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PubMed1982

Formation of N-nitrosamines and N-nitramines by photolysis.

N-Nitrosamines are generated by the photolysis of neutral aqueous solutions of nitrite salts and heterocyclic amines. With nitrate salts, photolysis produces a mixture of N-nitrosamines and N-nitramines. The reactions occur with low (5 mmol/l) reagent concentrations under very mild conditions and are faster than the concurrent decomposition of N-nitrosamines and N-nitramines by photolysis. Furthermore, both N-nitrosamines and N-nitramines effect transnitrosation reactions under mild neutral conditions when photolysed in the presence of other amines.

Amines↗
PubMed1982

Urinary excretion of N-nitrosamines in rats and humans.

Various sources may contribute to the total human exposure to nitrosamines (foods, drugs, cosmetics, polluted air and endogenous formation of N-nitroso compounds). The average intake of nitrosamines can be calculated using analytical data. The more relevant method of biological monitoring can be used, however, to estimate individual exposure, in which case possible in vivo formation may also be detected. Since blood measurements can be carried out only under great difficulty and reflect only the momentary situation, the urinary excretion of nitrosamines was studied in animal experiments. The urinary excretion of nitrosodimethylamine (NDMA), nitrosomorpholine (NMOR) and nitrosodiethanolamine (NDELA) in SD-rats was measured within 24 h after epicutaneous, intratracheal, oral and intravenous application. The dose range covered was 5, 50 and 500 micrograms/animal for NDMA, 4, 44 and 440 micrograms/animal for NMOR and 0.03-300 mg/animal for NDELA. Under the influence of diethylether, a 7- to 20-fold increase of excretion was observed. Biological monitoring in humans at low doses (10-100 micrograms NDMA) is possible only if the excretion rate is increased by administration of ethanol. By reducing the activity of metabolizing enzymes with ethanol or other suitable compounds, possible in vivo formation of nitrosamines might also be more easily detectable. Excretion rates do not seem to be dose-dependent in the ranges investigated.

Animals↗
PubMed1982

Screening procedure for detection of volatile N-nitrosamines in cooked bacon by one-trap mineral oil vacuum distillation and thermal energy analyzer.

A rapid screening procedure for the detection of volatile N-nitrosamines in fried bacon has been developed for the regulatory monitoring of bacon. This procedure uses vacuum mineral oil distillation of an alkaline sample. The distillate is collected in a prewet trap immersed in liquid nitrogen. After thawing, the distillate is transferred to a separator. The trap is rinsed with methylene chloride which is then used to extract the nitrosamines. The methylene chloride is dried with Na2SO4 and concentrated. A gas-liquid chromatograph coupled to a thermal energy analyzer is used to identify and quantitate the nitrosamines. Recoveries of 7 volatile N-nitrosamines added to 25 g fried bacon at the 10 ppb level (microgram/kg) ranged from 78 to 92%.

Animals↗
PubMed1980

Model system studies on N-nitrosamine formation in relation to cured meat: the non-polar phase and S-nitroso peptides.

In view of recent findings that N-nitrosamine formation occurs principally in the adipose tissue of frying bacon, an heterogeneous protein-based model system has been developed which incorporates a 20% decane phase. The N-nitrosation reactions of a series of secondary amines, of varying lipophilicity, have been studied at 37 degrees C, pH 5.25, in the model system, formulated with and without the non-polar phase. In the presence of decane, a 20-fold enhancement in the formation of N-nitrosodihexylamine was observed, whereas no increase was found for N-nitrosopyrrolidine. Ascorbic acid enhanced the N-nitrosation of lipophilic amines in the presence of decane, but did not affect the yield of N-nitrosopyrrolidine under the same conditions. Ascorbyl palmitate had little influence on the N-nitrosation reactions in the presence or absence of decane. The results are discussed in relation to N-nitrosamine formation in the lean and adipose components of fried bacon. The degree of N-nitrosation afforded by S-nitroso amino acids and peptides has been investigated as a function of the size of the 'peptide' molecule in aqueous solution. The reactions of N-methylaniline with sodium nitrite, S-nitrosocysteine, S-nitrosoglutathione and S-nitrosoglutathione bound to a polysaccharide gel have been examined at 37 degrees C, pH 5.5. The rates of N-nitrosamine formation were found to be higher for S-nitrosocysteine than for the peptide systems, although the rate for the polysaccharide model system was dependent upon the local S-nitroso concentration on the gel. The results are discussed in relation to N-nitrosamine formation in cured meats and in the digestive tract.

Amino Acids↗
PubMed1981

Metabolic fate of N-butyl-N-(4-hydroxybutyl) nitrosamine and N, N-dibutylnitrosamine in the guinea pig, with reference to their carcinogenic effects on the urinary bladder.

The metabolic fate of two urinary bladder carcinogens, N-butyl-N-(4-hydroxy-butyl) nitrosamine (BBN) and N-N-dibutylnitrosamine (DBN), was studied in the guinea pig, in order to elucidate species differences of response to these N-nitrosamines in this animal species and the rat. Based on the urinary metabolites characterized after oral administration of these compounds, the metabolic pathways of BBN and DBN in the guinea pig were shown to be essentially similar to those in the rat. The principal urinary metabolite of BBN and DBN in the guinea pig, however, was not N-butyl-N-(3-carboxypropyl) nitrosamine (BCPN), as was the case in the rat, but the glucuronic acid conjugate of BBN and that of N-butyl-N-(3-hydroxybutyl) nitrosamine, respectively. The species variation in response to BBN and DBN as bladder carcinogens in these animals is discussed on the basis of the urinary excretion of BCPN.

Animals↗
PubMed1991

Urothelial hyperplasia and neoplasia. III. Detection of nitrosamine production with different bacterial genera in chronic urinary tract infections of rats.

Various agents have been implicated in inducing urothelial cancer. Although drugs, occupational and environmental carcinogens are more widely accepted as playing a major role as urothelial carcinogens, several investigations suggest that bacteria may play a role. The mechanism of how bacteria may interact with the host to augment the development of urothelial carcinoma is not well understood. Clinically, investigators have linked the development of infection, urinary stones and indwelling catheters with urothelial cancer. Other investigators have suggested that the mechanism may be related to the production of carcinogenic compounds (nitrosamines) which can be detected during urinary tract infection. In our laboratory, we showed that rats with chronic urinary tract infections produced increasing urinary levels of N,N dimethylnitrosamine over a 24 week period and that the production correlated with hyperplasia and early neoplasia of the bladder epithelium. Three bacterial genera were used and two of these (Escherichia coli and a protein sp.) showed production of increasing levels of urinary nitrosamine and correlated with infection. The purpose of this current study is to determine if other bacterial genera and strains can also produce similar increasing nitrosamine levels in the rat model of chronic urinary tract infection and thus provide evidence that a number of bacterial genera and strains can produce nitrosamines in vivo. Also, the histology of the chronically infected bladder was examined for hyperplasia and neoplasia.

Animals↗
PubMed1999

Exposure to N-nitroso compounds in a population of high liver cancer regions in Thailand: volatile nitrosamine (VNA) levels in Thai food.

The recent case-control studies in Thailand indicate that a high incidence of liver cancer in Thailand has not been associated with common risk factors such as hepatitis B infection, aflatoxin intake and alcohol consumption. While the infestation by the liver fluke Opisthorchis viverrini (OV) accounted for the high risk in north-east Thailand, there was no such exposure in the other regions of the country where the incidence of liver cancer is also high. Case-control studies suggest that exposure to exogenous and possibly endogenous nitrosamines in food or tobacco in betel nut and cigarettes may play a role in the development of hepatocellular carcinoma (HCC), while OV infestation and chemical interaction of nitrosamines may also be aetiological factors in the development of cholangiocarcinoma (CCA). Over 1800 samples of fresh and preserved food were systematically collected and tested between 1988 and 1996. All the food items identified by anthropological studies to be consumed frequently in four major regions of Thailand were analysed for volatile nitrosamines using gas chromatography combined with a thermal energy analyser. Relatively high levels of N-nitrosodimethylamine (NDMA), N-nitrosopiperidine (NPIP) and N-nitrosopyrrolidine (NPYR) were detected in fermented fish ("Plasalid"). NDMA was also detected at levels ranging from trace amounts to 66.5 microg/kg in several salted and dried fish ("Larb-pla" and "Pla-siu"). NDMA and NPYR were frequently detected in several vegetables, particularly fermented beans ("Tau-chiau") at levels ranging between 1 and 95.1 microg/kg and 0-146 microg/kg, respectively. The possible role of nitrosamines in Thai food in the aetiology of liver cancer (HCC, CCA) is discussed.

Case-Control Studies↗
PubMed2002

Decomposition of N-nitrosamines, and concomitant release of nitric oxide by Fenton reagent under physiological conditions.

N-Nitrosodimethylamine (NDMA) in phosphate buffer was rapidly decomposed by Fenton reagent composed of H2O2, and Fe(II) ion. Electron spin resonance (ESR) studies using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) showed that characteristic four line 1:2:2:1 ESR signals due to the DMPO-OH adduct formed on treatment of DMPO with Fenton reagent disappeared in the presence of NDMA, and N-nitrosodiethylamine (NDEA), suggesting the interaction of the N-nitrosamines with Fenton reagent. Treatment of the N-nitrosamines with Fenton reagent generated nitric oxide (NO) as estimated by ESR technique using cysteine-Fe(II), and N-methyl-D-glucaminedithiocarbamate (MGD)-Fe(II) complexes. Characteristic 3, and single line signals due to 2 cysteine-Fe(II)-NO, and 2 cysteine-Fe(II)-2 NO complexes, respectively, and three line signals due to MGD-Fe(II)-NO were observed. Considerable amount of NO were liberated as determined by NO2-, the final oxidation product of NO formed by reaction with dissolved oxygen in the aqueous medium. Spontaneous release of a small amount of NO from the N-nitrosamines was observed only on incubation in neutral buffers. Above results indicate that the N-nitrosamines were decomposed accompanying concomitant release of NO on contact with reactive oxygen species.

Electron Spin Resonance Spectroscopy↗
PubMed2002

Dietary exposure and urinary excretion of total N-nitroso compounds, nitrosamino acids and volatile nitrosamine in inhabitants of high- and low-risk areas for esophageal cancer in southern China.

We assessed the exposure of total N-nitroso compounds (TNOCs) in the inhabitants of high- and low-risk areas for esophageal cancer in southern China. Samples of 24 hr diet and 12 hr overnight urine were collected from 120 male adults in each of the 2 areas, a high-risk area (Nan'ao County) and a low-risk area (Lufeng County) for esophageal cancer. Annual standardized mortality rates of esophageal cancer in Nan'ao and Lufeng are 110/10(6) and 10/10(6) respectively. The 240 healthy male subjects (35-64 years old) were selected by a 3-stage random cluster sample procedure. Levels of TNOCs, NAAs and volatile nitrosamines in the samples were measured. The TNOC detection rate (95%) in the diet, the TNOC daily intake (4.25 +/- 0.84 micromol), TNOC excretion levels (0.04 +/- 0.01 nmol/12 hr) and daily intake of volatile nitrosamines (5.84 +/- 0.71 micromol) in the high-risk area were significantly greater than values in the low-risk area (A +/- B = mean +/- SE). The TNOC detection rate in the diet, the TNOC daily intake, TNOC excretion levels and daily intake of volatile nitrosamines in the low-risk area were 70%, 0.25 +/- 0.06 micromol, 0.02 +/- 0.01 nmol/12 hr and 3.18 +/- 0.31 micromol, respectively. NAA excretion levels showed no difference between the 2 areas (16.3 +/- 7.18 micromol/12 hr for Nan'ao and 31.2 +/- 26.4 micromol/12 hr for Lufeng). Thus, TNOCs are implicated in the etiology of esophageal cancer in southern China.

Adult↗
PubMed1979

Analysis of nitrosamines in aqueous and biological fluids based on measurement of photochemically liberated nitrite.

A method is described for the analysis of nitrosamines in aqueous solution and in biological fluids (blood, plasma, and rat liver microsomal suspensions). The method is based on photochemical degradation of the nitrosamine in a controlled environment to yield the corresponding amine and nitrite ion, and the latter is subsequently used to form a chromophoric or fluorescent product. The analysis scheme is a modular three-component system consisting of a column to remove contaminating nitrite prior to photolysis, a photochemical reactor, and a chemical reactor. Additional modules are used to accommodate biological samples or large-volume (5--50 ml) aqueous samples. In this study, N-nitrosopyrrolidine, N-nitrosodimethylamine, and N,N-diethanolnitrosamine were utilized as substrates. Because of intersubstrate variability in the photochemical decomposition rate and overall nitrite yield, the structure (i.e., photochemical behavior) of the particular nitrosamine in the sample must be known prior to analysis. With a colorimetric readout, the sensitivity for analysis of N-nitrosopyrrolidine was 800 ng/ml for a 5-ml sample and the measurement precision was +/- 6% in the biological fluids. Fluorometric analysis improved sensitivity to 4 ng/ml with a precision of +/- 10% in biological media.

Animals↗
PubMed1992

Quantitative structure-activity relationship study of the biophysicochemical behavior of nitrosamine.

The partition coefficients of 14 aliphatic nitrosamines were measured in six water-organic solvent systems. Correlations between Hansch's hydrophobic parameter (pi) and Kier and Hall's topological index (1 chi) allowed pi to be substituted by 1 chi in the structure-activity correlations of the carcinogenicity data of the nitrosamines studied. The use of high-performance liquid chromatographic capacity factors of nitrosamines in these correlations is also discussed.

Chemical Phenomena↗
PubMedDate not supplied

Tobacco-specific nitrosamines--metabolism and biological monitoring of exposure to tobacco products.

Tobacco-specific nitrosamines are derived from nicotine and related tobacco alkaloids and can be detected in tobacco products as well as in mainstream and sidestream smoke. Two of them, N-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, are strong carcinogens in laboratory animals. Because of its organospecificity for the lung, the latter is considered to be a causative factor in tobacco-related human lung cancer. Upon metabolic activation both nitrosamines give rise to a common reactive intermediate binding to macromolecules such as DNA and haemoglobin and hydrolysing to 4-hydroxy-1-(3-pyridyl)-1-butanone. Because of easy access to large quantities of haemoglobin from blood samples, it is most suitable for biomonitoring human exposure to tobacco-specific nitrosamines. A highly sensitive analytical method for determination of femtogram amounts of 4-hydroxy-1-(3-pyridyl)-1-butanone provides an approach to assess individual exposure to active and passive smoking.

Alkaloids↗
PubMed1982

Carcinogenicity of N-alkyl-N-(acetoxymethyl)nitrosamines after subcutaneous injections in F-344 rats.

As model compounds for metabolically activated N,N-dialkylnitrosamines, five N-alkyl-N-(acetoxymethyl)nitrosamines were synthesized and their carcinogenicity was tested in F-344 rats of both sexes. Compounds used in this study are N-methyl-(MAMN), N-ethyl-(EAMN), N-propyl-(PAMN), N-butyl-(BAMN), and N-isobutyl-N-(acetoxymethyl)nitrosamines (i-BAMN). All chemicals were dissolved in olive oil and rats received 10 weekly subcutaneous injections of these chemicals (10 X 5 mg MAMN or equimolar amounts of other chemicals) at the interscapular region. Subcutaneous tumors were detected in many rats of all groups treated with the chemicals, although no tumor was detected in the control group. Lung and/or thyroid tumors were also observed in many rats in the experimental groups. The incidence of subcutaneous tumors was highest in EAMN, followed in order by MAMN, PAMN, BAMN, and i-BAMN. On the contrary, the incidence of lung and thyroid tumors was highest in MAMN and decreased as the length of the alkyl chain of the chemicals increased. Histologically, almost all subcutaneous tumors were malignant fibrous histiocytomas. The results indicate that the chemicals possess systemic as well as local carcinogenicity in F-344 rats. The potent carcinogenic effects at the injection site of the alpha-acetoxy nitrosamines, coupled with their direct mutagenic activity reported previously, support the notion that these derivatives are useful as models for the ultimate form in the metabolic activation of N,N-dialkylnitrosamines.

Animals↗
PubMed1990

Interaction and inhibition of acetylcholinesterase from Electrophorus electricus by nitrosamines.

Kinetic analysis has shown that dimethylnitrosamine, dipropylnitrosamine, dibutylnitrosamine, and diphenylnitrosamine initially act as reversible competitive inhibitors with respect to the substrate, acetylthiocholine chloride. The inhibitor constants Ki vary from 21-30 microM for the aliphatic nitrosamines to 8.2 microM for the aromatic diphenylnitrosamine. With time they act as irreversible covalent inhibitors with dimethylnitrosamine producing 82% inactivation after 40 min. Pseudo-first-order kinetics are observed with the rate constant being proportional to the concentration of the nitrosamine and the order of reaction being equal to one. Fluorometry, gel chromatography, and equilibrium dialysis have been used to study the binding of the nitrosamines with acetylcholinesterase. Scatchard analysis indicates that dimethyl-, dipropyl-, and dibutylnitrosamine have a weaker affinity for the enzyme (Kd 5.6-8.08 microM) compared to diphenylnitrosamine (Kd 2.32 microM). In all cases the number of binding sites was four.

Acetylcholinesterase↗
PubMed1990

Protein-ligand interactions: interaction of nitrosamines with nicotinic acetylcholine receptor.

Fluorimetry and spectrophotometry have been used to study the binding of dimethyl, dipropyl, dibutyl and diphenylnitrosamine to nicotinic acetylcholine receptor isolated, and purified, from Torpedo fuscomaculata. Scatchard analysis indicates that all four ligands are true agonists of the receptor exhibiting positive cooperative binding with the existence of more than one class of binding site. The number of binding sites for the nitrosamines approximates 2. Diphenylnitrosamine binds to the receptor more tightly at low concentrations (Kd1 = 1.3 microM) than the aliphatic nitrosamine (Kd1 = 8-12 microM). Yet at high concentrations all nitrosamines behaved with similar Kd values (27-38 microM).

Acetylcholine↗
PubMed1984

Structure-activity relationships of nitrosamines and nitramines which stimulate UDP-glucuronosyltransferase activities in vitro.

Examination of twelve nitrosamines and seven nitramines revealed that nitramines modify UDP-glucuronosyltransferase activity in a manner similar to that of nitrosamines. Only N,N-diethyl-substituted nitrosamine and nitramine significantly stimulated transferase activity toward 2-aminophenol and 4-nitrophenol but not toward phenolphthalein and androsterone. Elongation of the alkyl chains or introduction of carboxy, hydroxy, or oxo groups into the alkyl chains did not result in stimulatory ability, and some of these compounds inhibited the transferase activity.

Aminophenols↗
PubMed1990

Use of differential DNA-repair host mediated assays to investigate the biotransformation of xenobiotics in Drosophila melanogaster. I. Genotoxic effects of nitrosamines.

A rapid differential DNA-repair assay procedure was developed to investigate the biotransformation of xenobiotics in Drosophila melanogaster in vivo. Indicator of genotoxic activity was a pair of streptomycin-dependent Escherichia coli strains differing vastly in DNA repair capacity (uvr+/rec+ vs. uvrB/recA). Prior to the experiments with test compounds, mixtures of the two strains were injected into the abdomina of untreated animal hosts (male Berlin-K flies) and the time-dependent recovery kinetics determined. Subsequently, different aliphatic and aromatic nitrosamines were tested. Solutions of the compounds were injected simultaneously with the indicator cells. Three hours later, the flies were killed, homogenized and the induction of (repairable) DNA damage determined by comparison of the survival rates of the two strains in single animals. Eight carcinogenic compounds (nitrosodiethylamine, NDEA; nitrosodimethylamine, NDMA; nitrosodi-npropylamine, NDPA; nitrosodiethanolamine, NDELA; nitrosomethylaniline, NMA; 4-methyl-nitrosopiperidine, MNPIP; nitrosopyrrolidine, NPYR; nitrosomorpholine, NMOR) and one whose tumorigenic activities are still controversially discussed (nitrosodiphenylamine, NDPhA) induced dose-dependent differential killing effects in the present system. One agent which has not been found carcinogenic in rodents (2.6-dimethyl-nitrosopiperidiine. NDMPIP) gave negative results. The ranking order of genotoxic activities of the nitrosamines found in Drosophila in vivo is in good agreement with those of carcinogenic potencies established on the basis of experiments with rats. The most pronounced exceptions are the rather weak response towards NMA and the stronger DNA damaging activity of NMPIP compared to NDMA. Phenobarbital (5-ethyl-5-phenyl-2,4,6-trioxohepatahydropyramidine) (PB) feeding of the flies resulted in an increase of the DNA damaging potencies of all nitrosamines tested. Substantial enhancement of the induction of DNA damage was however, restricted to NDEA, NPYR and NMOR, whereas with nitrosodiphenylamine (NDPhA), NDELA and NDMA only a moderate (less than 25%) increase of differential killing effects was found. In the case of the two latter compounds, these results might be due to the fact that enzymes other than the MFO are involved in their activation. Attempts to localize the formation and/or distribution of metabolites in the bodies of fruitflies by separation of the tagmata of chemically treated animals and determination of genotoxic effects in the different segments indicate that the most pronounced effects occur in the abdomina whereas in heads and thoraxes comparatively lower activities are detectable.

Animals↗
PubMed1977

Mutagenicities of N-nitrosamines on Salmonella.

The mutagenic activities of 11 N-nitrosamines were tested using Salmonella typhimurium TA100 and TA98. All the carcinogenic N-nitrosamines were mutagenic on TA100 with a drug-activating system from the rat liver, whereas N,N-diphenylnitrosamine, a non-carcinogen, was not mutagenic. None of the N-nitrosamines was mutagenic on TA98, except N,N-diethylnitrosamine which was weakly mutagenic. To detect the mutagenicity of N,N-dimethylnitrosamine, the pre-incubation of bacteria and N,N-dimethylnitrosamine with S-9 Mix before if was poured onto plates was obligatorily required. Dimethyl sulfoxide inhibited the mutagenic effect of N,N-dimethylnitrosamine.

Animals↗