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PubMed2004

Detection of nitric oxide from pig trachea by a fluorescence method.

A nitronyl nitroxide radical covalently linked to an organic fluorophore, pyrene, was used to detect nitric oxide (NO) from freshly excited tissues. This approach is based on the phenomenon of the intramolecular fluorescence quenching of the fluorophore fragment by the nitroxide. The pyrene-nitronyl (PN) reacts with NO to yield a pyrene-imino nitroxide radical (PI) and NO(2). Conversion of PN to PI is accompanied by changes in the electron paramagnetic resonance (EPR) spectrum from a five-line pattern (two equivalent N nuclei) into a seven-line pattern (two nonequivalent N nuclei). The transformation of the EPR signal is accompanied by an increase in the fluorescence intensity since the imino nitroxide radical is a weaker quencher than the nitronyl one. The results indicate that the fluorescence measurements enable detection of nanomolar concentrations of NO compared to a sensitivity threshold of only several micromolar for the EPR technique. The method was applied to the determination of NO and S-nitroso compounds in tissue from pig trachea epithelia. The measured basal flux of S-nitroso compounds obtained from the tissues was about 1.2 nmol/g x min, and NO-synthase stimulated by extracellular adenosine 5'-triphosphate produced NO flux of 0.9 nmol/g x min.

Animals↗
PubMed2001

Association between gastric cancer mortality and nitrate content of drinking water: ecological study on small area inequalities.

The carcinogenic feature of N-nitroso compounds has been well established. Similarly, the transformation of ingested nitrate to N-nitroso compounds in the stomach has been thoroughly documented, nevertheless nitrates' carcinogenic effect has not been proved convincingly in human. The present study was aimed to investigate a population of small villages provided by drinking water with high and widely variable nitrate content (72 mg/l median, 290.7 mg/l 95-percentile concentration). Empirical Bayes estimates for settlement-specific age-, sex-, and year-standardised mortality ratios of gastric cancer (GC) were related to the settlement level average nitrate concentrations in drinking water controlling for confounding effects of smoking, ethnicity and education. The log-transformed average nitrate concentration showed significant positive association with stomach cancer mortality in linear regression analysis (p = 0.014). The settlements were aggregated according to the nitrate concentration into 10-percentile groups and the standardised mortality ratios (SMRs) were calculated. Those groups with higher than 88 mg/l average nitrate concentration showed substantial risk elevation and the log-transformed exposure variables proved to be significant predictors of mortality (p = 0.032) at this level of aggregation also. The association seemed to be fairly strong (r2 = 0.46). Although this investigation constituting an ecological study has certain limitations, it supports the hypothesis that the high level of nitrate in drinking water is involved in the development of GC.

Bayes Theorem↗
PubMedDate not supplied

A method for the investigation of free and protein-bound N-nitrosoproline in beer.

Hydrolysis of beer peptides and proteins by both mild enzymatic and vigorous alkaline conditions has established that peptide-bound N-nitrosoproline residues are not present in beer in significant quantities. Free N-nitrosoproline remains the single most abundant identified N-nitroso compound, and this accounts for up to 10% of the apparent total N-nitroso compounds (ATNC). Both hydrolysis and extractability studies strongly indicate that the majority of the ATNC are not associated with beer peptides, but rather are likely to be low molecular weight possessing in some cases an acidic functional group.

Beer↗
PubMed1987

Characterization of a CHO variant in respect to alkylating agent-induced biological effects and DNA repair.

From the Chinese hamster ovary line CHO-9 a resistant variant, Cl 3, was isolated after treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Cl 3 cells were much more resistant to the cytotoxic effects of MNNG (D10 of 1.8 microgram/ml MNNG as compared to 0.23 microgram/ml for parental line) and other methylating N-nitroso compounds, but they had the same sensitivity to various other alkylating agents. MNNG was equally effective in sensitive parent line and resistant variant in inducing sister-chromatid exchanges (SCEs) and mutations to 6-thioguanine resistance. The increased resistance of Cl 3 was not due to reduced cellular uptake of MNNG, to a more efficient repair of methylated purine bases, or to differences in MNNG-induced inhibition of DNA synthesis. It is concluded that the resistant variant has some unknown tolerance mechanism which alters the cytotoxic, but not the SCE- and mutation-inducing effects of methylating N-nitroso compounds.

Alkylating Agents↗
PubMed1987

Nitrosation of drugs under in-vivo conditions.

Application of the WHO Nitrosation Assay Procedure (NAP test) to a range of potentially nitrosatable drugs has given rise to considerable variations in the formation of volatile N-nitrosamines and N-nitroso compounds as a group. No nitrosation whatsoever was observed with 40 mM nitrite in some instances. In simulating more closely the conditions likely to be encountered in the human stomach, however, the order of susceptibility of the drugs to N-nitrosation has proved to be very different. At a constant nitrite concentration of 25 microM, which is considered to represent the upper limit of those likely to be encountered in the acidic human stomach, the drugs giving rise to the greatest yields of products reacting as N-nitroso compounds from a maximum adult dose were the penicillins, G, V, cloxacillin and ampicillin.

Chemical Phenomena↗
PubMed1989

Cytotoxic and genotoxic effects of areca nut-related compounds in cultured human buccal epithelial cells.

Because betel quid chewing has been linked to the development of oral cancer, pathobiological effects of an aqueous areca nut extract, four areca nut alkaloids (arecoline, guvacoline, guvacine, and arecaidine), and four nitrosated derivatives [N-nitrosoguvacoline, N-nitrosoguvacine, 3-(N-nitrosomethylamino)propionaldehyde and 3-(N-nitrosomethylamino)propionitrile] have been investigated using cultured human buccal epithelial cells. Areca nut extract in a dose-dependent manner decreases cell survival, vital dye accumulation, and membrane integrity, and it causes formation of both DNA single strand breaks and DNA protein cross-links. Depletion of cellular free low-molecular-weight thiols also occurs, albeit at quite toxic concentrations. Comparisons of the areca nut-related N-nitroso compounds and their precursor alkaloids, at concentrations up to 5 mM, indicate that 3-(N-nitrosomethylamino)propionaldehyde is the most potent on a molar basis to decrease both survival and thiol content and to cause significant formation of DNA single strand breaks. Arecoline, guvacoline, or N-nitrosoguvacoline decreases survival and cellular thiols, whereas arecaidine, guvacine, N-nitrosoguvacine, and 3-(N-nitrosomethylamino)propionitrile have only minor effects on these variables. Taken together, the present studies indicate that aqueous extract and, in particular, one N-nitroso compound related to areca nut, i.e., 3-(N-nitrosomethylamino)propionaldehyde, are highly cytotoxic and genotoxic to cultured human buccal epithelial cells, of potential importance in the induction of tumors in betel quid chewers.

Arecoline↗
PubMed1989

[Malignant transformation of NIH 3T3 cells by urine NTCA in normal population of Lin-xian County].

N-Nitrosothiazolidine 4-carboxylic acid (NTCA), a nonvolatile N-Nitroso compound containing sulfur was first found in the urine of normal subjects in Lin-xian county, a high risk area of esophageal cancer. The content of NTCA in the urine of the general population of Lin-xian is higher than that in Fan-xian county, a low risk area of esophageal cancer. NTCA could induce mutation in V79 cells. The results showed that NIH 3T3 cells could be induced to undergo malignant transformation by NTCA. If NIH 3T3 cells were cultured in soft agar medium, transformed cells could grow progressively to form colonies and became anchorage-independent. These transformed cells were tumorigenic in nude mice. The above results indicate that NTCA formed in vivo, being one of the risk factors of esophageal cancer in Lin-xian county, is a potential carcinogen. This investigation also demonstrates that the N-Nitroso compounds are closely related to esophageal cancer.

Animals↗
PubMed1999

Mutagenicity of potassium alkanediazotates in Chinese hamster V79 cells and their alkylating activity.

Alkanediazohydroxides are the key intermediates of carcinogenic N-nitroso compounds, and exist as geometrical isomers. In this paper, the mutagenicity and cytotoxicity of (E)- and (Z)-potassium alkanediazotates, precursors of alkanediazohydroxides, in Chinese hamster V79 cells were investigated. Mutagenic and cytotoxic activities of (E)-diazotates were dose-dependent, and activity decreased with an increase in the alkyl chain length; methyl>ethyl>propyl, butyl. On the other hand, (Z)-diazotates were less mutagenic and cytotoxic than (E)-diazotates, however (Z)-potassium methanediazotate did show weak mutagenicity. To compare chemical reactivity with biological activity, alkylating activity towards nicotinamide in an aqueous phosphate buffer system was evaluated as an index of the chemical reactivity of diazotates. Using a fluorometric HPLC method, alkylated nicotinamides were detected with high sensitivity in the reaction with all diazotates tested. The alkylating activity of (Z)-methanediazotate was higher than that of the corresponding (E)-diazotate, but the other isomers with ethyl, propyl and butyl groups had similar reactivity under the conditions used. The activity decreased by increasing the alkyl chain-length, which correlated well with the mutagenicity in V79 cells and also with that in Salmonella typhimurium, which we reported earlier. The results for (E)-diazotates were similar to the corresponding N-nitroso-N-(hydroxymethyl)alkylamines, further supporting the notion that alpha-hydroxy nitrosamines decompose through alkanediazohydroxide and alkylate DNA, and suggests that geometrical isomerism influences the carcinogenicity of -nitroso compounds in mammals.

Alkylating Agents↗
PubMed1982

N-nitrosamines in grass silages.

During the fermentation of silages from nitrate-rich grass, the conditions are suitable for the formation of N-nitrosamines. Earlier investigations had shown that only low concentrations of volatile N-nitrosamines were formed. The first ten days of ensilage were investigated. The formation of nitrite was accompanied by the formation of volatile N-nitrosamines. NDMA and NDEA were detected in concentrations of up to about 2 micrograms/kg. After stabilisation of the silage, these concentrations dropped to about 0.6 microgram/kg. Preliminary results are presented concerning the presence of non-volatile N-nitroso compounds. The method of Walters et al. (1980) indicates that non-volatile N-nitroso compounds were present in amounts equivalent to 85 mg NPIP/kg sample.

Animal Feed↗
PubMed1984

Animal feeding study with nitrite-treated meat.

In order to detect possible formation of carcinogenic N-nitroso compounds from nitrite and nitrosatable compounds in meat, studies were carried out with 70 male and 140 female F0 rats, divided into six groups, and 60, 100, 70, 60, 60 and 66 of their male and female offspring. One control group received casein and other groups chopped pork as the sole protein source (45%, mass/mass) on a fresh basis, either salted (sodium chloride) or not. For test groups, nitrite was also added to the meat before autoclaving and storing the diet and represented mass fractions of 200, 1 000 and 4 000 mg/kg, as sodium nitrite. The results do not demonstrate any effect on reproduction and no significant carcinogenic effect was revealed. However, an observed tendency toward an increased number of tumour-bearing rats in the highest dose group, plus the possible formation of carcinogenic N-nitroso compounds in nitrite-treated meat products, led to a recommendation to reduce the use of nitrite. Results from a concomitant study demonstrate that it is possible to produce many cured-meat products with the addition of only 50 mg/kg nitrite.

Animal Feed↗
PubMed1994

Liver fluke infection and cholangiocarcinoma: model of endogenous nitric oxide and extragastric nitrosation in human carcinogenesis.

Cancers arising during bacterial, viral and parasitic infection provide useful models to investigate the link between inflammation and carcinogenesis. Because the inflammatory agent is known, relationships between immune responses, the production of DNA-damaging agents, such as nitric oxide, oxygen radicles and N-nitroso compounds, and cancer risk can be explored. This paper first describes the close relationship between infection with the liver fluke, Opisthorchis viverrini, and cholangiocarcinoma in humans. Data are then presented which demonstrate an elevation in levels of salivary nitrite and urinary and plasma nitrate among men with moderate and heavy liver fluke infections compared to uninfected controls which was absent 4 months after the parasites were cleared with praziquantel. Because of the strict control over subject selection and dietary intake plus the absence of the increase following treatment, we conclude that the higher levels of nitrate and nitrite reflect endogenous generation of nitric oxide resulting from liver fluke infection. Excess nitric oxide generation in the inflamed tissue is likely to lead directly to the formation of N-nitroso compounds mediated by activated macrophages. Further work will attempt to demonstrate a link between this increase and both parasite-specific immune responses and the risk of cancer.

Adult↗
PubMed2001

Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation.

Human male volunteers were studied in a metabolic facility whilst they were fed randomized controlled diets. In eight volunteers there was a significant increase in faecal apparent total N:-nitroso compounds (ATNC) and nitrite excretion (P < 0.0001 and P = 0.046, respectively) when randomized doses of meat were increased from 0 to 60, 240 and 420 g/day over 10 day periods. Mean (+/- SE) faecal ATNC levels were 54 +/- 7 microg/day when the diets contained no meat, 52 +/- 11 microg/day when the diets contained 60 g meat/day, 159 +/- 33 microg/day with 240 g meat and 199 +/- 36 microg/day with 420 g meat. Higher concentrations of NOC were associated with longer times of transit in the gut (r = 0.55, P = 0.001) and low faecal weight (r = -0.51, P = 0.004). There was no significant decline in levels in individuals fed 420 g meat for 40 days. The exposures found on the higher meat diets were comparable with other sources of N:-nitroso compounds (NOC), such as tobacco smoke. Many NOC are known large bowel initiators and promotors in colon cancer, inducing G-->A transitions in codons 12 and 13 of K-ras. Endogenous NOC formation, combined with prolonged transit times in the gut, may explain the epidemiological associations between high meat/low fibre diets and colorectal cancer risk.

Adult↗
PubMed1981

A possible role of iron deficiency in gastric cancer in Colombia.

Through the efforts of Correa, Cuello, Haenszel, Tannenbaum and others it was learned that the incidence of gastric cancer in certain areas of Narino (Colombia) was among the highest in the world. These areas of high risk for gastric cancer were adjacent to an area of substantially lower risk. Gastric biopsies from healthy volunteers residing in the "high risk" area exhibited a greater incidence of superficial gastritis and chronic atrophic gastritis with and without intestinal metaplasia than those from the low risk area. The latter pathological finding is considered to be a precursor lesion to gastric cancer. Volunteers from the "low risk" area as well as individuals from Cali in the coastal region and Cartegena on the coast, also exhibited a similar spectrum of pathology but at a substantially reduced frequency. Natives of both cities were also at lower risk for gastric cancer than inhabitants of Narino. It was found that the water supply of the "high risk" area contained a higher concentration of nitrate than water in the "low risk" area. Correa et al. hypothesized that the high nitrate concentrations of well water contributed to the formation of N-nitroso compounds in the stomachs of these individuals early in life. The occurrence of this putative carcinogen in combination with the abrasive action of dietary grains contributed to a series of mutations in the gastric epithelium progressing through a sequence of pathologic changes, loss of gastric acid and culminating in gastric cancer. In the current report individuals in a Medellin population who were admitted with abdominal complaints and were found to be iron deficient exhibited the same spectrum of gastric pathology described by previous investigators. Superficial gastritis, chronic atrophic gastritis and achlorhydria have also been described in association with chronic iron deficiency (and/or associated nutritional defects) per se. The development of these lesions are likely to occur within the first two decades of life when iron requirements are maximal. It is suggested that these changes preceed the development of gastric cancer. Bacterial colonization of the achlorhydric stomach may facilitate nitrate reduction and the formation of a putative carcinogen N-nitroso compound(s) from nitrate in the water supply. Additionally, the effects of chronic iron deficiency on host immune defense may compromise these mechanisms and permit tumor growth with minimal immune intervention.

Achlorhydria↗
PubMedDate not supplied

Susceptibility of nonhuman primates to carcinogens of human relevance.

Nonhuman primates are a valuable experimental model for the evaluation of human carcinogenic risk but have not been widely used for various reasons, such as high cost and lack of availability. The present review discusses the findings from a long-term carcinogenesis study in nonhuman primates that was carried out under contract by the National Cancer Institute from 1961 to 1997. Among the classes of compounds investigated were model rodent carcinogens, food additives, food and environmental contaminants, heterocyclic amines, N-nitroso compounds, and antineoplastic and immunosuppressives. Of the model rodent carcinogens tested, only urethane was carcinogenic in monkeys. Long-term administration of saccharin or cyclamate did not result in toxicity or carcinogenicity in nonhuman primates, which is commonly seen in rodent models. Similar to rodent models and suspected in the human population, the fungal toxins, aflatoxin B1 and sterimatocystin, induced malignant liver tumors in monkeys. Relatively few animals administered DDT developed malignant tumors, however, hepatic and CNS toxicity was commonly observed. Hepatocellular carcinoma developed in a majority of monkeys administered the heterocyclic amine, IQ but not the structurally similar MeIQx. Resultant toxicity and carcinogenicity from N-nitroso compounds was variable. While diethylnitrosamine proved to be the most potent hepatocarcinogen tested, no malignant tumors were seen in animals administered N-methyl-N-nitro-N-nitrosoquanidine. Susceptibility of nonhuman primates to chemotherapeutic agents was also variable. Only procarbazine and N-methyl-N-nitrosourea were highly carcinogenic, whereas few tumors were seen as a result of cyclophosphamide, Adriamycin, melphalan, or azathioprine.

Animals↗
PubMed2003

[Megaesophagus microbiota and carcinogenesis].

BACKGROUND: The risk of development of spin cell carcinoma of the esophagus is 33 times higher in patients with chagasic achalasia. It is possible that the production of N-nitroso compounds in the esophageal lumen by of bacterial action in the stasis liquid that reduce nitrates from diet into nitrites may play a role in this process. AIM: To analyze qualitatively and quantitatively the microbiota in chagasic megaesophagus with special attention to bacteria capable of transforming nitto reduction. PATIENTS: Fifteen patients (six men and nine women) were prospectively studied, with ages varying from 28 to 73 years. Patients were divided into three sub-groups according to Rezende et al. classification of esophageal dilation (grade I, grade II and grade III). METHOD: The sample collection was performed using a method specially developed to avoid contamination with microorganisms of the oral cavity and oropharynx, using a Levine catheter n 14 and a 7,5 oro-traqueal tube. RESULTS: Ninety three point three percent of the cultures were positive, with great bacterial variability and predominance of a variety of aerobic Gram-positive and anaerobic bacteria. The bacterial concentrations were generally more elevated in grade III in comparison to grade I and grade II. Among the microorganisms found, Staphylococcus sp, Corynebacterium sp, Peptostreptococcus sp e a Veillonella sp were those with the capability of nitrate reduction. CONCLUSION: It was concluded that patients with megaesophagus present some bacteria in the esophageal lumen that are able to reduce nitrates intro nitrites, an important step in the formation of N-nitroso compounds.

Adult↗
PubMed1999

Childhood cancer in relation to cured meat intake: review of the epidemiological evidence.

Over the past two decades a series of epidemiological studies have examined the relationship between consumption of cured meats during pregnancy and the subsequent risk of brain tumors, as well as other cancers, in the offspring. The research was prompted in large part by experimental investigations showing that transplacental exposure to certain N-nitroso compounds, i.e., nitrosoureas, could produce brain tumors in laboratory animals. Fourteen such epidemiological studies, 13 of which used the case-control approach, are reviewed here. Most of the studies showed no significant association between total cured meat intake and childhood cancer risk but more found positive than negative relationships. Furthermore, several studies reported significant positive associations for maternal and sometimes childhood or paternal consumption of one or more cured meats, with odds ratios of twofold or greater reported among the highest consumers. On the other hand, a correlation analysis found no positive concordance between temporal trends from the 1970s to 1990s in childhood brain cancer rates and cured meat consumption, inasmuch as cancer rates rose over time while residual nitrite levels in cured meats fell sharply. Because of the potential for bias, especially recall bias, and/or confounding, the relatively weak magnitude of the associations reported, and the inconsistency between study findings, at this time it cannot be concluded that eating cured meat has increased the risk of childhood brain cancer or any other cancers. Moreover, although N-nitroso compounds are sometimes found in cured meats or may be formed endogenously, there is no empirical evidence that eating cured meats results in human neural nitrosourea exposure. Nevertheless, the hypothesis that eating nitrite-cured meats may influence childhood and perhaps adult brain cancer cannot be dismissed. Unbiased evaluation of the hypothesis may derive from the conduct of cohort studies, where the interview-derived information on cured meat intake precedes, or is not otherwise associated with, the diagnosis of cancer.

Brain Neoplasms↗
PubMed1977

Quantitation of dimethylnitrosamine in the whole mouse after biosynthesis in vivo from trace levels of precursors.

A simple and highly sensitive procedure is described for the recovery and quantitative identification of nanogram quantities of preformed N-nitroso compounds in the whole mouse. This procedure has also been applied to the quantitation of N-nitroso compounds after they have been biosynthesized from trace amounts of precursors. The whole animal is frozen in liquid nitrogen and homogenized to a frozen powder; the powder is then extracted and analyzed by a thermal energy analyzer interfaced to a gas-liquid and a high-pressure liquid chromatograph.

Animals↗
PubMed1980

Gastric bacteria, nitrate, nitrite and nitrosamines in patients with pernicious anaemia and in patients treated with cimetidine.

Patients with pernicious anaemia have a high risk of gastric cancer and we are investigating the role of N-nitroso compounds in their gastric carcinogenesis. We have carried out bacteriological studies and analyses of nitrite and N-nitroso compounds. Patients with duodenal or gastric ulcer are often treated with H2-receptor inhibitors such as cimetidine. This treatment induces hypochlorhydria similar to that in pernicious anaemia patients and it has been suggested that this might put these patients at risk of developing gastric cancer later. Analyses similar to those for p.a. patients have therefore been carried out in patients treated with cimetidine. We have set up an animal model of achlorhydria, using piglets, that will allow us to test in vivo the efficacy of compounds known to inhibit N-nitrosation in vitro. This is clearly necessary, in view of the growing size of the population now thought to be at risk.

Anemia, Pernicious↗