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PubMed1990

The role of nitrate, nitrite and N-nitrosamines in carcinogenesis of colon tumours following ureterosigmoidostomy.

Urinary diversion in both a rat model for ureterosigmoidostomy and in ureterosigmoidostomy patients result in an increased incidence of colon tumours. Bacterial and chemical investigations on feces-urine mixtures from both the rat model and ureterosigmoidostomy patients showed the presence of a complex nitrate-reducing bacterial flora in both rats and humans. This bacterial flora actively reduced urinary nitrate to nitrite in humans and increased the endogenous formation of N-nitroso compounds. No evidence of urinary nitrate reduction and increased nitrosamine formation in the rectosigmoid of rats was found. The results support the N-nitrosamine theory of carcinogenesis of the colon following ureterosigmoidostomy in humans, but not in rats. As the rat model induces colon carcinomas, factors other than the increased endogenous formation of N-nitroso compounds in the rectosigmoid may contribute to the initiation of colon carcinomas following ureterosigmoidostomy.

Animals↗
PubMed1986

Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver.

Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.

Alkylation↗
PubMed1984

Dose-response study of the carcinogenicity of tobacco-specific N-nitrosamines in F344 rats.

Tobacco and tobacco smoke contain relatively high amounts of four tobacco-specific N-nitrosamines. Of these, N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N'-nitrosoanatabine (NAT) were bioassayed at three dose levels by subcutaneous injections into male and female F344 rats in 60 subdoses amounting in total to 9,3, and 1 mmol/kg. Compared with the solvent control group (trioctanoin), both NNN and NNK induced significant numbers of tumors of the nasal cavity (P less than 0.01) at all three dose levels in both male and female rats. Significant numbers of tumors were also induced by NNK in the lung at all three dose levels and in the liver at the highest dose level (P less than 0.05). In addition to nasal tumors NNN also induced esophageal tumors at a significant rate in male rats at the high and medium dose levels and in female rats at the high level (P less than 0.05); NAT was inactive at the three doses tested. Bioassays at lower dose levels as well as biochemical studies are strongly indicated for NNN and NNK since these nitrosamines occur in relatively high amounts in both chewing tobacco and tobacco smoke.

Animals↗
PubMed1984

Volatile nitrosamines in the main stream smoke of black tobacco.

The cigarettes studied are smoked through an automatic device. The mainstream smoke is trapped in Citrate-Phosphate buffer pH 4.5 containing 20 mM ascorbic acid. The volatile nitrosamines are extracted in dichloromethane, purified on alumina column, then analysed by gas-chromatography with a thermal energy analyzer (TEA) detector. The two main volatile nitrosamines quantified are: Nitrosodimethylamine and Nitrosopyrrolidine.

Nitrosamines↗
PubMed1989

Effects of tobacco-specific nitrosamines and snuff extract on cell proliferation and activities of ornithine decarboxylase and aryl hydrocarbon hydroxylase in mouse tongue primary epithelial cell cultures.

Tobacco and its related compounds, including snuff, have been implicated in oral cancers. Tobacco-specific nitrosamines have been shown to be the causative agents present in tobacco and its related compounds. Both, N-nitrosonornicotine (NNN) and its butanone derivative (NNK) are carcinogenic in animals. In our in vitro studies using embryonic mouse tongue epithelial cells, NNN is linked to an increase in [3H]dT uptake along with a concomitant increase in ornithine decarboxylase and aryl hydrocarbon hydroxylase activities. NNK, the more potent compared to NNN, causes a further increase in [3H]dT uptake, cell count and ornithine decarboxylase activity. However, aryl hydrocarbon hydroxylase behaves differently in cultures treated with NNK compared to those treated with NNN. Snuff extract has an overall inhibitory effect on cell count, [3H]dT uptake, and ornithine decarboxylase and aryl hydrocarbon hydroxylase activities when administered either alone or in combination with NNN and NNK. How the inhibitory effect of snuff in the presence of tobacco-specific nitrosamines is involved in oral carcinogenesis should be further investigated.

Animals↗
PubMed1983

An experimental study on bacterial colonization, nitrite and nitrosamine production in the operated stomach.

Intragastric bacterial growth and nitrite and nitrosamine formation were investigated in animal experiments after different surgical procedures of ulcer management with regard to carcinogenesis in the operated stomach. The operative procedures resulted in an alteration in the gastric flora with an increase and predominance of nitrate-reducing bacteria. There was an increase in the intragastric nitrite and nitrosamine concentration corresponding to the increase in nitrate-reducing bacteria. All three parameters showed the greatest increase after gastric resection, whereas there were no significant differences after vagotomy with pyloroplasty, compared with a control group. These findings in animal experiments are of etiopathological relevance to the known danger of cancer in the resected human stomach and should be taken into consideration when choosing a procedure for surgical ulcer therapy.

Animals↗
PubMed1982

The effect of oxygen on nitrosamine formation in bacon.

Bacon has been cooked in air and in nitrogen atmospheres and the effect on the formation of N-nitrosodimethylamine and N-nitrosopyrrolidine has been studied. Under nitrogen, reductions of 50%-90% were obtained in the concentrations of both nitrosamines in the cooking vapour. The results are discussed in terms of the likely role of nitric oxide in nitrosamine formation in cooking bacon.

Anaerobiosis↗
PubMed1987

Determination of volatile nitrosamines in cheese and cured meat products. Model study of a temperature- and pH-dependent artefact formation phenomenon in alkaline medium.

The present paper describes how the formation of artefactual nitrosodimethylamine (NDMA) may jeopardize attempts at determining volatile nitrosamines in cheese by the mineral oil technique (MOT) or the glycerol isolation technique (GIT). When such isolation techniques were performed at an initial pH of about 11 and a final temperature of 100 degrees C (compared to 70 degrees C), up to about 10 micrograms NDMA per kg was formed. In a meat product, which was examined for comparison, even more extensive artefact formation (up to 70 micrograms NDMA per kg) was found. The addition of 10 mg/kg morpholine, as a readily nitrosatable substrate, to this meat product resulted (under the most unfavourable conditions) in formation of 250 micrograms/kg artefactual nitrosomorpholine. Alkalization of samples before nitrosamine analysis is a widely practised method to prevent artefact formation and has been emphatically recommended by an international working group, convened by the International Agency for Research on Cancer (Lyon). The mechanism of this peculiar artefact formation, which is strongly temperature- and pH-dependent, is not as yet known. It may however involve transnitrosation by C-, S- or O-nitroso compounds, e.g. nitrosophenols, nitrosothiols, alkyl nitrites, sugar nitrite esters, or lipid-nitrite reaction products. Several parameters of initial pH, final temperature and use of inhibitors under which the phenomenon will or will not occur are discussed. The artefact formation described here occurs mostly at pH values which are common to laboratory situations, but which are rare as for as the preparation of food in the household is concerned. Therefore, the effect does not appear to imply a risk to the consumer's health.

Cheese↗
PubMed1976

The effect of antioxidants on the production of volatile nitrosamines during the frying of bacon.

In model system studies simulating the frying of bacon a considerable variation in the production of N-nitrosopyrrolidine (NOPyr) has been observed, as occurs in sliced bacon fried conventionally. The inclusion of ascorbate or erythorbate (isoacorbate) has led consistently to a fall in or an elimination of NOPyr production up to an addition of 300 ppm (1,5 mM). Above this concentration of ascorbate, the elimination of NOPyr formation persisted in some instances but in others an increased production of the nitrosamine occurred. Using alpha-tocopherol, a fall of NOPyr production during the simulated frying of bacon was obtained with increase of concentration of the antioxidant, there being a consistent elimination of the volatile nitrosamine following an additionof 500 ppm (1.16 mM). Whilst ascorbyl palmitate had a similar action in reducing or eliminating NOPyr production, no synergistic effect between it and alpha-tocopherol was noted in an experiment combining the two antioxidants. When bacon was fried in fat containing 400 or 800 ppm alpha-tocopherol, the total production of NOPyr and DMN in the fried bacon, cooked out fat and condensate was markedly reduced but not completely eliminated as in the model system studies. Similarly, the curing of bacon with a brine containing a mixture of alpha-tocopherol, ascorbyl palmitate and citric acid has led to considerable reductions in NOPyr and DMN output on frying when the combined concentrations of the two anti-oxidants were calculated to be 800 ppm.

Animals↗
PubMed1977

[A gas-chromatographic method for the determination of volatile nitrosamines in plant material and soil (author's transl)].

A method is described which enables low molecular nitrosamines to be determined in plant material and mineral soils. The principle of this method is based on the steam volatility of these nitrosamines by means of which they can be isolated. Their detection and quantiative determination is then carried out by gas chromatography. The limit of detection in this method is 4 to 8 ppb fresh plant material or soil, the possible sample weigth in each case being decisive. The various species of plants or soils have no influence.

Carcinogens↗
PubMed1977

Spectral changes resulting from the interaction of some N-alkyl nitrosamines and rat liver microsomes.

Dimethyl (DMN) and diethyl nitrosamine (DEN) do not give characteristic spectral changes upon interaction with rat liver microsomes, while dipropyl (DPN) and dibutyl (DBN) nitrosamine cause type I spectral changes. The spectral binding constant is 100 mM for DPN and 1.17 mM for DBN. The maximal spectral change is 3.2 X 10(6) and 1.0 X 10(6) absorbance units per milligram protein for DPN and DBN respectively.

Animals↗
PubMed2001

Automated flow-injection spectrophotometric determination of nitrosamines in solid food samples.

A spectrophotometric method using a flow-injection system is proposed for the determination of nitrosamines in foods (cured-meats). The method is based on the photochemical cleavage of the N-NO bond of the nitrosamine to yield the corresponding amine and nitrite. The nitrite is then detected spectrophotometrically, at 542 nm, by use of its reaction with a modified Griess reagent. Different linear ranges between 0.8 and 2000 ng mL(-1) are obtained for the method, depending on the time of exposure of the sample to the UV radiation. The relative standard deviation varies between 2.0 and 3.9% and the sample throughput is between three and seven samples per hour, depending on the experimental conditions. The proposed method was successfully applied to the analysis of N-nitrosodimethylamine in cured ham and loin, bacon, and sausages.

Animals↗
PubMed2006

The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells.

Identification of the mechanisms leading to malignant transformation of respiratory cells may prove useful in the prevention and treatment of tobacco-related lung cancer. Nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) can induce tumors both locally and systemically. In addition to the genotoxic effect, they have been shown to affect lung cells due to ligating the nicotinic acetylcholine receptors (nAChRs) expressed on the plasma membrane. In this study, we sought to establish the role for nAChRs in malignant transformation caused by NNK and NNN. We used the BEP2D cells that represent a suitable model for studying the various stages of human bronchial carcinogenesis. We found that these cells express alpha1, alpha3, alpha5, alpha7, alpha9, alpha10, beta1, beta2, and beta4 nAChR subunits that can form high-affinity binding sites for NNK and NNN. Exposure of BEP2D cells to either NNK or NNN in both cases increased their proliferative potential which could be abolished in the presence of nAChR antagonists alpha-bungarotoxin, which worked most effectively against NNK, or mecamylamine, which was most efficient against NNN. The BEP2D cells stimulated with the nitrosamines showed multifold increases of the transcription of the PCNA and Bcl-2 genes by both real-time polymerase chain reaction and in-cell western assays. To gain a mechanistic insight into NNK- and NNN-initiated signaling, we investigated the expression of genes encoding the signal transduction effectors GATA-3, nuclear factor-kappaB, and STAT-1. Experimental results indicated that stimulation of nAChRs with NNK led to activation of all three signal transduction effectors under consideration, whereas NNN predominantly activated GATA-3 and STAT-1. The GATA-3 protein-binding activity induced by NNK and NNN correlated with elevated gene expression. The obtained results support the novel concept of receptor-mediated action of NNK and NNN placing cellular nAChRs in the center of the pathophysiologic loop, and suggest that an nAChR antagonist may serve as a chemopreventive agent.

Anticarcinogenic Agents↗
PubMed1985

High-performance liquid chromatographic analysis of metabolites of the nicotine-derived nitrosamines, N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

An improved high-performance liquid chromatographic system was developed for separation of 11 metabolites of the nicotine-derived nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The new system employed a 5-microns octadecylsilane bonded column eluted with aqueous sodium acetate-methanol gradients of varying pH. Analysis times were typically 30 min for NNN metabolites and 50 min for NNK metabolites, compared to 80 and 90 min, respectively, when 10-microns columns were used. The E and Z isomers of all nitrosamine-containing metabolites of NNK were separated. The chromatographic behavior of the 11 metabolites as well as NNN and NNK was studied between pH 4.0 and 7.5. The retention times of several metabolites were altered significantly as a function of pH. The results of the pH study provide valuable additional criteria for metabolite identification as well as optimized conditions for their separation. Applications of the system to the metabolism of [2'-14C]NNN in cultured rat esophagus and [carbonyl-14C]NNK in rat liver slices are presented.

Animals↗
PubMed1985

Demethylation and denitrosation of nitrosamines by cytochrome P-450 isozymes.

Metabolism of nitrosamines was studied in a reconstituted monooxygenase system composed of cytochrome P-450 isozymes purified from liver microsomes of ethanol- and phenobarbital-treated rats. The ethanol-induced isozyme (P-450et) was efficient in catalyzing the demethylation of N-nitrosodimethylamine (NDMA), with a Km of 2.4 mM and Vmax of 7.2 nmol min-1 nmol P-450(-1), but less active with N-nitrosomethylbenzylamine and N-nitrosomethylaniline. The phenobarbital-induced form (P-450b) was ineffective in NDMA metabolism but was active in catalyzing the demethylation of N-nitrosomethylaniline, with an estimated Km of 0.08 mM and a Vmax of 7.2 nmol min-1 nmol-1. P-450et also catalyzed the denitrosation of NDMA with a Km of 13.6 mM and a Vmax of 1.36 nmol min-1 nmol-1. With control liver microsomes, multiple Km values were observed for the demethylation and denitrosation of NDMA. Involvement of superoxide radicals in the metabolism of NDMA was suggested by the action of superoxide dismutase, which inhibited the denitrosation by 43 to 73% and the demethylation by 13 to 22% in different monooxygenase systems. The P-450et-dependent NDMA demethylation was strongly inhibited by 2-phenylethylamine and 3-amino-1,2,4-triazole; these compounds were previously believed not to be inhibitors of P-450-dependent reactions but were found to inhibit microsomal NDMA demethylase. The present results establish the role of P-450 in nitrosamine metabolism and help to clarify some of the previous confusion in this area of research.

Amitrole↗
PubMed1992

Inhibition of herpes simplex virus replication and protein synthesis by non-smoked tobacco, tobacco alkaloids and nitrosamines.

Inhibitory effects of snuff extract and the tobacco chemicals nicotine, anabasine, diethyl-N-nitrosamine (DEN), and the tobacco-specific nitrosamines (TSNA), N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on herpes simplex virus type 1 (HSV-1) replication in vitro and on HSV-1 protein synthesis in infected cells were analysed. Snuff extract and nicotine caused a significant reduction of HSV-1 attachment to cell membranes whereas anabasine, DEN, NNN and NNK did not affect adsorption of HSV-1. Virus production assays in the presence of snuff added after virus adsorption resulted in a significantly reduced production of virus at low multiplicities of infection (MOI), but at high MOI the inhibitory effect of snuff extract was less pronounced. DEN, NNN and NNK only affected virus production at toxic concentrations. Nicotine and anabasine reduced virus production in non-toxic doses but not at the concentrations present in snuff extract. In HSV-infected cells exposed to snuff extract, the immediate early (alpha-) infected cell proteins (ICPs) 4 and 27 (as well as the early (beta-) ICPs 6 and 8) were markedly increased, whereas the late (gamma-) ICPs 5, 11 and 29 were reduced. Nicotine had a less pronounced stimulating effect on the production of alpha-proteins but no detectable effect on production of beta- or gamma-proteins. Anabasine, DEN, NNN and NNK did not affect HSV protein synthesis at non-toxic concentrations. Synthesis of thymidine kinase and DNA polymerase was significantly reduced by snuff extract. Also nicotine and anabasine affected thymidine kinase and DNA polymerase but only at toxic concentrations. The production of the cellular protein actin, which almost disappears a few hours after HSV-1 infection, remained at a significant level in HSV-infected cells exposed to snuff. Thus snuff extract blocks the replicative cycle of HSV at an early stage, which results in an increased production of alpha-proteins in the infected cells and in prolonged maintenance of cellular functions. This may be of importance for HSV-induced transformation and the development of HSV-associated tumours.

Alkaloids↗
PubMed1977

Liposolubility as an aspect of nitrosamine carcinogenicity: quantitative correlations and qualitative observations.

Carcinogenicity data for a number of nitrosamines have been examined for possible structure-activity correlations with liposolubility by the method of Hansch. Correlations were found in two cases which support a previous mechanistic suggestion and which also suggest a possible difference between the action of nitrosopiperidines and dinitrosopiperazines in inducing olfactory carcinomas. No correlations were found for non-cyclic nitrosamines.

Alcohols↗
PubMed1984

Formation of epsilon-hydroxycaproate and epsilon-aminocaproate from N-nitrosohexamethyleneimine: evidence that microsomal alpha-hydroxylation of cyclic nitrosamines may not always involve the insertion of molecular oxygen into the substrate.

The formation of the products of microsomal metabolism of the cyclic nitrosamine, nitrosohexamethyleneimine (NO-HEX) were studied. Information on the origins of the oxygen atoms in four major metabolites of NO-HEX was obtained by metabolizing this compound in an 18O2 atmosphere using microsomes and cytosol, beta- and gamma-Hydroxy-NO-HEX are formed as a result of the insertion of a hydroxyl group derived from molecular oxygen into NO-HEX. All of the oxygen atoms in epsilon-aminocaproate (EAC) were derived from water. Approximately half of the molecules of epsilon- hydroxycaproate ( EHC ) contain an 18O atom; thus, half of the alpha-hydroxy-NO-HEX formed incorporates a hydroxyl group derived from molecular oxygen with the remainder of the hydroxyls being from water. To account for the above data and the related metabolic origins of EAC and EHC ( Hecker and McClusky , Cancer Res., 42 (1982) 59; Hecker et al., Teratogen. Carcinogen. Mutagen (1982) in press), we have proposed a mechanism for the formation of these compounds from cyclic nitrosamines catalyzed by microsomal and cytosolic enzymes.

Aminocaproates↗