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PubMed1986

Use of diethyldithiocarbamate as a probe to detect stable intermediates during the decomposition of several mutagenic and nonmutagenic N-nitroso compounds.

By showing that methyldiethyldithiocarbamate is formed from the reaction of methylnitrosourea and disulfiram, we demonstrated in previous experiments that one of the anticarcinogenic/antimutagenic mechanisms of disulfiram is the scavenging of reactive species. We propose that this reaction may be employed additionally as a model for elucidating the following: (a) possible reactions between alkylating species and nucleophilic sites within the cell, and (b) the existence of stable intermediates during the metabolism of N-nitroso compounds. With structurally related pairs of nitrosoureas (n-propyl/isopropyl; cyclopropyl/allyl; 2-phenylethyl/l-phenylethyl), for which each alkylating group of the first compound can spontaneously rearrange to form the alkylating group of the second isomer, we investigated whether the alkylation proceeds via a monomolecular (sn1) or a bimolecular substitution (sn2). For this, we comparatively determined the relative mutagenic activities of each isomer in Salmonella typhimurium TA 1535, as well as their reactivities towards diethyldithiocarbamate (DDTC) by identifying the reaction products. These studies were aimed at revealing the possible formation of a free carbonium ion in the decomposition of several nitrosoureas in the rat liver supernatant fraction. Our system showed that DDTC reacts by two competing mechanisms: attack at the diazonium ion and at the free carbonium ion. Therefore the striking differences which were observed in the mutagenic potency of cyclopropylnitrosourea and N-nitrosoallylurea as well as of N-nitroso-2-phenylethylurea and N-nitroso-1-phenylethylurea cannot be explained only by the different electrophilic reactivities of the respective intermediates.

Animals↗
PubMed1979

Problems of dose-response studies in chemical carcinogenesis with special reference to N-nitroso compounds.

Dose-response studies in chemical carcinogenesis are a valuable method for evaluating the risk involved by a certain carcinogen. This article deals with the methods that are presently applied for dose-response studies. It is emphasized that there are many possible mistakes that are already hidden in the method itself; a critical approach is made to the indicative value of dose-response studies. It is also emphasized that the conclusions which may be drawn from dose-response studies can always only be extrapolative but never mathematically calculable. Finally, some practical examples for dose-response studies with n-nitroso compounds are described.

Animals↗
PubMedDate not supplied

[Food inhibitors of the formation of carcinogenic nitroso compounds].

A study was made of the effect of plant preparations, pectin, plantastin, tiliaflan, cholosas and carbonic acid phytoextract from the fruit of the Umbelliferae family (CO2-EP) on the synthesis of carcinogenous nitrosodimethylamine from amidopyrine and sodium nitrite. Gas chromatography made in vitro and in short-term experiments on animals demonstrated plantastin to display an inhibitory action, which was less marked for tiliaflan, CO2-EP and cholosas. The system of experiments in question may be recommended for preliminary screening of the inhibitors of nitrosation with a purpose of using them for the prophylaxis of carcinogenesis induced by nitroso compounds.

Animals↗
PubMed2002

A brain nitric oxide synthase study in the rat: production of a nitroso-compound NA and absence of nitric oxide synthesis.

The products of brain NO-synthase (NOS) were studied by different analytical techniques with the same incubation conditions. Voltammetric techniques used a micro cell containing NOS and its substrate (10 mM arginine). Using porphyrin microelectrodes with differential pulse amperometry nitric oxide (NO) was not detected when nafion membrane was present (less than 0.3 muM). Nitrite was detected with the same microelectrode without membrane (0.42 mM). Differential pulse voltammetry (DPV) with micro carbon electrode detected a nitroso-compound (NA) in reduction (1 mM) and not NO. In oxidation the observed DPV peak was due to nitrite (0.43 mM). Citrulline was detected by high performance liquid chromatography (0.51 mM). Using Diels Alder reaction in NOS preparation a NA-cycloadduct was observed by capillary electrophoresis (0.2 mM) and mass spectrometry (0.22 mM). Diels Alder reaction is the reaction of the identification of the nitroso group. NA-cycloadduct degradation by retro Diels Alder reaction gave equimolar concentrations of citrulline and nitrite without NO production. These observations lead us to affirm that NOS synthesizes NA.

Animals↗
PubMed1992

Caffeine-derived N-nitroso compounds--I: Nitrosatable precursors from caffeine and their potential relevance in the etiology of oesophageal and gastric cancers in Kashmir, India.

Salted tea prepared in Kashmir by adding sodium bicarbonate shows high methylating activity (equivalent to 3 p.p.m. N-methylnitrosourea) upon in vitro nitrosation. Pure caffeine treated under conditions of the tea preparation formed caffeidine and caffeidine acid. We report here the formation of two new compounds, mononitrosocaffeidine, an asymmetric nitrosamine, and dinitrosocaffeidine, a N-nitrosamide, on in vitro nitrosation of caffeidine. Mononitrosocaffeidine is also found after nitrosation of the typical Kashmir tea. The nitrosation of caffeidine acid produced N,N'-dimethyl-parabanic acid, mononitrosocaffeidine and N,N'-dimethyl-N-nitrosourea. In view of the well-known structure-activity relationships of these N-nitroso compounds, their possible endogenous formation due to high consumption of salted tea may be a critical risk factor for the high occurrence of oesophageal and gastric cancers in Kashmir.

Bicarbonates↗
PubMed1985

[Formation of volatile carcinogenic N-nitroso compounds from drugs under simulated human gastric conditions].

41 commercial drugs approved for peroral application in the GDR, whose active agents contain N,N-dialkylamino groups in their chemical structures, have been investigated under simulated conditions of the human stomach. With the drugs containing aminophenazone, amitriptyline, doxycycline and oxytetracycline as active agents N-nitrosodimethylamine is formed as a result of nitrosation reactions. With the drugs containing clomiphene++, disulfiram, probenecid and a diethylamine-containing liquid hypnoticum, there occurred N-nitrosodiethylamine. In no case N-nitrosodi-n-propylamine or N-nitrosopiperidine were detectable. The isolated active agents amitriptyline, clomiphene++ and probenecid themselves proved not to be nitrosatable. The positive findings with these drugs were caused by not yet identified nitrosatable contaminants of these drugs. The quantitative determination of volatile N-nitroso compounds was done upon steam distillation by means of gas chromatograph and chemiluminescence detector.

Aminopyrine↗
PubMed1979

Rapid screening for chemical carcinogens: transforming activity of selected nitroso compounds detected in a transplacental host-mediated culture system.

The transplacental host-mediated hamster cell culture system was used to test a variety of solvents and chemicals of unknown and known (positive and negative) activity for their ability to induce morphologic transformation of cells and growth in agar. Examination of approximately 13,000 colonies of cells from untreated animals yielded no transformants, thus demonstrating no spontaneous transformation in the system. Similar negative results were obtained after animals were treated with the solvents acetone, ethanol, dimethyl sulfoxide, dimethylformamide, and trioctanoin oil. Several known carcinogens, including benzo[a]pyrene, methylnitrosourethane, urethan, and diethylnitrosamine, were positive for transforming activity. Three pesticides, carbaryl, methomyl, and landrin, and their N-nitroso derivatives were tested. All the nitrosated forms had transforming activity, but only one of the pesticides, landrin, was positive. In all experiments conducted, results of the agar-growth test correlated well with tests for morphologic transformation. The transplacental hamster embryol cell culture system therefore detected transforming activity of N-nitroso compounds and some known carcinogens.

Agar↗
PubMed1984

A new N-nitroso compound, N-2-methylpropyl-N-1-methylacetonyl-nitrosamine, in moldy millet and wheat flour.

A new N-nitroso compound, N-2-methylpropyl-N-1-methylacetonyl-nitrosamine (MAMPNA), was found in millet and wheat flour inoculated with Fusarium moniliforme Sheldon, a common species of fungi occurring in foods in Linxian County, after 8-day incubation and an addition of a small amount of NaNO2. The compound has been identified by GC-MS and confirmed by synthesized MAMPNA. The present paper reports the isolation and detection of MAMPNA in moldy foods, and discusses the role of the fungus in processes of nitrosamine formation and possible biosynthetic approach of the new compound.

Chromatography, Thin Layer↗
PubMed1994

Precursors of N-nitroso compounds in some Nigerian medicinal plants.

Twenty-seven tropical plants of medicinal importance were analysed for primary and secondary amines by chemiluminescence detection on a Thermal Energy Analyzer (TEA) modified for use on 'nitrogen mode' following derivatization with benzene sulphonyl chloride (BSC) and gas chromatographic (GC) separation of their sulphonamides. Nitrite was determined by colorimetry at 540 nm after diazotization with sulphanilamide and coupling with N-(1-naphthyl)ethylenediamine to form an azo dye. Nitrate was determined as nitrite following on-line reduction by granulated cadmium. Dimethylamine in the range of 0.5 ppm to 18.2 ppm was detected in 96% of samples, while pyrrolidine ranged between 0.7 ppm and 12.78 ppm in 14 samples. Isobutylamine, methylamine and ethylamine were the most ubiquitous primary amines. Largest number of secondary amines (four) was found in Azadirachta indica (Neem) while largest number of primary amines (six) was detected in Azadirachta indica and Tamarindus indica (Tsamiya) which also contained the highest amount of total primary amines (148.8 ppm). Nitrate and nitrite were seldom found in plant extracts whose pH were generally below 7.0. These findings suggests that early exposures to precursors of N-nitroso compounds via medicinal plants might contribute to total risk posed by environmental carcinogens in Nigeria.

Amines↗
PubMed1991

Bacterial formation of N-nitroso compounds in the rat stomach after omeprazole-induced achlorhydria.

N-Nitrosamine formation by bacteria in the achlorhydric stomach has been proposed as an important factor in the development of gastric cancer. Thus, the effect of the presence of bacteria in the stomach on endogenous nitrosation was investigated in rats given omeprazole (an inhibitor of gastric H+, K((+)-ATPase) which reduces gastric secretion sufficiently to allow survival of a bacterial suspension of Escherichia coli or Pseudomonas. When rats were given both thiazolidine 4-carboxylic acid and nitrate, greater endogenous nitrosamine formation was observed in rats receiving omeprazole and an E. coli suspension than in control or omeprazole-treated rats. A similar result was obtained when rats were given morpholine and nitrate. Since the endogenous formation of N-nitrosomorpholine (NMOR) can be evaluated more precisely from the levels of its urinary metabolites, N-nitrosohydroxyethylglycine (NHEG), the metabolism of NMOR was studied in omeprazole-treated rats. In this preliminary study, we showed that 60% of an oral dose of NMOR was excreted as NHEG, while in rats with a higher gastric pH 20% was excreted as NHEG. The amount of endogenously formed NMOR was increased in omeprazole-treated rats given morpholine and nitrite together with bacteria, and greater excretion of unchanged urinary NMOR was observed. Thus, as shown in this in-vivo model, bacteria efficiently reduce nitrate to nitrite and catalyse nitrosation, resulting in increased endogenous formation of N-nitroso compounds in the achlorhydric stomach.

Achlorhydria↗
PubMed2005

N-hydroxyurea and acyl nitroso compounds as nitroxyl (HNO) and nitric oxide (NO) donors.

Hydroxyurea has emerged as a new therapy for sickle cell disease but a complete mechanistic description of its beneficial actions does not exist. Patients taking hydroxyurea show evidence for the in vivo conversion of hydroxyurea to nitric oxide (NO), which also has drawn interest as a sickle cell disease treatment. While the chemical oxidation of hydroxyurea produces NO or NO-related products, NO formation from the reactions of hydroxyurea and hemoglobin do not occur fast enough to account for the observed increases in patients taking hydroxyurea. Both horseradish peroxidase and catalase catalyze the rapid formation of nitric oxide and nitroxyl (HNO) from hydroxyurea. In these reactions, hydroxyurea is converted to an acyl nitroso species that hydrolyzes to form HNO. The ferric heme protein then oxidizes HNO to NO that combines with the heme iron to form a ferrous-NO complex that may act as an NO donor. In general, acyl nitroso compounds, regardless of the method of their preparation, hydrolyze to form HNO and the corresponding carboxylic acid derivative. Similarly, the incubation of blood and hydroxyurea with urease rapidly form NO-related species suggesting the initial urease-mediated hydrolysis of hydroxyurea to hydroxylamine, which then reacts quickly with hemoglobin to form these products. These studies present two NO releasing mechanisms from hydroxyurea that are kinetically competent with clinical observations.

Animals↗
PubMed1993

The effects of nitrate, nitrite, and N-nitroso compounds on animal health.

The clinical signs of acute nitrate toxicity vary according to species. In general, ruminant animals develop methemoglobinemia while monogastric animals exhibit severe gastritis. Nitrate ingestion has also been linked to impairment of thyroid function, decreased feed consumption, and interference with vitamin A and E metabolism. Hematologic changes seen with chronic high nitrate exposure include both compensatory increases in red blood cells and anemia, along with increased neutrophils and eosinophils. Unlike nitrate, nitrite is capable of inducing methemoglobinemia in a wide range of species, ie cattle, sheep, swine, dogs, guinea pigs, rats, chickens and turkeys. In rats, chronic nitrite exposure causes pathologic changes in a variety of tissues, alterations in motor activity and brain electrical activity, and alters gastric mucosal absorption. Nitrite affects the metabolism of sulfonamide drugs in animals such as the pig, guinea pig, and rat. The N-nitroso compound dimethylnitrosamine causes toxic hepatosis in cattle, sheep, mink, and fox. Nitrosamines have been reported in cows milk and been found to pass into the milk of goats under experimental conditions.

Abortion, Veterinary↗
PubMed1998

Caffeine-derived N-nitroso compounds. V. Carcinogenicity of mononitrosocaffeidine and dinitrosocaffeidine in bd-ix rats.

Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N-nitroso compounds obtained from in vitro nitrosation of caffeidine, a hydrolysis product of caffeine present in a typically made and widely consumed tea from Kashmir (India), a high incidence area of esophageal and stomach cancer. The chemical synthesis, in vitro metabolic studies and mutagenicity of the compounds has been previously reported. DNC, a nitrosamide is highly mutagenic both with and without metabolic activation whereas MNC, like several other aromatic asymmetric nitrosamines, does not exhibit genotoxic or mutagenic properties. We now report the results of the first carcinogenicity experiments on chronic oral administration of these compounds in BD-IX rats. The acute LD50 of MNC and DNC were about 1300 and 230 mg/kg b.w., respectively. Lung oedema and gastrointestinal haemorrhages were the first symptoms of intoxication observed after 2 days for both the compounds. All three dose groups of MNC treated rats showed localization of tumours in nasal cavity (93.9-100% of all malignant tumours). The tumours were histologically diagnosed as neuroepitheliomas of the olfactory epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell carcinoma of the nasal cavity in the ratio of 3:1. No tumours of the nasal cavity were observed in the untreated controls. DNC, in contrast, induced squamous cell carcinoma of forestomach in 100% animals at low and high doses, of which nearly half the tumours metastasized predominantly into the peritoneum. No forestomach tumours were seen in the untreated controls. The data presented here clearly show the potential for induction of malignant tumours and distinct organ-specificity by MNC and DNC in rats, and support the postulate that a chronic exposure to these compounds may provide a carcinogenic risk for high incidence of gastrointestinal cancers in Kashmir.

Administration, Oral↗
PubMed2003

Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity.

In the United States, pancreatic cancer is the fourth most frequent cause of cancer death in males as well as females, after lung, prostate or breast, and colorectal cancer. Each year, approximately 30 000 Americans are diagnosed with pancreatic cancer and about the same number die of it. Germline mutations in a few genes including p16 and BRCA2 have been implicated in a small fraction of cases, as has chronic pancreatitis. The one established risk factor for pancreatic cancer is cigarette smoking: current smokers have two to three times the risk of nonsmokers. Studies of dietary factors have not been entirely consistent but do suggest associations of higher risk with consumption of smoked or processed meats or with animal foods in general and lower risk with consumption of fruits and vegetables. Colonization by Helicobacter pylori appears to increase risk, and a history of diabetes mellitus may also increase risk. The purpose of this epidemiologic review is to consider the possibility that risk of pancreatic cancer is increased by factors associated with pancreatic N-nitrosamine or N-nitrosamide exposures and with chronic excess gastric or duodenal acidity. Host genetic variation in inflammatory cytokine mechanisms may also be involved in this process. Many features of the evidence bearing on the pathophysiology of pancreatic cancer appear to support connections with N-nitroso compounds and with gastric acidity.

Animals↗
PubMed1980

Studies on the enzymatic reduction of C-nitroso compounds. I. Distribution of c-Nitrosoreductase activity in animal tissues and partial purification of the enzyme from porcine liver.

The subcellular distribution of NADH-p-nitrosophenol (p-NSP) reductase activity at pH 6.0 in porcine liver was studied by spectrophotometric assay. About two-thirds of the activity was found in the cytosol fraction and the pH optimum of this fraction was about 5.5. The activity at pH 5.8 of cytosol fractions from various tissues of rats, quails, frogs, carp, and scallops was also studied. All these fractions showed more or less NADH-p-NSP reductase activity but the activity of NADH-aldehyde reductase (alcohol dehydrogenase [EC 1.1.1.1]) was detected only in these from liver and a few other tissues. Supernatants from sonicated cells of Bacillus subtilis and Escherichia coli also showed C-nitrosoreductase activity but were devoid of aldehyde reductase activity. The major C-nitrosoreductase of porcine liver cytosol was purified 20- to 30-fold by fractionation with ammonium sulfate, gel filtration, and ion-exchange chromatography. The pH optimum of this preparation was 5.5 and activity was strongly inhibited by p-chloromercuribenzoate (p-CMB). The enzyme preparation was stable at 5 degrees C for at least a week in the presence of NADH at pH 8.4. High concentrations of ammonium sulfate also stabilized the enzyme. An equilibrium between monomeric and dimeric forms of the enzyme was found and the molecular weight was estimated to be about 83,000 and 160,000 daltons for the monomeric and dimeric forms, respecively. The enzyme utilized NADH almost specifically and 2 mol of NADH were consumed per mol of p-NSP reduced to p-aminophenol. Nitrosobenzene and aldehydes could also serve as the electron acceptor. The aldehyde reductase activity became concentrated roughly in parallel with the C-nitrosoreductase activity during the course of the purification and these two activities could not be separated even after further purification by 5'-AMP-Sepharose affinity chromatography. N-Nitroso compounds were not affected by this enzyme.

Alcohol Oxidoreductases↗
PubMed1992

Studies on endogenous formation of N-nitroso compounds in the guinea pig supplemented with proline or thioproline and sodium nitrate.

The endogenous formation of N-nitrosoproline (NPRO) and N-nitrosothioproline (NTPRO, N-nitrosothiazolidine-4-carboxylic acid) was studied by monitoring their excretion in the urine of guinea pigs given oral doses of 10 mg proline or thioproline after supplementation with 34 mg (0.4 mmol) sodium nitrate. In order to estimate the conversion of nitrate to nitrite, the animals were also supplemented with 3.5 mg (0.05 mmol) sodium nitrite instead of sodium nitrate. In animals fed commercial diets, the excretion of NPRO and NTPRO under supplementation with sodium nitrate was 2.0 micrograms and 28.7 micrograms/animal/day, respectively, whereas the excretion under supplementation with sodium nitrite was 0.7 micrograms and 13.3 micrograms/animal/day, respectively. The higher excretion of NTPRO than NPRO in each case shows that thioproline is more effective for nitrite trapping than proline. The animals supplemented with nitrate excreted more than twice the amounts of NPRO or NTPRO than those supplemented with nitrite. It is assumed, therefore, that more than 0.1 mmol nitrate is reduced to nitrite and takes part in the endogenous nitrosation of the guinea pig. When various concentrations of L-ascorbic acid (AsA), known to inhibit the formation of N-nitroso compounds, were also administered orally to animals immediately after supplementation with sodium nitrate, the NPRO excretion decreased with increasing AsA concentration. These data indicate that the guinea pig, which is unable to synthesize AsA as well as humans, may be an appropriate animal model for evaluation of the endogenous nitrosation ability of humans ingesting nitrate.

Animals↗
PubMed1976

Different susceptibilities of the urinary bladder epithelium of animal species to three nitroso compounds.

Differences in the susceptibilities of the urinary bladder epithelium of Wistar rats, ICR mice, Syrian golden hamsters, and Hartley guinea pigs to three N-nitroso compounds, N-butyl-N-(4-hydroxybutyl)nitrosamine, N-ethyl-N-(4-hydroxybutyl)nitrosamine, and N-butyl-N-(3-carboxypropyl)nitrosamine, were examined histologically. The urinary bladder epithelium of rats was the most susceptible to all three compounds, and especially to N-ethyl-N-(4-hydroxybutyl)nitrosamine, and bladder cancers developed in all the rats given this compound. The bladder epithelium of mice was less susceptible than that of rats but, although the incidence of cancer was lower than in rats, that of cancer with invasion was higher. Hamsters were far less susceptible than mice, and cancer developed only in 3 of 41 animals given N-ethyl-N-(4-hydroxybutyl)nitrosamine. Guinea pigs were the least susceptible of the 4 species and no tumors were found. Hisotlogically, most of the tumors induced in rats and mice were transtitional cell carcinomas. The incidence of undifferentiated carcinoma was higher in mice than in rats and cellular or structural atypism of the cancer was also greater in mice. Cancers induced in hamsters were all transitional cell carcinomas showing invasion.

Animals↗