Approaches to hazard control in the carcinogenesis laboratory: N-nitroso compounds.
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Adsorption↗
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A rapid and sensitive method for the determination of non-volatile n-nitroso compounds in foods and human urine: recent data concerning volatile N-nitrosamines in dried foods and malt-based beverages.
Methods are described for the rapid screening of various foods for the presence of nitrosamino acids (mainly NPRO and NSAR) and of hydroxylated nitrosamines (mainly BHBN, NHPYR and NDELA). Rapid screening methods (HPLC-TEA and GC-TEA) are also described for the determination of the above mentioned nitrosamines in human urine. Recent monitoring data indicate that, in Canada, the NDMA levels in both malt and beer have decreased significantly during the last two years. Contrary to published reports, no volatile nitrosamines could be detected in vegetable oils or pasteurized milk. A new method, based on oxidation of nitrosamines and nitramines and reanalysis by GC-TEA, is described for the confirmation of low microgram/kg levels of volatile nitrosamines in foods.
Beer↗
Research on environmental N-nitroso compounds in the USSR.
Food samples from various parts of the USSR have been analysed for volatile N-nitrosamines (NA). The results are comparable to data published elsewhere. Kilning of malt with direct combustion gases accounts for the presence of NA in beer. NA have been found in city air, diesel exhausts and in a rubber factory. Vulcanized rubber contains NDMA and NMOR. Nitrosoproline has been determined in a variety of foodstuffs. Variations of nitrate contents in vegetables due to mineral fertilizers and some herbicides are reported. A steady increase of average nitrate concentrations in vegetables has been observed in Estonia over a period of 12 years. Precursors of NA have been found in water (Moldavia), and soil (Moscow district and Tshuvash republic). Nitramines can be formed in vivo from NA, and vice versa. Formation of NDMA from aminopyrine has been inhibited under gastric conditions by properly composed meals. Numerous food components have been studied as nitrite scavengers. Modifications of analytical methods for NA have been proposed. Four laboratories in the USSR are equipped with the Thermal Energy Analyzer.
Air Pollutants↗
Formation of N-nitroso compounds during cooking of Japanese food.
N-Nitrosamines in several traditional Japanese meals, such as 'Nebemono', 'Ten-pura' and Kara-age', were analysed. No appreciable amount, or only trace quantities, of NDMA and NPYR could be detected in these meals. The effects of various gases on nitrosamine formation in dried squid have been examined at higher cooking temperatures and the highest yield of NDMA was observed by exposure to the gas produced by the combustion of kerosene, followed by that of city gas, while very low levels of NDMA were formed when samples were wrapped in aluminium foil or broiled in air or argon atmospheres. The principal precursor of NDMA in dried squid was found to be TMAO, which is abundant in the squid muscle and from which nitrosatable DMA can be produced during broiling at higher temperatures.
Cooking↗
Amines in soil as possible precursors of N-nitroso compounds.
Volatile nitrogen bases in soil have been analysed by gas chromatography. Two samples of soils taken from different regions have been investigated. The first sample was loam. The second was a mixed sample with a predominance of chernozem. At least 48 amines have been found in the samples and 34 of them have been identified. Among the compounds identified are primary, secondary and tertiary amines and heterocyclic bases. The most numerous group is that of the secondary amines (14 compounds), which can be directly nitrosated to give carcinogenic N-nitrosamines. In the chernozem soil, the qualitative amine analysis is practically identical to that of the loam, but the total amount of amines is approximately 10 times higher. For the first time, a wide variety of amines capable of undergoing nitrosation has been found in soils not cultivated by man.
Amines↗
[Effect of fruit and vegetable juices on the changes in the production of carcinogenic N-nitroso compounds in human gastric juice].
The study was made of the effect of apple, grapefruit, orange and beet juices on in vitro formation of N-nitrosodimethylamine (NDMA) from sodium nitrite and amidopirin in human gastric juice (GJ). Experimental samples of GJ from outpatients attending the outpatient department of the AMS Cancer Research Center were used. The patients had various forms of gastritis and gastric cancer. It was found that fruit and beet juices may inhibit or enhance NDMA formation depending on the GJ composition, pH in particular. In acid medium (pH-1.3-3.4) there was a trend to inhibition of NDMA synthesis, while in neutral and alkaline (pH = 7.4-8.5) medium NDMA synthesis is activated. Practical implications of the findings are discussed.
Beverages↗
[Inhibiton of endogenous synthesis of nitroso compounds by Selenium in rats].
The inhibiting effect of organic Se (selen-enriched yeast Bioselen) on the endogenous synthesis of N-nitrosubstances was investigated in the Wistar rats, receiving 15 mg of sodium nitritis and 24 mg of diethylamin per 1 kg of bodyweight during 22 days. The level of nitrosoprolin synthesis and (NPro) and the level of nitrosodiethyl (NDie) in the stomach of rats served as the main indices. The highest level of NPro and NDie were revealed in the rats, without selen supplementation (581.2 +/- 113.3 mg per kg of bodyweight and 29.8 +/- 3.0 mg per kg of bodyweight). The highest inhibiting effect of Se was 54.5% for NPro and 54.7% for NDie and it was shown for the Se concentration of 1.5 mg per 1 kg of forage. The increase of Se dosage to 3.0 mg per 1 kg of forage was less effective and resulted in 25.5% of inhibiting of NPro u 47.0% - NDie.
Administration, Oral↗
N-nitroso compounds and man: sources of exposure, endogenous formation and occurrence in body fluids.
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Carcinogens↗
Mechanisms of nitroso compound-induced inhibition of superoxide generation in neutrophils: fluorescence quenching of perylene by nitroso-compounds in the membrane fractions of neutrophils.
To investigate the mechanism of nitroso compound-induced inhibition of the respiratory burst in neutrophils, we studied fluorescence quenching of perylene by nitroso-compounds in the membrane fractions of neutrophils at 17, 27, and 37 degrees C and the reagent-induced inhibition of superoxide generation at 28 and 37 degrees C. With increasing temperature, the quenching of perylene fluorescence and inhibition of superoxide generation by nitrosobenzene (NB) were both diminished, while those by 2-nitrosotoluene (NT) were both enhanced. The temperature dependence of the inhibition constants and the quenching constants indicates that the binding of NB is exothermic (deltaH= -27 kJ/mol for inhibition and deltaH= -29 kJ/mol for quenching) and essentially enthalpy-driven. On the other hand, that of NT is endothermic (deltaH= +16 kJ/mol for inhibition and quenching) and essentially entropy-driven. Quenching studies of perylene fluorescence in synthetic vesicles made of endogenous polar lipids of neutrophils showed that the enthalpy changes of NB- and NT-binding with perylene in lipids were similar to each other. Moreover, their values were in good agreement with that of NT, but not of NB, in the membrane fractions, an assembly of proteins and lipids, of neutrophils. These results suggest that NB inhibits the activity by binding to proteins in the membrane, whereas inhibition by NT occurs through hydrophobic interaction with lipids and/or proteins.
Animals↗
Inhibitors of N-nitroso compounds-induced mutagenicity.
N-Nitroso compounds are environmental mutagens that are present in the air, water, soil etc. or can be formed by nitrosation of various nitrosatable compounds. The present paper gives a survey of inhibitors of N-nitroso compounds-induced mutagenicity. Inhibitors covered include: thiols, metals, vitamins, phenolic acids, complex mixtures of plant, animal and human origin, organic solvents, inhibitors of mixed-function oxidases etc. Data on inhibitors that prevent the formation of N-nitroso compounds are not covered in this review.
4-Aminobenzoic Acid↗
Simple synthesis of alpha-hydroxyamino carbonyl compounds: new scope of the nitroso aldol reaction.
[reaction: see text] The reaction of nitroso compounds with enolates, "the nitroso aldol reaction", occurs in high yield to generate alpha-hydroxyamino carbonyl compounds. Yields range from 42% to 98% with N-selectivity >99:1 from commercially available aromatic or aliphatic nitroso compounds and a variety of alkali metal or tin enolates.
Journal Article↗
Mechanisms of inhibition of N-nitroso compounds-induced mutagenicity.
In this review we describe the mechanisms of the inhibitory effects of various chemical agents towards the mutagenicity of N-nitroso compounds, including direct-acting mutagens such as N-nitroso derivatives of alkylureas, alkylnitroguanidines and alkylurethanes, and promutagenic nitrosamines. Possible mechanisms by which the inhibitors may exert their effects outside and inside the target cells include chemical and enzymatic deactivation of the mutagen, inhibition of metabolic activation of nitrosamines, scavenging mutagenic products, inhibition of cellular uptake, induction of detoxifying mechanisms, protecting nucleophilic centers in DNA and modulating DNA repair.
Humans↗
Studies on the antimutagenic activity of ascorbic acid in vitro and in vivo.
The possibility that ascorbic acid, as a nucleophile, may inhibit mutagenicity induced by electrophilic metabolites of N-nitroso compounds was examined. In vitro data are presented to show that ascorbic acid does not decrease the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a modified Ames bacterial mutagenicity system if deionized water is used to prepare the incubation medium. However, ascorbic acid prevents the mutagenicity of MNNG in vitro if added to bacteria in a medium prepared with either sterile tap water or deionized water and Cu2+ ions and that this antimutagenic response is blocked by EDTA. Additional in vitro experiments suggest that when ascorbic acid and Cu2+ ions are mixed in aqueous solution, H2O2 and free radicals derived from H2O2 are formed and these compounds may deactivate N-nitroso compounds. In vivo data are presented to show that ascorbic acid supplementation to guinea pigs (2000 mg/kg body weight/day) has no effect on the mutagenicity of N-nitrosodimethylamine, MNNG, N-methylnitrosourea and streptozotocin using the intrahepatic host-mediated bacterial mutagenicity assay. Additional in vivo studies demonstrate that simultaneous oral administration of ascorbic acid prevents the mutagenicity that follows the intragastric nitrosation of aminopyrine by nitrite while dietary pre-treatment with ascorbic acid does not. These findings suggest that ascorbic acid can block the intragastric formation of mutagenic N-nitroso compounds but that ascorbic acid has no effect on mutagenicity of N-nitroso compounds once they are formed.
Animals↗
Dinitroso and polynitroso compounds.
The growing interest in the chemistry of C-nitroso compounds (RN=O; R = alkyl or aryl group) is due in part to the recognition of their participation in various metabolic processes of nitrogen-containing compounds. C-Nitroso compounds have a rich organic chemistry in their own right, displaying interesting intra- and intermolecular dimerization processes and addition reactions with unsaturated compounds. In addition, they have a fascinating coordination chemistry. While most of the attention has been directed towards C-nitroso compounds containing a single -NO moiety, there is an emerging area of research dealing with dinitroso and polynitroso compounds. In this critical review, we present and discuss the synthetic routes and properties of these relatively unexplored dinitroso and polynitroso compounds, and suggest areas of further development involving these compounds. (126 references.).
Chemistry, Organic↗
Biotransformation of N-substituted aromatic compounds in mammalian spermatozoa. Nonoxidative formation of N-hydroxy-N-arylacetamides from nitroso aromatic compounds.
The metabolism of N-substituted aromatic compounds, i.e. aniline, acetanilide, N-hydroxyacetanilide, nitrosobenzene, and nitrobenzene in mammalian spermatozoa was investigated. In boar spermatozoa fortified with glucose, no acetylation, deacetylation, and monooxygenation of these compounds were found. Nitrobenzene was reduced slowly, but nitrosobenzene was a good substrate for this reductive activity. In the latter reaction, the products were N-hydroxyacetanilide, azoxybenzene, and an organic phase-nonextractable metabolite(s). Pyruvate was found to be involved in the formation of N-hydroxyacetanilide from nitrosobenzene, and the reaction occurred through a ping-pong mechanism. This enzymatic activity, located in the mid-piece fraction of spermatozoa, was enhanced by thiamine pyrophosphate and Mg2+ and inhibited by thiamine thiazolone pyrophosphate. N-Hydroxyacetanilide formed from [3(-13)C]pyruvate showed complete retention of the isotope at the methyl carbon of the molecule. 2-Nitrosofluorene and 4-nitrosobiphenyl were also transformed into the corresponding N-hydroxy-N-arylacetamides. N-Hydroxyacetanilide was also formed in rat and human spermatozoa. These facts suggest that the formation of N-hydroxy-N-arylacetamides from the nitroso aromatic compounds and pyruvate is mediated by a pyruvate dehydrogenase complex located in the mitochondria of spermatozoa. The formation of both azoxybenzene and the organic phase-nonextractable metabolite(s) was found to be a pyruvate-independent nonenzymatic reaction.
Amines↗
New NO-donors with antithrombotic and vasodilating activities, Part 19. Pseudonitroles and their dimeric azodioxides.
Thirteen geminally substituted nitro-nitroso compounds (pseudonitroles) have been synthesized, four of them for the first time. In the solid state the pseudonitroles are dimerized to azodioxides. This is proved by IR spectroscopy, with the dimeric N-O valence vibration being observed between 1293 and 1306 cm-1. Only 1,3-diphenyl-2-nitro-2-nitrosopropane is monomeric even when solid. This is backed by its blue color and an IR band at 1574 cm-1. When dissolved in chloroform these azodioxides dissociate completely to the blue monomers (lambda max approximately 650 nm). Eight pseudonitroles inhibited the aggregation of blood platelets half-maximally at concentrations below 10 microM (Born test, collagen). When administered orally to rats (60 mg/kg) the thrombus formation in mesenteric arterioles and venules was inhibited up to 25 percent (k; 1-nitro-1-nitrosocyclohexane). When kept in aqueous media at 37 degrees C nitric oxide and its reduced from, i.e. nitrosohydrogen, are released. This suggests that the above biological effects arise from an NO dependent mechanism. The lack of influence on the blood pressure of spontaneously hypertensive rats, however, strongly suggests that an enzyme supported rather than a thermal formation of NO occurs in vivo.
Animals↗
New NO-donors with antithrombotic and vasodilating activities, Part 21. Pseudonitrosites and other azodioxides with vicinal electron acceptors.
Twelve vicinally substituted nitro-nitroso compounds (pseudonitrosites) were synthesized, nine of them for the first time. In the solid state the dimeric azodioxides are present. In the class of the pseudonitrosites 2a-h, all compounds exhibited comparatively strong antiplatelet activity in vitro (Born test, collagen). Four of them showed an IC50 below 10 microM, 2a being the most active substance with an IC50 = 2.1 microM. When administered orally to rats (60 mg/kg) small antithrombotic effects were observed. The pseudonitrosite 6d was the most active compound (18% inhibition in arterioles). The in vitro decomposition of 2a at 37 degrees C gave NO and N2O, indicating that the above pharmacological effects were mediated by an NO-dependent mechanism. The replacement of the nitro group in the pseudonitrosite partial structure by other electron acceptors i.e. acetyl, carboxyl, or acetyloxy groups leads to inactive (10a) or less active compounds (10b, e).
Animals↗
Formation of mutagens by sorbic acid-nitrite reaction: effects of reaction conditions on biological activities.
Conditions of the reaction between sorbic acid and sodium nitrite generating mutagenic principles were examined. In the rec-assay and the Ames reversion assay, the maximal mutagenic activity was obtained in a pH range of 3.5-4.2. Mutagenic and growth-inhibitor activities of five C-nitro and C-nitroso compounds were studied. The product Y, 2-methyl-1,4-dinitropyrrole, was the strongest mutagen among them.
Drug Interactions↗