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PubMed1976

Calcium-independent modulation of cyclic GMP and activation of guanylate cyclase by nitrosamines.

Nitrosamines markedly increase concentrations of guanosine 3', 5' - monophosphate (cyclic GMP) in several tissues from the rat and in human colonic mucosa. These agents are effective in the absence of extracellular calcium and enhance guanylate cyclase activity in tissue homogenates. Stimulation of cyclic GMP was greatest in liver, where the carcinogenic activity of nitrosamines is also most pronounced.

Animals↗

PubMed1979

Formation of N-nitrosamines from seconday animes and nitrite by resting cells of Escherichia coli B.

In the presence of resting cells of Escherichia coli B, the formation of N-nitrosamines from nitrite and secondary amines, such as dimethylamine and piperidine, was proportional to the incubation time and to the cell concentration. Optimum pH was 8.0. Boiled cells were incapable of nitrosating secondary amines. Although these experiments were carried out by using intact cells of E. coli B, the reaction followed Michaelis-Menten kinetics, and the apparent Km values calculated from Lineweaver-Burk plots were 0.12 +/- 0.03 M for dimethylamine and 0.07 +/- 0.02 M for nitrite. The apparent Km for piperidine was 0.15 +/- 0.05 M. The nitrosation was inhibited by high substrate concentrations. These results suggested that the formation of n-nitrosamines by resting cells of E. coli B apparently depends on their enzyme activities.

Dimethylamines↗

PubMed1973

Effect of sodium nitrite and sodium nitrate on botulinal toxin production and nitrosamine formation in wieners.

Wieners were formulated and processed approximating commercial conditions as closely as possible. Twenty-four batches of product were made with the addition of six levels of sodium nitrite (0, 50, 100, 150, 200, and 300 mug/g), four levels of sodium nitrate (0, 50, 150, and 450 mug/g), and two levels of Clostridium botulinum (0 and 620 spores/g). After formulation, processing, and vacuum packaging, portions of each batch were incubated at 27 C or held for 21 days at 7 C followed by incubation at 27 C for 56 days. The latter storage condition approximated distribution of product through commercial channels and potential temperature abuse at the consumer level. Samples were analyzed for botulinal toxin, nitrite, and nitrate levels after 3, 7, 14, 21, 28, and 56 days of incubation. When nitrite was not added, toxic samples were detected after 14 days of incubation at 27 C. At the lowest level of nitrite added (50 mug/g), no toxic samples were observed until 56 days of incubation. Higher levels of nitrite completely inhibited toxin production throughout the incubation period. Nine uninoculated samples, representing various levels and combinations of nitrite and nitrate, were evaluated organoleptically. The flavor quality of wieners made with nitrite was judged significantly higher (P = 0.05) than of wieners made without nitrite. The nine samples were negative for 14 volatile nitrosamines at a sensitivity level of 10 ng/g. The results indicated that nitrite effectively inhibited botulinal toxin formation at commercially employed levels in wieners and that detectable quantities of nitrosamines were not produced during preparation and processing of the product for consumption.

Botulinum Toxins↗

PubMed1977

A search for volatile nitrosamines in East African spirit.

Spirits from areas of high and low incidence of cancer of the oesophagus were examined for volatile nitrosamines using a chemiluminescent detector. No nitrosamines were found, the detection limit being 0.001 microng/ml.

Africa, Eastern↗

PubMed1982

Intragastric nitrites, nitrosamines, and bacterial overgrowth during cimetidine treatment.

A six week course of cimetidine (1 g/day) healed peptic ulcers in 20 of 23 patients (14 with duodenal ulcer, nine with gastric ulcer). Reduction of basal acid output by 73% and peak acid output by 36% led to a rise in concentrations of intragastric aerobic bacteria and nitrate-reducing bacteria. While the mean intragastric concentration of nitrate was unchanged by treatment, there were statistically significant rises in nitrite and N-nitrosamine concentrations. The conversion from nitrates to nitrites was closely related to the occurrence of nitrate-reducing bacteria. In three patients the intragastric milieu had returned to normal two months after cimetidine treatment had been discontinued. Mean nitrite and N-nitrosamine concentrations did not return to pre-treatment levels in the group of eight patients who remained on maintenance cimetidine (0.4 g at night-time) for three months after the full dose treatment. This study shows that cimetidine treatment can create an intragastric milieu resembling that of atrophic gastritis. Large scale and long-term studies are necessary to establish whether these findings have any clinical significance.

Adult↗

PubMed2004

The case of the disappearing nitrosamines: a potentially global phenomenon.

The cigarette usually carries in its smoke significant doses of carcinogenic tobacco specific nitrosamines (TSNAs), which have been implicated as causes of oral, lung, oesophageal, and pancreatic cancer. However, there is substantial variation in nitrosamine content of the smoke of modern cigarettes. This variation is both unacceptable and unnecessary, as TSNAs can be readily removed during the manufacturing process. Removing a known carcinogen needs no justification, even though proof of benefit may not be forthcoming for decades.

Carcinogens↗

PubMed1996

Occurrence of nitrate, nitrite and volatile nitrosamines in certain feedstuffs and animal products.

Nitrate, nitrite and nitrosamines were analysed in poultry feeds, meat and eggs. The poultry meat was boiled and roasted while the eggs were raw and boiled, and the effects of these processing treatments on the level of these compounds were investigated. Nitrate levels in the meat samples were significantly (P < 0.05) reduced by boiling and roasting, with boiling being more effective. Nitrite levels were also reduced significantly by processing (P < 0.05). The feed samples contained levels of nitrate which were significantly different (P < 0.05) from one producer to another. Nitrite levels were generally low in all feed samples. Nitrosamines were not detected in any of the feed samples and in the meat samples except in two samples of boiled meat which contained 0.001 g/kg each.

Animal Feed↗

PubMed1979

Mesotheliomas and proliferative lesions of the testicular mesothelium produced in Fischer, Sprague-Dawley and Buffalo rats by methyl(acetoxymethyl)nitrosamine (DMN-OAc).

A single intraperitoneal dose of methyl(acetoxymethyl)nitrosamine (13 mg/kg body weight) given to 78 5-week-old male rats induced 25 mesotheliomas; two mesotheliomas were found in 67 control rats. All mesotheliomas arose from the peritesticular mesothelium and had a typical microscopic appearance of branching papillary fronds with a collagenous core covered by one or many layers of plump tumor cells. Cytoplasm of tumor cells contained material that reacted positively to a colloidal iron stain and was labile to hyaluronidase. In addition to frank mesotheliomas, 16 lesions, which we called atypical mesothelial proliferations, were found. These consisted of a single focus of plump mesothelial cells overlying an area of thick stroma. Often these foci included short, non-branched papillary projections above the surface of adjacent normal mesothelium. Twelve of the 16 lesions occurred in methyl(acetoxymethyl)nitrosamine-treated rats.

Animals↗

PubMed1989

Lack of effect of selenium on induction of tumors of esophagus and bladder in rats by two nitrosamines.

The effect of differences in level of dietary selenium on the induction of esophageal and bladder tumors in rats by two nitrosamines was investigated. Groups of 20 female F344 rats were given a synthetic diet containing less than 0.05 ppm Se to which selenium (as sodium selenite) was added at the concentration of 0.35, 0.7, 1.4 and 2.1 ppm selenium. These four groups, plus one without added Se, were treated with 20 ml per rat per day, 5 days a week, of a solution of nitrosomethylcyclohexylamine containing 5 mg/liter. A parallel five groups were treated in the same way with a solution of nitrosomethyl-3-carboxypropylamine in drinking water containing 600 mg per liter, as drinking water. Treatment lasted 28 weeks, at which time some animals had developed tumors. A group of 20 rats fed 0, 1.4 and 2.1 ppm Se was not treated with carcinogen. Rats consuming 1.4 ppm or 2.1 ppm Se gained weight more slowly than other groups. There was no significant difference in survival between the five groups treated with each carcinogen but receiving different dietary levels of selenium. Neither was there any significant difference between groups receiving each carcinogen in the incidence of tumors of the esophagus induced by nitrosomethylcyclohexylamine or of tumors of the urinary bladder induced by nitrosomethylcarboxypropylamine. Control rats on the synthetic diets did not survive as well as untreated rats eating regular chow diet. In these conditions there was no effect of dietary selenium levels on the induction of tumors in female rats by the two carcinogenic nitrosamines we used.

Animals↗

PubMed1985

Pattern recognition analysis of a set of mutagenic aliphatic N-nitrosamines.

A set of 21 mutagenic aliphatic N-nitrosamines were subjected to a pattern recognition analysis using ADAPT software. Four descriptors based on molecular connectivity, geometry and sigma charge on nitrogen were capable of achieving a 100% classification using the linear learning machine or iterative least squares algorithms. Three descriptors were capable of a 90.5% and two descriptors of a 85.7% overall correct classification. Three of the four descriptors were each capable of classifying 15 of the 16 active chemicals while it required three of the four descriptors to classify correctly two of the five inactive chemicals. These results are in concert with previous observations that molecular connectivity, geometry, and sigma charge on nitrogen are powerful descriptors for separating active from inactive mutagenic and carcinogenic N-nitrosamines.

Mutagens↗

PubMed1985

Formation and metabolism of nitrosamines in vivo, monitored by 14N-stable isotope labelling.

Microsomal metabolism of N-nitrosodimethylamine entails release of molecular nitrogen; the extent is determined by 15N stable isotope labelling and mass-spectrometric isotope ratio measurements. Exhalation of labelled nitrogen by rats treated with 15N-dimethylamine and nitrite or 15N-nitrite alone indicates that nitrogen may arise from nitrite via two pathways: either directly from nitrosation of primary amines or from secondary and tertiary amines with subsequent enzymic N-demethylation. The overall yield of nitrosamine formation, N-demethylation and nitrogen-release represent about 0.3-6% or the administered dose of dimethylamine (1.1 mmol/kg), depending upon the dose of nitrite (0.55-2.2 mmol/kg). 15N-stable isotope labelling and mass-spectrometric isotope ratio measurements are powerful tools for assessment of endogenous nitrosamine formation from nitrite. One hundred nmol of labelled nitrogen are easily detectable in vivo; with further methodological refinement the limit of detection may be lowered by two orders of magnitude.

Animals↗

PubMed2006

Nicotinic receptors mediate tumorigenic action of tobacco-derived nitrosamines on immortalized oral epithelial cells.

Frequent users of smokeless tobacco (ST) have an increased risk for developing oral cancer. Nicotine and its derivatives may contribute to tumorigenesis through stimulation of nicotinic acetylcholine receptors (nAChRs) in target cells. Emerging evidence indicates that nAChRs can be stimulated by the nicotine-derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) that can induce oral cavity tumors in laboratory animals. This study was designed to elucidate the receptor-mediated mechanisms of the initiation and progression of NNK-, and NNN-induced oral cancers. We used Het-1A cells that were found to express alpha3, alpha5, alpha7, alpha9, beta2 and beta4 nAChR subunits. Both NNK and NNN competed with nicotinic radioligands for binding to Het-1A cells. NNK showed a higher than NNN affinity to the [3H]nicotine-labeled binding sites, and NNN-to the [3H]epibatidine-sensitive nAChRs. NNK and NNN increased proliferative potential of Het-1A cells and produced an anti-apoptotic effect, which was alleviated by antagonists. alpha-Bungarotoxin was most effective against NNK and mecamylamine against NNN. Treatment of Het-1A cells with either NNK or NNN led to acquisition of capability of anchorage independent growth and ability to produce tumors in nude mice, both of which can be by inhibited by antagonists. To elucidate the signaling mechanisms, we studied transcription of the genes encoding the cell cycle, apoptosis and signal transduction regulators at both the mRNA and protein levels. The Het-1A cells stimulated with nitrosamines showed multifold increases of the mRNA transcripts encoding PCNA and Bcl-2, and upregulated expression of the transcription factors GATA3, nuclear factor-kappaB, and STAT-1. The STAT-1 protein-binding activity induced by NNK and NNN correlated with elevated gene expression. The obtained results establish the role of specific nAChR subtypes in tobacco-related carcinogenesis and open a novel avenue for oral cancer chemoprevention.

Humans↗

PubMed2002

Monitoring of nitrite and N-nitrosamine levels in irradiated pork sausage.

Residual nitrite and N-nitrosamine levels were monitored on irradiated emulsion-type cooked pork sausage in aerobic or vacuum packaging states during storage. The sausage was irradiated at 0, 5, 10, and 20 kGy and stored at 4 degrees C for 4 weeks. The residual nitrite levels were significantly reduced by gamma irradiation (P < 0.05), whereas the vacuum packaging was more effective for nitrite reduction than aerobic packaging during storage. N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) levels were significantly reduced in the vacuum packaged sausage irradiated with 20 kGy after 4 weeks. Reduction of NPYR in aerobically packaged sausage was also found after 4 weeks by irradiating with a 5-kGy or higher dose. NDMA reduction was shown in vacuum packaging and irradiation at 20 kGy. Gamma irradiation was effective in reducing the residual nitrite all throughout storage and N-nitrosamines in sausage after storage.

Animals↗

PubMed1976

Volatile nitrosamines in fried bacon.

Higher levels of NPy and NDMA in cooked bacon and its cooked-out fat were associated with those cures which contained higher levels of nitrite, but no correlation between nitrosamine concentrations and initial nitrate levels was observed. There was a higher proportion of nitrosamines in cooked-out fat than in cooked bacon, but by far the greatest amounts were lost in the vapours produced during cooking.

Animals↗

PubMed1999

The effect of epigallocatechin galleate and sarcophytol A on DNA strand breakage induced by tobacco-specific nitrosamines and stimulated human phagocytes.

The tobacco-specific nitrosamines (TSNAs) are metabolites of nicotine and are major carcinogens in cigarette smoke. Chronic inflammation may promote the carcinogenic effect of these nitrosamines through the generation of oxygen radicals as evidenced by an increase in DNA strand breakage in cultured human lung cells treated with stimulated human phagocytes and TSNAs. Sarcophytol A (SaA), a simple monohydroxycembratetraene isolated from marine soft coral, and (-)-epigallocatechin galleate (EGCG), one of the main constituents of green tea, both inhibit tumor promotion. To evaluate their effect on TSNA-induced genetic damage, cultured human lung cells were pretreated with SaA or EGCG and then exposed to the TSNA 4-(N-methyl-N-n-trosamino)-1-(3-pyridyl)-1-butanone (NNK) and stimulated human phagocytes and then assayed for single-strand DNA breaks. Both SaA and EGCG provided significant protection against the induction of genetic damage in these cells and may prove useful in the chemoprevention of tobacco-induced carcinogenesis.

Anticarcinogenic Agents↗

PubMed1999

Glyoxal-guanine DNA adducts: detection, stability and formation in vivo from nitrosamines.

The glyoxal-deoxyguanosine adduct (gG) is formed from alpha-nitrosamino aldehydes and dG in vitro and in vivo from nitrosamines carrying the 2-hydroxyethyl side-chain as well as from N-nitrosomorpholine. The structures of all of the diastereomeric forms of both the cis and trans isomers of the adduct have been investigated by ab initio calculations and with nuclear magnetic resonance spectroscopy at 500 MHz. The preferred orientation of the OH groups is trans, but at equilibrium a small amount of the cis isomer was observed. The pH-independent equilibrium constant for the hydrolysis of the gG adduct is K = 1.36 x 10(-4) mol/L, and its rate of formation at pH 7.3 is k = 5.3 min-1 mol-1. In acid (pH 2), the hydrolysis of the nucleosidic linkage is nearly twice as rapid as the hydrolysis of gG to glyoxal and dG. We used a gG analogue to explore a number of reductive methods for derivatization of the adduct, but all of the processes either gave low yields or product mixtures which rendered them impractical for derivatizing the adduct in DNA. A 32P-postlabelling method for detection of the pH-sensitive gG adduct has been developed, which permitted detection of the adduct in the liver DNA of male Wistar rats after administration of selected nitrosamines. The levels of adducts found were: N-nitrosodiethanolamine > 2-hydroxyethylmethynitrosamine > N-nitrosomorpholine > 2-hydroxyethyethylnitrosamine. In separate experiments, N-nitrosodiethanolamine gave greater adduct levels than its metabolite 2-hydroxy-N-nitrosomorpholine. Mechanistic pathways for the generation of gG adducts in vitro and in vivo are discussed.

Animals↗

PubMed1979

Mutagenic and DNA-damaging effects of N-alkyl-N-(alpha-acetoxyalkyl)nitrosamines, models for metabolically activated N,N-dialkylnitrosamines.

Mutagenic and DNA-damaging effects of a series of N,N-dialkylnitrosamines monosubstituted at the alpha-carbon with an acetoxyl group were tested in Salmonella typhimurium, Escherichia coli, and Bacilus subtilis in the absence of metabolic activation system. The compounds comprised 8 N-alkyl-N-(acetoxymethyl)nitrosamines (alkyl=methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl) and N-butyl-N-(1-acetoxybutyl)nitrosamine. All the compounds, except one with a tert-butyl group, gave positive results in these mutagenicity and repair tests. Presumed release of alkyl cations from the corresponding alpha-acetoxy derivatives by hydrolysis and heterolysis caused mutagenic and DNA-damaging effects in the bacteria. Structure-activity correlation of the compounds was noted in these tests and discussed in regard to the mutagenicity with metabolic activation and carcinogenicity of N,N-dialkylnitrosamines. The results support the hypothesis that alpha-carbon hydroxylation is one probable mechanism involved in the metabolic activation of N,N-dialkylnitrosamines.

Bacillus subtilis↗

PubMed1976

Survey of food products for volatile N-nitrosamines.

A variety of food products containing nitrite were analyzed for 14 volatile N-nitrosamines by using a method demonstrated to be sensitive to 10 ppb. A total of 121 food samples were screened for volatile N-nitrosamine content. N-Nitrosopyrrolidine was confirmed in fried bacon at levels up to 139 ppb. N-Dimethylnitrosamine, N-nitrosopyrrolidine, and N-nitrosopiperidine were also confirmed in spice-cure mixtures at levels ranging from 50 to 2000 ppb.

Dimethylnitrosamine↗