDM), nitrosodiethylamine, nitrosodiallylamine, nitrosopyrrolidine (NP), nitrosomorpholine (NM), nitrosodiethylmethylurea (NDEMU), and nitrosodimethyl-ethylurea (NDMEU) to mutagenic forms. The use of hamster S9 preparations with NP and NM resulted in up to 14 times the number of revertant colonies obtained with rat preparations; in the presence of hamster hepatocytes, up to 32 times the number of revertants were obtained. The S9 preparations from male hamsters not treated with the enzyme inducers phenobarbital and Aroclor 1254 were more effective than were those from female hamsters for activating NP, NM, and NDM, NDEMU and NDMEU, which have been reported to be carcinogens but not mutagens, were mutagenic in the presence of induced liver S9 or hepatocyte preparations from hamsters but not from rats. When tested with any of the S9 or hepatocyte preparations, nitrosodiphenylamine and nitrosomethylaniline, also reported to be carcinogens but not mutagens, gave no mutagenic responses. Nitrosodioctyl-amine, which has been reported to be noncarcinogenic, was also not mutagenic.

Animals↗
PubMed1995

[Pathogenesis of stomach carcinoma--significance of nitrates, N-nitroso compounds, nutritional factors and Helicobacter pylori-induced chronic active and chronic atrophic gastritis].

Epidemiological data on gastric cancer, time trends and histological classification are reviewed. Known models on gastric carcinogenesis including the pathogenetic importance of nitrates and N-nitroso compounds and protective effects of dietary components are discussed and recent evidence on Helicobacter pylori (Hp) induced chronic active gastritis, its progression to chronic atrophic gastritis and its role in gastric carcinogenesis is summarized. Epidemiological, clinical and pathological support for a causal relationship of Hp and gastric carcinoma is included in a new multistep model on aetiopathogenesis of gastric cancer. The follow-up of patients at risk as well as the question of cancer prevention by Hp eradication are mentioned.

Feeding Behavior↗
PubMed1975

Trace analysis of volatile N-nitroso compounds by combined gas chromatography and thermal energy analysis.

Thermal energy analysis (TEA) has been combined with gas chromatography (GC). The new GC-TEA technique is highly specific to compounds which contain heat labile nitrosyl groups. Because of the specificity of the technique, full use may be made of the TEA sensitivity. Analysis by direct injection of solutions containing less than 1 ng/ml N-nitroso compound is demonstrated.

Chromatography, Gas↗
PubMedDate not supplied

The application of a chemical denitrosation and chemiluminescence detection procedure for estimation of the apparent concentration of total N-nitroso compounds in foods and beverages.

The apparent total N-nitroso content of foods can be measured by a procedure based on chemical denitrosation and chemiluminescent detection of the eliminated nitric oxide. Procedures have been established which substantially reduce the 'apparatus blank' response to the denitrosating agent and allow total nitroso contents down to 10 micrograms (N-NO)/kg to be measured reproducibly on a 1-g sample. Typically, duplicate analyses of samples containing 10-1000 micrograms (N-NO)/kg differ by less than 15% of their mean. Potentially the method can be subject to some interference from compounds other than N-nitroso compounds, but at least in some commodities these interfering compounds do not exist in measurable amounts.

Beverages↗
PubMed1982

Computer-assisted studies of structure-activity relationships of N-nitroso compounds using pattern recognition.

Pattern-recognition techniques have been applied to the study of relationships between the molecular structure of nitrosamines and their carcinogenic potential. A set of 150 nitrosamines (112 carcinogenic and 38 noncarcinogenic) was used. Each compound was represented by a set of calculated molecular structure descriptors. Discriminants were found that could separate 146 of the compounds into the two activity classes based on a set of 22 descriptors. Internal consistency checking showed that the 22 descriptors used supported a meaningful discriminant. The results show that sufficient information is contained within the structure of N-nitroso compounds to allow classification into carcinogenic activity classes.

Carcinogens↗
PubMed2000

Endogenous N-nitroso compounds, and their precursors, present in bacon, do not initiate or promote aberrant crypt foci in the colon of rats.

Processed meat intake is associated with increased risk of colorectal cancer. This association may be explained by the endogenous formation of N-nitroso compounds (NOC). The hypothesis that meat intake can increase fecal NOC levels and colon carcinogenesis was tested in 175 Fischer 344 rats. Initiation was assessed by the number of aberrant crypt foci (ACF) in the colon of rats 45 days after the start of a high-fat bacon-based diet. Promotion was assessed by the multiplicity of ACF (crypts per ACF) in rats given experimental diets for 100 days starting 7 days after an azoxymethane injection. Three promotion studies were done, each in 5 groups of 10 rats, whose diets contained 7%, 14%, or 28% fat. Tested meats were bacon, pork, chicken, and beef. Fecal and dietary NOC were assayed by thermal energy analysis. Results show that feces from rats fed bacon-based diets contained 10-20 times more NOC than feces from control rats fed a casein-based diet (all p < 0.0001 in 4 studies). In bacon-fed rats, the amount of NOC input (diet) and output (feces) was similar. Rats fed a diet based on beef, pork, or chicken meat had less fecal NOC than controls (most p < 0.01). No ACF were detected in the colon of bacon-fed uninitiated rats. After azoxymethane injection, unprocessed but cooked meat-based diets did not change the number of ACF or the ACF multiplicity compared with control rats. In contrast, the bacon-based diet consistently reduced the number of large ACF per rat and the ACF multiplicity in the three promotion studies by 12%, 17%, and 20% (all p < 0.01). Results suggest that NOC from dietary bacon would not enhance colon carcinogenesis in rats.

Animals↗
PubMedDate not supplied

[Histopathological studies of the acute and chronic toxic effects of 2 N-nitroso compounds on the blue mussel (Mytilus edulis)].

The acute and chronic effects of two N-Nitroso compounds (N-Nitrosodimethylamine) (DMN) and N-Methyl-N-Nitro-N-Nitrosoguanidine (MNNG) were studied by light microscopy after injection of the chemicals into the foot of the mussel, Mytilus edulis. Acute toxic effects: DMN produced dose-dependent (0.1 to 0.8 mg DMN/mussel) tissue alterations characterized by extensive inflammatory reactions in the Leydig cell tissue of the digestive gland, and necrosis in the germinal epithelium lining the genital ducts. MNNG produced dose-dependent (0.063 to 0.5 mg MNNG/mussel) tissue alterations characterized by extensive necrosis in the epithelial lining of the tubules of the digestive gland. Chronic toxic effects: 0.2 mg DMN/mussel given once a week for 8 weeks, and examined over a period of 30 weeks, revealed tissue alterations characterized by extensive collagenous scar tissue formation in between the tubules of the digestive gland, presence of numerous granulocytomas, and necrosis of the germinal epithelium of the genital ducts. 0.125 mg MNNG/mussel given once a week for 4 weeks, and examined over a period of 7 months, produced tissue alterations mainly characterized by encapsulation or replacement of damaged digestive tubules by collagenous scar tissue.

Animals↗
PubMed1980

Synergistic effects of N-nitroso compounds in experimental long-term carcinogenesis studies.

Combination effects in chemical carcinogenesis can be described either as syncarcinogenesis action of two or more carcinogens or as modified effects of noncarcinogenic substances on the action of carcinogens. Combination experiments in which one or more carcinogenic N-nitroso compounds are administered to experimental animals together with other cancer-inducing or noncarcinogenic xenobiotics show that in animal experimental animals together with other cancer-inducing or noncarcinogenic xenobiotics show that in animal experiments independent activities, additive effects, and synergistic actions as well as inhibitions may occur. After the administration of several carcinogenic substances predominantly additive effects were observed so far. A large number of experiments demonstrate the influence of different modifying xenobiotics on the action of chemical carcinogens. It is shown that in animal experiments there are real synergistic and inhibitory effects of noncarcinogenic compounds of different chemical structure on the action of chemical carcinogens. As far as the mechanism of action can be made plausible, these are either enzyme-inducing or enzyme-inhibiting effects, competitive or noncompetitive inhibitions of substrates on the enzymes, or alterations of the rate of cell division and correspondingly of the cell-specific protein synthesis. Before establishing acceptable risk values for individual chemical carcinogens it should be taken into account that as a rule interactions are to be expected in man.

Animals↗