[Reaction of diene hydrocarbons with nitroso-compounds].
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Hydrocarbons↗
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Examination of some fermented foods for the presence of apparent total N-nitroso compounds.
The fermented foods yoghurt, bread and cheese were analysed for the presence of apparent total N-nitroso compounds (ATNC) by a group-selective procedure involving direct chemical denitrosation and chemiluminescence detection of the released nitric oxide. The levels of ATNC were below the 20 micrograms(N-NO)/kg detection limit in all 20 yoghurts, 23 of the 24 bread samples and 28 out of 31 different varieties of cheese analysed. ATNC were detected in most of those cheese samples manufactured with added nitrate, including Edam, Gouda and Havarti, in concentrations ranging from 30 to 210 micrograms(N-NO)/kg.
Bread↗
Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach.
A literature review has shown that the daily intakes of various N-nitroso-precursor classes in a typical European diet span five orders of magnitude. Amides in the form of protein, and guanidines in the form of creatine and creatinine, are the nitrosatable groups found most abundantly in the diet, approaching levels of 100 g/day and 1 g/day, respectively. Approximately 100 mg of primary amines and amino acids are consumed daily, whereas aryl amines, secondary amines and ureas appear to lie in the 1-10 mg range. The ease of nitrosation of each precursor was estimated, the reactivities being found to span seven orders of magnitude, with ureas at the top and amines at the bottom of the scale. From this information and an assessment of the carcinogenicity of the resulting N-nitroso derivatives, the potential health risk due to gastric in vivo nitrosation was calculated. The combined effects of these risk variables were analysed using a simple mathematical model: Risk = [daily intake of precursor] X [gastric concentration of nitrite]n X [nitrosatability rate constant] X [carcinogenicity of derivative]. The risk estimates for the various dietary components spanned nine orders of magnitude. Dietary ureas and aromatic amines combined with a high nitrite burden could pose as great a risk as the intake of preformed dimethylnitrosamine in the diet. In contrast, the risk posed by the in vivo nitrosation of primary and secondary amines is probably negligibly small. The risk contribution by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes. Thus three priorities for future work are a comprehensive study of the sources and levels of arylamines and ureas in the diet, determination of the carcinogenic potencies of key nitrosated products to replace the necessarily vague categories used so far, and the development of short-term in situ tests for studying the alkylating power of genotoxicity of N-nitroso compounds too unstable for inclusion in long-term studies.
Amides↗
Experimental models for the biological detection of N-nitroso compounds formed from amines and nitrite.
The secondary and tertiary amines morpholine, aminopyrine and cimetidine as well as their nitroso products were examined for mutagenicity with the Ames Salmonella typhimurium microsome test (strains TA1535 and TA100) and the host-mediated assay. The formation of mutagenic nitroso compounds from morpholine and aminopyrine in the presence of nitrite could be demonstrated in artificial gastric juice and was confirmed in the stomach of mice in vivo. In contrast, the positive response of the chemical nitrosation in vitro with cimetidine did not match with the mammalian host-mediated assay results. To enhance sensitivity the role of modifiers of nitrosation, such as ascorbic acid and thiocyanate as well as the influence of biotransformation were studied.
Amines↗
Biological and chemical properties of alkanediazotates as active species of N-nitroso compounds.
The mutagenicity and chemical reactivity of (E)- and (Z)-potassium alkanediazotates, as precursors of corresponding alkanediazohydroxides, were investigated. In three microbial strains, Salmonella typhimurium TA1535 and Escherichia coli WP2 and WP2hcr-, the effect of changing the alkyl group on mutagenic potency was similar for (E)- and (Z)-diazotates, N-alkyl-N-nitrosoureas and alpha-hydroxynitrosamines. The capacity to alkylate nicotinamide, measured in an aqueous phosphate buffer, decreased with increasing alkyl chain length. Specific mutagenicity in S. typhimurium TA1535 was linearly related to alkylating activity. These results confirm that alkanediazohydroxides are the active alkylating species of N-nitroso compounds, and that their mutagenicity is determined by their alkylating activity.
Alkylating Agents↗
Systemic and local carcinogenesis by directly acting N-nitroso compounds given to rats by intravesicular administration.
A number of directly acting carcinogenic N-nitroso compounds were administered to female F344 rats intravesically, to assess their ability to induce tumors locally in the urinary bladder and systemically following absorption through the bladder mucosa. The compounds were alkylnitosoureas and alkylnitrosocarbamates and could be formed by interaction of amides with bacterially produced nitrite in infected bladders. Methylnitrosourethane was very toxic: doses of 1-2 mg caused death of some rats. A total dose of 0.15 mmol of ethylnitrosourethane, which was much less toxic, was administered to each rat and almost all developed bladder tumors. Ethylnitrosourea also gave rise to bladder tumors following intravesical treatment, and induced some tumors systemically, whereas methylnitrosourea, 2-methoxyethylnitrosourea and 2-hydroxypropylnitrosourea induced bladder tumors in high incidence and few tumors systemically. Nitrosooxazolidone was quite toxic and induced few bladder tumors. The dialkylnitrosoureas were more stable and some induced more tumors systemically than the monoalkylnitrosoureas. 1,3-Dimethylnitrosourea induced no bladder tumors and 1,3-diethylnitrosourea very few, but both induced tumors systemically that were similar to those induced by gavage treatment of rats. 1-Ethyl-1-nitroso-3-hydroxyethylurea, 1-hydroxyethyl-1-nitroso-3-ethylurea and 1-(2-hydroxypropyl)-1-nitroso-3-(2-chloroethyl)-urea induced bladder tumors in a majority of rats treated intravesically; the first induced many tumors systemically. Most of the bladder tumors were transitional cell papillomas and carcinomas, but there were a few squamous cell tumors, smooth muscle tumors, sarcomas and carcinosarcomas. The effects of intravesical administration of the directly acting alkylating compounds are compared with the effects of similar doses given to rats by gavage.
Administration, Intravesical↗
Alkylation of DNA and carcinogenicity of N-nitroso compounds.
The possible mode of action of two classes of highly organ- and species-specific carcinogenic N-nitroso compounds, namely the N-nitrosamines and N-nitrosamides, is outlined in this review. Chemical or enzymatic conversion of these agents into active alkylating species is a prerequisite for their biological activity. Although these species are capable of reacting with all cellular macromolecules, there is good evidence that their ability to attack DNA is related to their carcinogenicity. This paper reviews the reasons and experimental support for the hypothesis that it is specifically alkylation of DNA at the O6 position of guanine that initiates malignant transformation, an important factor being the presence of an enzyme system capable of eliminating O6-alkylguanine from DNA. No such repair reaction appears to exist for this or other alkylation products when they are present in RNA. The activity of this system is enhanced by chronic administration of alkylating agents, and the role that this may play in carcinogenesis is discussed.
Alkylation↗
Thermal energy analysis of N-nitroso compounds, including ureas, urethanes and guanidines.
Simple, selective, sensitive analytical methods have been developed for a number of N-nitroso compounds (NOC) which are applicable to environmental and biological matrices and have been used to quantify nitrosourea anticancer drugs in human plasma. These new chromatographic detection windows can be used to screen suspect matrices for NOC.
Antineoplastic Agents↗
Analytical determination of N-nitroso compounds in pesticides by the United States Environmental Protection Agency--a preliminary study.
Lijinsky, Eisenbrand and others have demonstrated the formation of N-nitroso derivatives of certain secondary amine pesticides under specified experimental conditions. Partly based on these studies and on reports of the industrial discharge of N-nitrosos compounds from several chemical manufacturing facilities the Environmental Protection Agency (EPA) has issued several reports on the nitroso problem, including a report by a special ad hoc committee under the Administrator's Science Advisory Board (1976). Unexpectedly high N-nitrosoalkylamine residues found in several pesticide products (Fine et al., 1976) have prompted EPA to conduct a survey, initially of approximately 70-80 pesticides that potentially were representative of the following three routes of contamination: 1. industrial process formation and carryover; 2. in situ (container) nitrosation and 3. utilization of contaminated amines in the manufacturing process. Environmental formation was not studied in this survey. Duplicate samples were analysed by two different laboratories using GC and HPLC interfaced with Hall, UV and chemiluminescent (TEA) detectors. Results of some analyses of this continuing survey are presented. Based partly on the results of this study, the Agency has decided to conduct risk-benefit analyses on pesticides suspected of containing N-nitroso contaminants, with special consideration given to oncogenic and mutagenic potential. The analytical results of the study are discussed, as is the cooperative effort within the Agency.
Chromatography, Gas↗
Urinary N-nitrosamino acids as indices of endogenous formation of N-nitroso compounds.
Exposure to their precursors (e.g., amines, nitrate/nitrite, NOx) can lead to formation in the human body of N-nitroso compounds (NOC), a class of potent animal carcinogens, which are also suspected of being carcinogenic in man. A non-invasive method, the 'N-nitrosoproline (NPRO) test', for estimating endogenous nitrosation in man was developed in our laboratory. This test, which monitors 24-hr-excretion of urinary N-nitrosamino acids, is now applied in clinical and field studies, with the aim of measuring nitrosamine exposure and of identifying dietary, life-style, and host factors, or disease states, that affect nitrosation in man. Results from such studies are used to identify populations/individuals at high risk for cancers of the stomach, oesophagus, and oral cavity possibly caused by endogenous nitrosamines, and to indicate preventive measures by which the body burden of endogenous nitroso carcinogens can be lowered efficiently.
Amino Acids↗
Determination of extractable, apparent total N-nitroso compounds in cured-meat products.
The modification of a newly developed method for determination of apparent total N-nitroso compounds by chemical denitrosation and chemiluminescence detection of nitric oxide (thermal energy analysis) is described. The minimum level of reliable measurement was 0.1 ppm, and the repeatability of the method was 0.2 ppm, based on the response of N-nitrosoproline(NPro). Seventy-three samples of cured-meat products, including frankfurters, bacon, and ham, were examined; 50 samples contained less than 1 ppm. The largest amounts, up to 24.8 ppm, were detected in canned corned beef. This method has several advantages over other methods.
Animals↗
The collaborative evaluation of a procedure for the determination of N-nitroso compounds as a group.
Two collaborative studies have been made of the method devized for the determination of N-nitroso compounds as a group, which involves their selective denitrosation with hydrogen bromide in glacial acetic acid, followed by the measurement of the nitric oxide liberated using a chemiluminescence analyzer, such as the TEA. Considerable variation was evident between the results in the first study, most of the values reported being low. This situation undoubtedly arose from the carry-over of traces of hydrogen bromide from one determination to the next, which resulted in premature denitrosation. The precision and consistency of the results were greatly improved in the second study, for which additional precautions had been recommended. All of the six participating laboratories reported reasonably consistent values, the coefficients of variation being 27.9% and 21.1% respectively, at the levels of spiking of N-nitrososarcosine equivalent to 32.9 ng and 146.4 ng of nitric oxide.
Indicators and Reagents↗
Group-selective determination of total N-nitroso compounds in nitrate-containing human urine samples.
A group-selective method for the determination of total N-nitroso compounds (NOC) has been adapted for analysing human urine samples. Nitrate was first removed from urine by an anion-exchange procedure that prevented the significant loss of various added reference NOC and unidentified urinary NOC. The total NOC were then determined by injecting the urine sample (nitrate content less than 1 mmol l-1) or anion-exchange eluate into refluxing ethyl acetate containing either acetic acid for determining heat and acetic acid labile thermal energy analyser responsive compounds (TAC) or into hydrogen bromide for the determination of TAC and NOC. The nitrogen monoxide levels released were measured using thermal energy analysis with chemiluminescence detection, and the differnce between the two determinations represented the concentrations of NOC. The optimum conditions for preventing artefactual nitrosation in urine samples by the addition of sodium hydroxide or sulphamic acid without decomposition of NOC were determined. The influence of time and storage conditions on NOC stability was investigated. Fifteen urine samples collected from volunteers dosed with proline were analysed for total NOC and N-nitrosamino acids revealing a preponderance of unknown NOC. The determination of total NOC in human urine using this group-selective method offers a new approach to the estimation of human exposure to NOC and to isolate hitherto unknown NOC and their metabolites.
Chromatography, Gas↗
Determination of total N-nitroso compounds and their precursors in frankfurters, fresh meat, dried salted fish, sauces, tobacco, and tobacco smoke particulates.
Total N-nitroso compounds (NOC) and NOC precursors (NOCP) were determined in extracts of food and tobacco products. Following Walters' method, NOC were decomposed to NO with refluxing HBr/HCl/HOAc/EtOAc and NO was measured by chemiluminescence. NOC were determined after sulfamic acid treatment to destroy nitrite, and NOCP were determined after treatment with 110 mM nitrite and then sulfamic acid. Analysis without HBr gave results < or =20% of those with HBr. This NOC method was efficient for nitrosamines but not nitrosoureas. The standard nitrosation for determining NOCP gave high yields for readily nitrosated amines, including 1-deoxy-1-fructosylvaline, but not for simple amines, dipeptides, and alkylureas. Mean NOC and NOCP results were (respectively, in micromol/kg of product) 5.5 and 2700 for frankfurters, 0.5 and 660 for fresh meat, 5.8 and 5800 for salted, dried fish, and 660 and 2900 for chewing tobacco (all for aqueous extracts) and 220 and 20000 nmol/cigarette for MeCN extracts of cigarette smoke filter pads.
Animals↗
N-Nitroso compounds, bacteria, and carcinoembryonic antigen in the gastric stump.
Analyses of biochemical and microbiological parameters such as pH, N-nitroso compound (NOC) concentration, carcinoembryonic antigen (CEA) level, and total viable counts (TVCs), and identification of microorganisms were carried out on 65 fasting gastric juice samples obtained at endoscopy from 45 patients previously submitted to partial gastrectomy for benign peptic ulcer disease (23 Billroth I, 22 Billroth II/Reichel-Polya) and 20 normal controls. Biopsy specimens were taken to determine histology, the Helicobacter pylori status, and both tissue CEA immunoreactivity and level. Significantly higher mean pH values, NOC and CEA concentrations, and TVCs were found in partial gastrectomies compared with normal controls. In relation to surgical methods, higher mean pH values, NOC concentrations, TVCs, and anaerobic bacterial counts were observed in the juice of patients with Billroth II compared with Billroth I gastrectomies. Mild CEA immunoreactivity and apical CEA localization were found significantly more often in Billroth II than in Billroth I stumps. Intensive CEA immunoreactivity and cytoplasmatic localization were found significantly more often in Billroth I than in Billroth II stumps. Independent of the type of surgical reconstruction, higher mean NOC levels were recorded in patients with more severe histological changes and H. pylori infection. Higher mean CEA levels in gastric juice and tissue were detected in the gastric stumps with more severe histological changes. All these data suggest that high levels of NOCs in the gastric juice could be a cofactor in gastric stump carcinogenesis and determination of CEA level in gastric juice and tissue could be included as a very useful marker in quantifying this process.
Adult↗
[The carcinogenic action of n-nitroso-compounds. Second communication. s (plus) and r(minus)-n-nitroso-2-methyl-piperidine (author's transl)].
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Animals↗
Comparative analysis of tobacco-specific nitrosamines and total N-nitroso compounds in moldovan cigarette tobacco.
While previous studies have evaluated levels of tobacco-specific nitrosamines (TSNA) and total N-nitroso compounds (NOC) in tobacco, there are no reports in the literature on TSNA and total NOC in the same tobacco products. We compared levels of TSNA, total NOC, and NOC precursors (NOCP) in tobacco of cigarettes purchased in Moldova and in some tobacco types commonly used for the manufacturing of Moldovan cigarettes. Cigarette tobaccos included those from non-Moldovan, traditional Moldovan, and blended Moldovan cigarettes. The results demonstrate that tobacco of non-Moldovan cigarettes contains higher TSNA and NOC levels (mean, 16 and 63 nmol/g tobacco, n = 6) than that of Moldovan cigarettes (mean, 5 and 23 nmol/g tobacco, n = 25). TSNA and NOC levels were also generally higher in tobacco of blended than in traditional Moldovan cigarettes. NOCP levels in Moldovan and non-Moldovan cigarette tobacco were similar as follows: 29000 +/- 30000 and 33000 +/- 28000 nmol/g tobacco (mean +/- SD). Total NOC were strongly correlated with total TSNA levels (r = 0.66; P < 0.0001). These findings demonstrate that current technologies involved in the manufacture of some blended cigarettes create conditions that favor N-nitrosation of alkaloids and other tobacco constituents.
Moldova↗
Inhibition of HIV-1 infectivity by zinc-ejecting aromatic C-nitroso compounds.
Retroviral nucleocapsid and gag-precursor proteins from all known strains of retroviruses contain one or two copies of an invariant sequence, Cys-X2-Cys-X4-His-X4-Cys, that is populated with zinc in mature particles. Modification of cysteine or histidine residues results in defective packaging of genomic viral RNA and formation of non-infectious particles, making these structures potentially attractive targets for antiviral therapy. We recently reported that aromatic C-nitroso ligands of poly(ADP-ribose) polymerase preferentially destabilize one of the two (Cys-X2-Cys-X28-His-X2-Cys) zinc-fingers with concomitant loss of enzymatic activity, coincidental with selective cytocidal action of the C-nitroso substituted ligands on cancer cells. Based on the occurrence of (3Cys, 1His) zinc-binding sites in both retroviral nucleocapsid and gag proteins and in poly(ADP-ribose) polymerase, we reasoned that the C-nitroso compounds may also have antiretroviral effects. We show here that two such compounds, 3-nitrosobenzamide and 6-nitroso-1,2-benzopyrone, inhibit infection of human immunodeficiency virus HIV-1 in human lymphocytes and also eject zinc from isoalted HIV-1 nucleocapsid zinc fingers and from intact HIV-1 virions. Thus the design of zinc-ejecting agents that target retroviral zinc fingers represents a new approach to the chemotherapy of AIDS.
Amino Acid Sequence↗