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PubMed1984

4-Chloro-6-methoxyindole is the precursor of a potent mutagen (4-chloro-6-methoxy-2-hydroxy-1-nitroso-indolin-3-one oxime) that forms during nitrosation of the fava bean (Vicia faba).

Fava beans (Vicia faba) upon treatment with nitrite under simulated gastric conditions, form a direct-acting bacterial mutagen, comparable in specific activity to the most potent known mutagens for several strains of Salmonella typhimurium. The precursor of the mutagen was isolated and identified as 4-chloro-6-methoxyindole by u.v., i.r., m.s. and n.m.r. The precursor was dechlorinated with NaBH4 and PdCl2 as the catalyst and the product obtained from this reaction was identified as 6-methoxyindole. Since synthetic 4-chloro-6-methoxyindole was not available, structure activity studies were conducted on substituted indoles. Nitrosation of 4-chloroindole closely follows the results for nitrosation of 4-chloro-6-methoxyindole. The major product of nitrosation of 4-chloroindole is 4-chloro-2-hydroxy-N1-nitroso-indolin-3-one oxime. Thus, it appears that the major nitrosation product of 4-chloroindole and of 4-chloro-6-methoxyindole is a stable alpha-hydroxy N-nitroso compound. This is the first reported case of stable alpha-hydroxy N-nitroso compounds. In the presence of N-(1-naphthyl)ethylenediamine dihydrochloride (NEDD), the alpha-hydroxy N-nitroso compound rearranges to an aromatic diazonium ion which couples with the diamine to form an azo dye. Studies on nitrosation kinetics indicate that the nitrosation of indoles are relatively fast reactions. Both the structural and rate studies give strong support to the hypothesis that intragastric nitrosation of fava beans yield the putative gastric carcinogen in the high-risk area in Colombia.

Fabaceae↗
PubMed1995

p-nitrosophenol reduction by liver cytosol from ADH-positive and -negative deermice (Peromyscus maniculatus).

Liver cytosolic fractions are known to catalyze the reduction of certain C-nitroso compounds to their corresponding hydroxylamines and amines. Alcohol dehydrogenase (ADH), NAD(P)H:quinone oxidoreductase, and xanthine and aldehyde oxidases have been implicated as C-nitroso reductases. To probe the role of these cytosolic enzymes in the reduction of C-nitroso compounds we have studied the effects of classical inhibitors of these enzymes on the ability of liver cytosolic fractions from ADH+ and ADH- deermice to reduce p-nitrosophenol to p-aminophenol. Pyrazole, a potent inhibitor of ADH, inhibited NADH-p-nitrosophenol reduction by ADH+ cytosol by > 85%. Thus, ADH contributes substantially to NADH-C-nitroso reduction by cytosol from ADH+ deermice. The NAD(P)H:quinone oxidoreductase inhibitor, dicumarol, inhibited NADH-dependent p-aminophenol formation by about 25%; however, dicumarol potently inhibited the NADPH-dependent formation (90-95%). As expected, cytosol from ADH- deermice did not catalyze pyrazole-sensitive (ADH-dependent) C-nitroso reduction with NADH as the cofactor. Both NADPH- and NADH-p-nitrosophenol reduction by ADH- cytosol were inhibited > 90% by dicumarol. The xanthine oxidase/aldehyde oxidase inhibitor, allopurinol, was without effect on NAD(P)H cytosolic p-nitrosophenol reduction from ADH- and ADH+ deermice under either aerobic or anaerobic conditions. Our findings suggest that in the ADH+ animal, ADH contributes significantly to NADH-dependent C-nitroso reduction by cytosol relative to NAD(P)H:quinone oxidoreductase. NADPH-dependent p-nitrosophenol reduction by liver cytosol of ADH+ animals is mostly dicumarol-sensitive, which implicates NAD(P)H:quinone oxidoreductase as the major NADPH-dependent activity. In ADH- deermice, both NADH- and NADPH-dependent p-nitrosophenol reduction are essentially dicumarol-sensitive (NAD(P)H:quinone oxidoreductase-dependent). Because the toxic expression of C-nitroso compounds is mediated by hydroxylamine intermediates, the present data indicate the importance of considering the role of ADH in the toxic sequelae of nitro and nitroso arenes.

Alcohol Dehydrogenase↗
PubMed2001

Mutagenicity in Salmonella typhimurium TA98 and TA100 of nitroso and respective hydroxylamine compounds.

Five aromatic nitroso compounds were prepared and their mutagenicity in Salmonella typhimurium strains TA98 and TA100 compared with that of the corresponding hydroxylamines and the previously studied nitroarenes. A remarkable correspondence of the dose-response curves was observed between the nitroso and the respective hydroxylamine compounds. This effect could be observed in TA98 and TA100. It was only marginally dependent on the metabolical activation by rat liver S9-mix. Even the presence of a bulky alkyl substituent either near to the functional group, or far away from it, previously shown to considerably influence the mutagenic properties of nitroarenes, does not remarkably affect the properties of the nitroso and hydroxylamine species. The similarity between the latter two is likely to be due to a fast reduction of the nitrosoarenes to the hydroxylamine species under the test conditions. It seems that enzymes are not responsible for that reduction step, because sterical crowding near the functional group does not influence that behaviour. The test results of the aromatic hydroxylamines bearing a bulky substituent show that there are at least two ways to influence the mutagenicity of an aromatic nitro compound by such a group. A substituent near the functional group (ortho-position) disturbs the enzymatic reduction of the nitro group, because 3-tert-butyl-4-hydroxylaminobiphenyl and its corresponding nitroso compound are highly mutagenic, whereas 3-tert-butyl-4-nitrobiphenyl was previously shown to be inactive even after addition of S9-mix. In contrast, 4'-tert-butyl-4-hydroxylaminobiphenyl with the tert-butyl group "far away" from the hydroxylamino functionality clearly shows decreased mutagenic activity suggesting a different influence of a substituent in that position. In addition, the substance shows only little cell toxicity even at higher concentrations. Both effects could be due to a reduced effective dose of the hydroxylamine in the cells compared to the non-alkylated compound, caused by a faster degradation of the hydroxylamine or a hindered interaction between that substance and the cells.

Biotransformation↗
PubMed1995

Effects of acid suppression on microbial flora of upper gut.

Decreased acid secretion, due to therapy or disease, predisposes to increased bacterial counts in gastric juice. As bacterial numbers increase, the number of nitrate-reducing strains and the concentration of luminal nitrite usually also increase. However, there is controversy (mainly because of assay problems) about whether decreased acid increases generation of N-nitroso compounds: these may be produced by acid or by bacterial catalysis, and the relative contributions of each are still uncertain. Other potentially important factors include ascorbate secretion (can prevent nitrite conversion to nitroso compounds) and the particular spectrum of nitroso compounds produced. Nitrosation of several histamine H2-receptor antagonists has been demonstrated experimentally, but under conditions that are very unlikely to be encountered clinically. Some acid suppressant therapies have been claimed to aid eradication of Helicobacter pylori, but more work is needed to evaluate this. If ulcer treatment regimens do not also address eradication of H. pylori (when present), gastritis will progress, and the recently documented association between H. pylori and gastric carcinoma needs to be considered. Enteric flora probably also increase if acid secretion is markedly reduced: this does not appear to have nutritional consequences but probably reduces the resistance to occasional infections, of which cholera is the best documented.

Antacids↗
PubMed1988

Nitrite inhalants: historical perspective.

There are important reasons for considering nitrite inhalation as a factor in the development of AIDS-related KS in young male homosexuals. These are (1) the pharmacologic properties of amyl, butyl, and isobutyl nitrites, which are toxic; (2) the mutagenic, teratogenic, and carcinogenic products resulting from metabolism of N-nitroso compounds; (3) the potent carcinogenicity of N-nitroso compounds in 39 different animal species; and (4) the deleterious effects of volatile nitrites on human lymphocytes both in vitro and in vivo. Specifically related to this epidemic, there are additional reasons for pursuing the connection between nitrite inhalation and development of KS. These include: (1) the timing of the production and sales of volatile nitrites for use as recreational drugs and the subsequent outbreak of the AIDS epidemic (7 to 10 years); (2) the extensive use of nitrites among male homosexuals; (3) the virtual universal history of nitrite use by young male homosexuals in whom KS has developed during the past 3 years; and (4) the age group in which KS is developing is consistent with a cohort initially exposed 7 to 10 years ago.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Effects of one year's treatment with ranitidine and of truncal vagotomy on gastric contents.

Fifteen patients with peptic ulcer underwent 24 hour studies of gastric contents: before and on completing six weeks' treatment with oral ranitidine 150 mg bd, twice on maintenance treatment for nine to 12 months and one month after stopping the drug. For comparison, 11 patients underwent identical 24 hour studies three to 38 months after truncal vagotomy for duodenal ulcer. During treatment with ranitidine median 24 hour intragastric pH, nitrate concentration, and counts of total and nitrate reducing bacteria increased significantly regardless of dietary nitrate content; there was no significant increase in the median day time concentration of N-nitroso compounds. Despite these changes, an acid tide at some point in each 24 hour study period prevented persistent bacterial colonisation of the stomach. There were no significant differences between the biochemical and microbiological changes recorded during one year of treatment with ranitidine, and the observations on patients after truncal vagotomy. One month after stopping one year's treatment with ranitidine all variables examined returned to pretreatment levels. Treatment with ranitidine or vagotomy was associated with significant positive correlations among pH, nitrate concentration and bacterial counts. Correlations between pH and N-nitroso compound concentration and between concentrations of nitrite and N-nitroso compounds were not significant.

Adult↗
PubMed1991

Effect of ascorbic acid on the intragastric environment in patients at increased risk of developing gastric cancer.

Ascorbic acid has been shown to decrease nitrosation in vivo, and epidemiological data suggest that the consumption of foods rich in this vitamin is associated with a reduced risk for gastric cancer. In order to study this suggestion further, fasting gastric juice samples were obtained from 62 high-risk patients (seven with atrophic gastritis, ten with pernicious anaemia, ten with partial gastrectomy, 21 with vagotomy and drainage and 14 with highly selective vagotomy), before, during four weeks' treatment with 1 g ascorbic acid four times daily, and four weeks after treatment. Samples were analysed for pH, total and nitrate-reducing bacterial counts, nitrite and N-nitroso compounds. Treatment with ascorbic acid lowered the median pH only in the vagotomized patients (p less than 0.001) but resulted in a reduction in median nitrate-reducing bacterial counts and in nitrite and N-nitroso compound concentrations in all groups, except for an increase in the nitrate-reducing bacterial count in atrophic gastritis patients and in nitrite in those with pernicious anaemia. These data suggest that treatment with a high dose of ascorbic acid reduces the intragastric formation of nitrite and N-nitroso compounds.

Adult↗
PubMed1989

[Drugs from the classes of tricyclic antidepressives and antiepileptics, nitrosatable under simulated human gastric conditions].

The nitrosatability of Pryleugan (imipramine), Herphonal (trimipramine), and Finlepsin (carbamazepine) was investigated under simulated human gastric conditions using a colorimetric measuring method. All of them proved to be nitrosatable even at very low nitrite concentrations. In the presence of ascorbic acid, the formation of N-nitroso compounds under model conditions was inhibited markedly. N-nitroso-dihydrodibenzazepine and N-nitroso-dibenzazepine could be identified by thin layer chromatography as main products. The biological effects of these N-nitroso compounds are not known up to now.

Carbamazepine↗
PubMed2004

Nitroxyl (HNO) release from new functionalized N-hydroxyurea-derived acyl nitroso-9,10-dimethylanthracene cycloadducts.

A thermal retro-Diels-Alder decomposition of N-hydroxyurea-derived acyl nitroso compounds and 9,10-dimethylanthracene cycloadducts followed by acyl nitroso compound hydrolysis produces nitrous oxide, evidence for the formation of nitroxyl, the one-electron reduced form of nitric oxide that has drawn considerable attention for its potential roles in biological systems. EPR and NMR spectroscopy provide further evidence for nitroxyl formation and kinetic information, respectively. Such compounds may prove to be useful alternative nitroxyl donors.

Anthracenes↗
PubMed1992

Inhibitory effect of diet related sulphydryl compounds on the formation of carcinogenic nitrosamines.

N-Nitroso compounds (NOCs) are known to be strong carcinogens in various animals including primates (Preussman and Stewart, (1984) N-Nitroso Compounds). Human exposure to these compounds can be by ingestion or inhalation of preformed NOCs or by endogenous nitrosation from naturally occurring precursors (Bartsch and Montesano, Carcinogenesis, 5 (1984) 1381-1393; Tannebaum (1979) Naturally Occuring Carcinogens, Mutagens and Modulators of Carcinogenesis; Shephard et al., Food Chem. Toxicol., 25 (1987) 91-108). Several factors present in the diet can modify levels of endogenously formed nitrosamines by acting as catalysts or inhibitors. Compounds in the human diet that alter nitrosamine formation would thus play an important role in carcinogenesis study. Earlier researchers have reported the nitrite scavenging nature of sulphydryl compounds (Williams, Chem. Soc. Rev., 15 (1983) 171-196). We therefore studied the modifying effect of sulphydryl compounds viz., cysteine (CE), cystine (CI), glutathione (GU), cysteamine (CEA), cystamine (CEI), cysteic acid (CIA) and thioglycolic acid (TGA) on the nitrosation of model amines viz., pyrrolidine (PYR), piperidine (NPIP) and morpholine (NMOR). Many of these compounds are present in the food we consume. The present work also describes the inhibitory effect of onion and garlic juices on the nitrosation reactions. Both onion and garlic are known to contain sulphur compounds (Block, Sci. Am., 252 (1985) 114-119). Most of these compounds behave as antinitrosating agents and their inhibitory activity towards formation of carcinogenic nitrosamines, under different conditions is described.

Allium↗
PubMed1984

O6-Methylguanine-DNA transmethylase activity in extracts of human gastric mucosa.

In view of the possible involvement of N-nitroso compounds in the etiology of gastric carcinoma in man, we have examined the abilities of extracts of human gastric mucosa for the removal from DNA of O6-methylguanine, the primary precarcinogenic lesion induced in DNA by methylating carcinogenic N-nitroso compounds. We find that all 20 specimens examined (including 14 non-neoplastic and 6 neoplastic) possess significant activity, removing on average 0.73 +/- 0.06 (s.e.m.) pmol O6-methylguanine per mg protein in the extract. This activity, which has the characteristics of an O6-methylguanine-DNA-transmethylase, while exhibiting wide interindividual variations, shows no significant differences between the groups of normal and of neoplastic tissues or between the groups of non-neoplastic tissues obtained from individuals with benign or with malignant gastric disease. It is estimated that the average O6-methylguanine-removing capacity of the cells of normal gastric mucosa (calculated as 166 000 +/- 26 000 (s.e.m.) molecules per cell) greatly exceeds the extent of DNA damage likely to be caused by gastric-juice N-nitroso compounds.

Adult↗
PubMed1989

Increased urinary nitrosamine excretion in patients with urinary diversions.

Tumor development at the site of ureterointestinal anastomosis is a recognized complication in patients with continent urinary diversions. Aerobic cultures of rectal urine samples from 30 patients with urinary diversions (26 ureterosigmoidostomies, two colon conduits, one ileal conduit and a Gersuny bladder) showed a complex bacterial flora containing nitrate-reducing organisms (Escherichia coli, Proteus and Klebsiella spp.). In comparison to normal bladder urine samples from control volunteers (n = 20), rectal urine samples from ureterosigmoidostomy patients (n = 26) showed a significant decrease (P less than 0.0001) in urinary nitrate (0.93 +/- 0.39 versus 0.27 +/- 0.23 mmol/l), a significant increase (P less than 0.0001) in urinary nitrite (not detected versus 29.24 +/- 39.93 mumol/l) as well as a significant increase (P = 0.013) in urinary N-nitroso compound excretion (57.33 +/- 33.87 versus 93.96 +/- 65.76 nmol/l). Significant increases were also found for the urinary excretion of individual volatile and non-volatile N-nitroso compounds, clearly demonstrating a bacterially mediated in vivo formation of N-nitroso compounds in the 'colon' bladders of patients with urointestinal diversions that may be an important etiological risk factor for colon carcinogenesis in this patient group.

Bacteria↗
PubMed1994

Alkyltransferase transgenic mice: probes of chemical carcinogenesis.

Transgenic mice expressing DNA-repair genes are an instructive model with which to study the protective role of DNA-repair pathways in both spontaneous and chemical carcinogenesis. Of particular interest in chemical carcinogenesis is the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which repairs O6-alkylguanine-DNA adducts. Transgenic mice carrying expression constructs for the alkyltransferase gene--either the human MGMT cDNA or the bacterial ada gene--express increased levels of alkyltransferase and have increased capacity to remove O6-methylguanine-DNA adducts. Protection from the DNA damaging effects of N-nitroso compounds occurs specifically in the cells and tissues in which the alkyltransferase transgene is expressed. For instance, mice carrying the PEPCKada construct have increased alkyltransferase in the liver and more rapid removal of O6methylguanine-DNA adducts. The protective effect is noted in hepatocytes, which express PEPCK-linked genes, not in nonparenchymal cells of the liver, which do not. Other tissues that express the transgene in the various models include the thymus, spleen, testes, muscle, stomach and brain. Mice expressing the human alkyltransferase in the thymus have a reduced incidence of thymic lymphomas following exposure to methyl nitrosourea (MNU), evidence of a role for this DNA-repair protein in protection from carcinogenesis due to N-nitroso compounds. Protection has also been observed in the induction of hepatic tumors by N-nitroso-dimethylamine (NDMA). These models will be used to identify whether overexpression of a single DNA-repair gene can block the carcinogenic process of N-nitroso compounds in many different tissues.

Actins↗
PubMed1980

[Role of nitrites and nitroso derivatives on the development of abnormal colorations in cheeses. Study of their decomposition].

Nitrites and nitroso compounds have been incriminated in the development of abnormal colourations of "pont-l'évêque". In a preparation of these cheeses nitrites were added either to the milk or during the manufacturing procedures and in all cases were noticed pink or brown stains and bursting of the cheese pulp with formation of cavities. Our results have demonstrated it is possible to break down these nitroso-compounds with an enzyme from yeast. This enzyme detoxifies the medium following a mechanism which has been elucidated. The addition of yeasts to the cheeses during manufacturing helps to accelerate the desintegration process of the coloured compounds and to obtain a uniform shade of the crust and a total absence of deeper stains. We have shown that the nitrites present in the cheeses will form nitroso compounds. The latter are then responsible for the abnormal and irregular stains; their rapid decomposition helps to detoxify the medium as well as ameliorating the aspect of the cheeses.

Cheese↗
PubMed2003

Nitrate in public water supplies and risk of bladder cancer.

BACKGROUND: Nitrate is a precursor compound in the formation of N-nitroso compounds, most of which are potent animal carcinogens. N-nitroso compounds and their precursors have not been extensively evaluated as bladder cancer risk factors. METHODS: We conducted a population-based case-control study of bladder cancer in Iowa. Cases were men and women newly diagnosed with bladder cancer in 1986-1989. Nitrate data for Iowa public water supplies were sparse before the 1960s. To reduce misclassification by unknown nitrate levels, we included only those who used public supplies with nitrate data for 70% or more of their person-years since 1960 (808 cases, 1259 controls). RESULTS: Among controls, the median average nitrate level for their Iowa residences with public water supplies was 1.3 mg/liter nitrate-nitrogen (interquartile range = 0.6-3.0). After adjustment for confounders, we found no increased risk of bladder cancer with increasing average nitrate levels in drinking water; the highest quartile odds ratio for women was 0.8 (95% confidence interval = 0.4-0.8), and for men 0.5 (0.4-0.8). We observed no association among those with high water nitrate exposure (>median) and low (<median) vitamin C intake compared with those who had low water nitrate and high vitamin C intake. CONCLUSIONS: Our data suggest that long-term exposure to nitrate in drinking water at levels in this study (90th percentile 5.5 mg/liter nitrate-nitrogen) is not associated with risk of bladder cancer.

Adult↗
PubMed2002

[Association between the excretion levels of urinary TNOC and NAAs in the inhabitants of high and low risk area for esophageal cancer in southern China].

To assess the role of urinary total N-nitroso compounds(TNOC) index in study etiology of N-nitroso compounds(NOC) of esophageal cancer in southern China and to study the association between TNOC index and traditional indexes of N-nitrosamino acids(NAAs). The samples of 12-hr overnight urine were collected from 120 male adults in high-risk area (Nanao county) and low-risk area(Lufeng county) for esophageal cancer. The 240 male healthy subjects(35-64 years old) were selected by a 3-stage random cluster sample procedure. Levels of TNOC and 4 categories of NAAs were measured in samples. The results showed that Urinary TNOC contents were positively correlated with esophageal cancer mortality in the south(rs = 0.25, P < 0.05). Only 7.5% content of urinary TNOC came from the 4 categories of NAAs in the high-risk area when 57% content of urinary TNOC came from the NAAs in the low-risk area. The urinary NOC components in the high-risk area were more complex than the components in the low-risk area. Urinary TNOC is a better index that is applied to assess the exposure dose of TNOC in humans and study etiology of NOC of esophageal cancer. When the categories of NOC in urine are less, TNOC index is correlated with NAAs indexes. The results imply that TNOC are implicated in the etiology of esophageal cancer in southern China.

Adult↗
PubMed2003

Nitrate in public water supplies and the risk of colon and rectum cancers.

BACKGROUND: Nitrate is a widespread contaminant of drinking water, but its potential health effects are unclear. In the body, nitrate is reduced to nitrite, which can react with amines and amides by nitrosation to form N-nitroso compounds, known animal carcinogens. N-nitroso compound formation is inhibited by certain nutrients, such as vitamin C, and increased by meat intake. METHODS: We investigated the association of nitrate in public water supplies with incident colon and rectum cancers in a case-control study conducted in Iowa from 1986 to 1989. Nitrate levels in Iowa towns were linked to the participants' water source histories. We focused our analyses on the period from 1960 onward, during which nitrate measurements were more frequent, and we restricted analyses to those persons with public water supplies that had nitrate data (actual or imputed) for greater than 70% of this time period (376 colon cancer cases, 338 rectum cancer cases, and 1244 controls). RESULTS: There were negligible overall associations of colon or rectum cancers with measures of nitrate in public water supplies, including average nitrate and the number of years with elevated average nitrate levels. For more than 10 years with average nitrate greater than 5 mg/L, the odds ratio (OR) for colon cancer was 1.2 (95% confidence interval [CI] = 0.9-1.6) and for rectum the OR was 1.1 (CI = 0.7-1.5). However, nitrate exposure (>10 years with average nitrate >5 mg/L) was associated with increased colon cancer risk among subgroups with low vitamin C intake (OR = 2.0; CI = 1.2-3.3) and high meat intake (OR = 2.2; CI = 1.4-3.6). These patterns were not observed for rectum cancer. CONCLUSIONS: Our analyses suggest that any increased risk of colon cancer associated with nitrate in public water supplies might occur only among susceptible subpopulations.

Adult↗