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PubMed1987

Roles of cysteine as both precursor of thiazolidine 4-carboxylic acids found in human urine and possible inhibitor of endogenous N-nitrosation.

In order to compare the utility and significance of 2-R-N-nitrosothiazolidine 4-carboxylic acids excreted in human urine as an index for exposure to N-nitroso compounds, the differences in formation of N-nitrosothiazolidine 4-carboxylic acid (NTCA; R = H) and N-nitroso-2-methylthiazolidine 4-carboxylic acid (NMTCA; R = CH3) were studied in vitro. It was determined that NMTCA has a 3:1 trans:cis stereoisomer ratio, while NTCA has a 1:1 trans:cis ratio; nitrosation acts on a pH-dependent equilibrium mixture of cysteine and aldehyde in equilibrium with thiazolidine 4-carboxylic acid, with cysteine blocking N-nitrosation. Previous reports on 2-R-N-nitrosothiazolidine 4-carboxylic acids in human urine show widespread involvement of cysteine, which has a dual role with nitrosating species. In view of this and the rapid blocking of N-nitrosation and slow trans-nitrosation by cysteine at acid pH, it is suggested that there may be a hitherto unrecognized protective role of thiol functions in dietary constituents.

Cysteine↗
PubMed2001

Electrochemical methods for monitoring of environmental carcinogens.

The use of modern electroanalytical techniques, namely differential pulse polarography, differential pulse voltammetry on hanging mercury drop electrode or carbon paste electrode, adsorptive stripping voltammetry and high performance liquid chromatography with electrochemical detection for the determination of trace amounts of carcinogenic N-nitroso compounds, azo compounds, heterocyclic compounds, nitrated polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines is discussed. Scope and limitations of these methods are described and some practical applications based on their combination with liquid-liquid or solid phase extraction are given.

Azo Compounds↗
PubMed1987

Photolysis of nitrosamines and nitrosamides at neutral pH: a spin-trap study.

A model system has been used to study the types of radicals formed on denitrosation of N-nitroso compounds. Free radicals were formed at room temperature (22 degrees-23 degrees C) and neutral pH by photolytic cleavage of N-nitroso bonds and were partially characterized following their addition to the spin traps 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and N-tert-butyl-alpha-phenyl-nitrone (PBN). Carbon-centered radical adducts were obtained during nitrosamine photolysis and nitrogen-centered radical adducts during nitrosamide photolysis. Since both the nitrosamines and nitrosamides initially form nitrogen-centered radicals on photolysis, a secondary reaction or rearrangement must occur after initial N-nitroso bond cleavage in the nitrosamines. Mechanisms are proposed to account for these results.

Electron Spin Resonance Spectroscopy↗
PubMed1997

N-nitrosation of medicinal drugs catalysed by bacteria from human saliva and gastro-intestinal tract, including Helicobacter pylori.

Micro-organisms commonly present in human saliva and three DSM strains (Helicobacter pylori, Campylobacter jejuni and Neisseria cinerea), which can be isolated from the human gastro-intestinal tract, were assayed in vitro for their capacity to catalyse N-nitrosation of a series of medicinal drugs and other compounds. Following incubation at pH 7.2 in the presence of nitrate (or nitrite) for up to 24 (48) h, the yield of N-nitroso compounds (NOC) was quantified by HPLC equipped with a post-column derivatization device, allowing the sensitive detection of acid-labile and acid-stable NOC. Eleven out of the 23 test compounds underwent bacteria-catalysed nitrosation by salivary bacteria, the yield of the respective nitrosation products varying 800-fold. 4-(Methylamino)antipyrine exhibited the highest rate of nitrosation, followed by dichlofenac > metamizole > piperazine > five other drugs, whilst L-proline and L-thioproline had the lowest nitrosation rate. Ten drugs including aminophenazone, cimetidine and nicotine, did not inhibit bacterial growth, allowing transitory nitrite to be formed, but no N-nitroso derivatives were detected. Three drugs inhibited the proliferation of bacteria and neither nitrite nor any NOC were formed. Using metamizole as an easily nitrosatable precursor, two strains, Campylobacter jejuni and Helicobacter pylori, were shown to catalyse nitrosation in the presence of nitrite at pH 7.2. As compared to Neisseria cinerea used as a nitrosation-proficient control strain, H. pylori was 30-100 times less effective, whilst C. jejuni had intermediary activity. The results of our sensitive nitrosation assay further confirm that bacteria isolated from human sources, possessing nitrate reductase and/or nitrosating enzymes such as cytochrome cd1-nitrite reductase (Calmels et al., Carcinogenesis, 17, 533-536, 1996), can contribute to intragastric nitrosamine formation in the anacidic stomach when nitrosatable precursors from exogenous and endogenous sources are present.

Bacteria↗
PubMed1997

Studies on N-nitroso bile acid amides in relation to their possible role in gastrointestinal cancer.

Cancers of the gastrointestinal tract account for a large proportion of neoplastic diseases which afflict humans. The etiology of gastrointestinal cancer has been attributed in part to exogenous carcinogens, such as food substances and environmental pollutants. Recent hypotheses suggest that carcinogens may arise endogenously. Evidence suggests that some bile acids and their isomeric metabolites may be involved in the pathogenesis of colon cancer. However, the mechanisms responsible for their cancer-promoting effect is not clear. We and others propose that one mechanism for the mitogenic effects of bile acids may be N-nitrosation of their glycine and taurine amides; human gastric aspirates do contain small quantities of N-nitroso compounds of other substrates. Many foods contain nitrites and nitrates, which can react with bile acid amides to form N-nitroso derivatives. Our recent studies demonstrated the potential for N-nitroso conjugate formation from ursodeoxycholic acid, a 7 beta-epimer of chenodeoxycholic acid used as a drug Actigall to dissolve gallstones. The N-nitroso derivative of this compound, a direct-acting carcinogen, has a long half-life and, once nitrosated is stable enough to survive passage through the gastrointestinal tract. We describe the synthesis of N-nitrosated derivatives of various bile acid conjugates and mechanisms of decomposition of (Z)- and (E)-bile acid diazoates. Studies of the effects of enzymes such as cholylglycine hydrolase on the N-nitroso bile acid conjugates and their reaction with DNA are also described. These studies may have important implications in the interplay of diet with endogenous substrates in the etiology of cancers of the stomach, liver, and colon.

Amidohydrolases↗
PubMed1983

Summation and new approaches to diet and cancer.

Epidemiological studies have shown a relationship between several types of human cancer, such as esophageal, breast, and colon, and particular kinds of diet, indicating the presence of carcinogenic factors in those diets. Observations in animals have shown that some types of cancer in them are related to certain carcinogens in their food. Several types of cancer similar to that in humans have been induced in experimental animals by administration of carcinogens, such as nitrosamines and mycotoxins, suggesting that their presence in human diets can increase cancer risk. The search for such carcinogens, and for others presently unsuspected in human diets, should be continued with the objective of reducing or eliminating human exposure to them. The role of promoting agents, such as fats, in colon and breast cancer needs to be further investigated, and exposure to them should be reduced. Two sources of carcinogens that need increased study are the formation of carcinogens in cooking, especially of fats and proteins, and the endogenous formation of carcinogens in the gastrointestinal tract, e.g., N-nitroso compounds.

Animals↗
PubMed2005

Production of NA by endothelial NO-synthase: an in vitro versus in vivo study.

Endothelial-derived relaxing factor (EDRF) is secreted by different endothelia in vivo. It is synthesised by endothelial NO-synthase (eNOS). Despite numerous works, its identity is not fully understood. Here the production of NA, a nitroso-arginine, which was shown to be synthesised by brain NO-synthase (bNOS), was studied in eNOS preparations. NA was quantified by reductive differential pulse voltammetry (RDPV) during its irreversible electrochemical transformation to N-hydroxy-arginine (NHA). Using microelectrodes, NA and nitrite were simultaneously measured in pure recombinant eNOS giving similar enzyme activity. NA was detected at the surface of human endothelial cells (HUVEC) and disappeared when D-arginine was introduced in the culture medium. NA production by endothelium tissue was studied in rat corpus cavernosum using voltammetric microelectrodes. NA concentration at the endothelium surface was linked to vasodilatation measured by laser Doppler induced by acetylcholine injection. LNMA ic injection induced NA disappearance. These preliminary new experiments suggested that NA could be the endogenous nitroso-compound presented early as EDRF.

Animals↗
PubMed1978

[Studies on the analysis of nifedipine considering in particular transformation products formed by light exposition (author's transl)].

Under the influence of light (VIS and UV) on thin-layer plates and in liquid solutions, 1,4-dihydro-2,6-dimethyl-4-(0-nitro-phenyl)-pyridine-3,5-carboxylic acid dimethylester (nifedipine, Adalat) is converted to the nitroso compound 4-(2-'nitrosophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-pyridine. The article also describes TLC-, GLC-, UV-, IR- and MS-data of nifedipine, the nitroso and the nitro derivative.

Chemical Phenomena↗
PubMed1991

Inhibition of bacterially mediated N-nitrosation by ascorbate: therapeutic and mechanistic considerations.

Ascorbate is known to inhibit the acid-catalysed N-nitrosation reactions of nitrite in the normally acid stomach, suggesting a useful therapeutic application of this compound to reduce exposure to the carcinogenic products of such reactions. However, in the achlorhydric stomach, which is particularly predisposed to cancer, increased exposure to endogenous N-nitroso compounds may result from bacterially catalysed reactions. The mechanism of these bacterially mediated reactions is only just beginning to be understood, and, indeed, more than one such mechanism may exist. Despite its usual lack of reactivity towards nitrite at neutral pH, ascorbate proved to be a potent inhibitor of the bacterially mediated (Pseudomonas aeruginosa) nitrosation of morpholine, competing with morpholine for the nitrosating agent elaborated by the bacteria from nitrite (the kinetics of the inhibition were classically competitive). This and other data, particularly with regard to the dependence of the bacterially mediated reaction on amine pKa, are discussed in relation to the potential mechanisms of these bacterially mediated reactions.

Ascorbic Acid↗
PubMed2003

Dietary cured meat and the risk of adult glioma: a meta-analysis of nine observational studies.

OBJECTIVE: N-nitroso compounds (NOCs) are recognized neural carcinogens in animal models and are suspected human carcinogens. A meta-analysis was performed examining the possible association of dietary N-nitroso intake from cured meats and the risk of gliomas in adults. METHODS: A prospective protocol was developed outlining the intent, methods, and statistical analysis of the meta-analysis. Data from nine epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals as described by Greenland. The outcome of interest was a summary relative risk (SRR) reflecting the risk of brain tumor (glioma) development associated with high dietary intake of cured meats (as defined by individual study investigators). Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. RESULTS: Nine observational studies met protocol-specified inclusion criteria. Analysis for heterogeneity demonstrated a lack of statistical heterogeneity (p = 0.58). Pooling the data on dietary cured meat intake of all types yielded an RR of 1.48 (1.20-1.83), suggesting a 48% increased risk of glioma development among adults ingesting high levels of cured meat. Analyzing brain tumor risk by meat type yielded an RR of 0.90 (0.63-1.25) for hotdogs (a nonstatistically significant result), 1.31 (1.00-1.71) for bacon, and 1.64 (1.27-2.14) for ham. Sensitivity analyses showed that the failure of most studies to adjust for total energy intake might lead to a spurious positive association between cured meat intake and brain tumor risk. Insufficient data were available for analyzing dose-response relationships, although a few individual studies showed evidence of increasing risk with increasing cured meat intake. CONCLUSION: The available data do not provide clear support for the suspected causal association between ingestion of NOCs from cured meat in adults and subsequent brain tumor risk. Uncontrolled confounding may account for the previously noted positive association seen in some epidemiological studies.

Adult↗
PubMed1986

DNA and protein adducts as indicators of in vivo methylation by nitrosatable drugs.

Exposure to methylating carcinogens may be monitored by measuring both the formation of S-methylcysteine in haemoglobin and the urinary excretion of N-7-methylguanine (7-MeG), which is derived in part from methylated nucleic acids. Female rats were exposed to methylmethanesulphonate, methylnitrosourea and to three drugs, aminopyrine, cimetidine and pyrilamine, which are potential methylating agents if nitrosation occurs in vivo. Because S-methylcysteine in haemoglobin and urinary 7-MeG occur naturally, the experiments were carried out with stable isotope-labelled analogues which contained trideutero (d3)-methyl groups. Gas chromatography-mass spectrometry was used for the quantitative determination of d3-labelled adducts after their separation from the biological matrix and chemical derivatization. Transfer of the intact d3-methyl group to cysteine and guanine was detected after intragastric administration of d3-methyl-methanesulphonate (50 mg/kg), d3-N-methyl-N-nitrosourea (50 mg/kg), and d6-aminopyrine (AP) and sodium nitrite (both 100 mg/kg). AP alone gave no detectable d3-methyl adducts. Co-administration of nitrite and d6-pyrilamine or d3-cimetidine yielded no d3-7-MeG, although N-nitroso-d3-cimetidine alkylated DNA in vitro in a dose-dependent fashion. For AP and nitrite combinations urinary excretion of d3-7-MeG was linearly related to the dose of nitrite and was essentially complete within 5 days. For d3-methylmethane-sulphonate (50 mg/kg) the ratio of haemoglobin d3-S-methylcysteine to urinary d3-7-MeG was considerably (greater than 9-fold) higher than for either d3-N-methyl-N-nitrosourea or AP/nitrite (100 mg/kg) mixture. This is in accord with the SN2 nature of the weak carcinogen methylmethanesulphonate compared with the SN1 nature of the reactive methylating agent derived from either one of the N-methyl-N-nitroso compounds.

Animals↗
PubMed1990

[Pulsed method of sampling in monitoring of carcinogenic substances in gaseous atmosphere].

Experiments using various types of gas samplers showed that application of A phi A type fibrous material-containing filters for benzo(a)pyrene monitoring may result in significant underestimation of the carcinogen level in the air. The authors developed pulsed sampler using suspended layer of sorbent which proved most effective in catching benzo(a)pyrene in gaseous atmosphere. The unit allows simultaneous sampling of carcinogenic polycyclic aromatic hydrocarbons and N-nitroso compounds.

Air Pollutants↗
PubMed1986

Increase in the levels of N-nitrosoproline, N-nitrosothioproline and N-nitroso-2-methylthioproline in human urine by cigarette smoking.

The effects of cigarette smoking on the urinary excretions of N-nitrosoproline (NPRO) and the sulfur-containing N-nitrosamino acids, N-nitrosothioproline (NTPRO) and N-nitroso-2-methylthioproline (NMTPRO), in a male volunteer were examined. This subject smoked for 20 non-consecutive days and did not smoke for another 20 non-consecutive days during a 4-month-period, and 24-h urine samples were collected. On the days of urine collection, he was given a fixed diet. On the smoking days, the urinary levels of NPRO, NTPRO and NMTPRO increased significantly from 1.1 +/- 0.5 (mean +/- S.D.) micrograms/day to 1.8 +/- 0.9 (P less than 0.01), from 3.9 +/- 1.1 to 8.7 +/- 4.6 micrograms/day (P less than 0.001), and from 5.6 +/- 1.9 to 8.5 +/- 4.1 micrograms/day (P less than 0.01), respectively. Thus, the total amount of these 3 N-nitrosamino acids in the urine also increased significantly by smoking from 10.6 +/- 2.8 to 19.0 +/- 6.5 micrograms/day (P less than 0.001). These results indicated that NOx in cigarette smoke can contribute to in vivo formation of N-nitroso compounds.

Chromatography, Gas↗
PubMed1991

Prevention of tumour production in rats fed aminopyrine plus nitrite by sea buckthorn juice.

Three groups of Wistar rats were fed a diet containing aminopyrine (0.2%) and NaNO2 (0.2%) and either tap-water (controls), sea buckthorn juice or ascorbic acid solution ad libitum for 38 weeks. All 17 rats given tap-water developed tumours in the liver, and six developed tumours in the lungs and four in the kidneys; in rats given sea buckthorn juice, 15 had tumours of the liver, 11 of the lungs and two of the kidneys; the incidences in rats given ascorbic acid were 18/18, 6/18 and 4/18, respectively. The average life span of the group given sea buckthorn juice was 270 days, which was significantly longer (p less than 0.01) than those of rats given tap-water (195 days) or ascorbic acid (220 days). Microscopic examination of the livers of rats receiving sea buckthorn juice showed fewer foci of carcinogenesis than those of the control and the ascorbic acid groups. The results suggest that sea buckthorn juice can block the endogenous formation of N-nitroso compounds more effectively than ascorbic acid and thereby prevent tumour production.

Aminopyrine↗
PubMed1987

Modulation of gastric carcinogenesis: updated model based on intragastric nitrosation.

The etiological model of gastric carcinogenesis is discussed. Its complexity and flexibility may be more applicable to human situations than experimental models utilizing high doses of carcinogens in homogeneous animal populations. The limitations of the epidemiological method and the use of a collaborative approach by epidemiologists and experimentalists are described. The need for markers of exposure to N-nitroso compounds is stressed.

Animals↗
PubMed1982

Catalysis of nitrosation in vitro and in vivo in rats by catechin and resorcinol and inhibition by chlorogenic acid.

Measurements were made of the effects of phenolic compounds, some of which are present in the human diet, on the nitrosation of proline by nitrite to give N-nitrosoproline (NPRO). In vitro, resorcinol, catechin, p-nitrosophenol and phenol were catalysts and chlorogenic acid an inhibitor; guaiacol showed a marginal catalytic effect. Both the catalytic and the inhibiting effects were dependent on pH and on the concentration of phenolic compounds; catalysis by resorcinol and catechin was increased at optimal ratios of [nitrite]: [phenolic compound]. Endogenous nitrosation was examined in vivo by co-administration of nitrite, proline and a phenolic compound to rats and by monitoring the amount of NPRO excreted in the urine. Under similar experimental conditions, the catalytic effects observed in vivo decreased in the same order as those observed in vitro: resorcinol greater than p-nitroso-phenol greater than catechin greater than phenol greater than or equal to guaiacol; chlorogenic acid acted as an inhibitor. Catalysis and inhibition of N-nitrosation in rats in vivo appears to occur via mechanisms similar to those in vitro, although the effects in vivo were smaller. The implications of our findings for the endogenous formation of N-nitroso compounds and for variations in exposure due to different dietary constituents in humans are discussed.

Animals↗
PubMed1977

Nitrosation in vitro and in vivo by sodium nitrite, and mutagenicity of nitrogenous pesticides.

37 nitrogenous pesticides, belonging to the chemical groups of amides, carbamates and ureas, were nitrosated with sodium nitrite in vitro. The nitrosated compounds were tested for mutagenic activity in the bacterial spot test with Salmonella typhimurium his G 46. Those pesticides reacting positively in this test after nitrosation were then fed to mice in combination with sodium nitrite in order to assess the formation and mutagenicity of these nitroso compounds in vivo. With the already known exception of ethylenethiourea (ETU), no pesticide produced enhanced numbers of micronuclei in mouse bone-marrow erythrocytes when fed together with nitrite. Dose-response experiments with intraperitoneal injection of N-nitroso-ETU revealed an apparent no-effect level of about 15--18 mg/kg. The findings are correlated with the pesticide residues actually present in the environment.

Animals↗