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PubMed1988

Mammalian cell toxicity and bacterial mutagenicity of nitrosoimidazoles.

It is currently believed that the biological activity of such therapeutic 5-nitroimidazoles as metronidazole is mediated by a short-lived, highly toxic species that arises from nitro group reduction. We found that the 5-nitroimidazole, 1-methyl-4-phenyl-5-nitroimidazole (5-NO2), is at least 1000-fold less cytotoxic for CHO cells and mutagenic for Ames tester strain TA100 than its homologous nitroso compound, 1-methyl-4-phenyl-5-nitrosoimidazole (5-NO). Such evidence, along with previous work showing a similar relative bactericidal potency of these compounds, is consistent with the labile nitrosoimidazole being a biologically active species of the nitroimidazole, and indicates that mammalian cells are very susceptible to such an active form. The high potency of both 5-NO and 1-methyl-4-nitroso-5-phenylimidazole (4-NO), in contrast to the lack of potency of 1-methyl-4-nitro-5-phenylimidazole (4-NO2) relative to 5-NO2, is additional evidence to support the suggestion that the activity of a nitroimidazole is determined mainly by the ease with which it is reduced.

Animals↗

PubMed1973

Microbial formation of nitrosamines in vitro.

Mortierella parvispora and an unidentified bacterium converted trimethylamine to dimethylamine, and the bacterium (but not the fungus) formed dimethylnitrosamine in the presence of nitrite. Dimethylnitrosamine also appeared in cell suspensions of Escherichia coli and Streptococcus epidermidis and in hyphal mats of Aspergillus oryzae incubated with dimethylamine and nitrate. Suspensions of a number of microorganisms produced N-nitrosodiphenylamine from diphenylamine and nitrite at pH 7.5, and soluble enzymes catalyzing the N-nitrosation of diphenylamine were obtained from two of these organisms. In the presence of these enzymes, several dialkylamines were converted to the corresponding N-nitroso compounds.

Aspergillus↗

PubMed1988

Marked increase in the urinary level of N-nitrosothioproline after ingestion of cod with vegetables.

When five volunteers were given food containing cod and vegetables (a traditional Japanese food, called tara-chiri), their urinary excretion of N-nitrosothioproline increased from 7.9 +/- 4.2 (SD) micrograms/day to 110 +/- 64.5 micrograms/day. This increase was accounted for by in vivo nitrosation of of thioproline by nitrite formed from nitrate in the vegetables. This finding was confirmed by results on a volunteer who ate boiled cod and Japanese radish (daikon) (a simple version of the food containing cod and vegetables). Boiled cod was found to contain 300-500 micrograms/100 g of thioproline, and the level nearly doubled when the cod was boiled with Japanese radish. This increase occurred during the cooking of cod with Japanese radish by the reaction of formaldehyde in the cod with cysteine in the Japanese radish. The nitrosation of thioproline was estimated to be 1000-fold that of proline in the human body. Thus thioproline is a very sensitive probe of in vivo nitrosation. Thioproline formation either in vivo or in vitro may have the following two roles in reducing tumorigenesis in humans: (a) detoxication of formaldehyde, which is genotoxic; and (b) blocking the formation of carcinogenic N-nitroso compounds by trapping nitrite and then being excreted in the urine.

Animals↗

PubMedDate not supplied

[Experimental study of the aftereffects of feeding rats certain types of canned fish].

For 3 years fish canned goods were added to the ration of rats. These additions included atlantic herring in tomato gravy ("Stavrida"), dressed sprat in tomato gravy (sprats-small-sized) or sprat in vegetable oil ("Sprat"). Rats receiving canned "small-sized sprats" or "sprats developed much more often malignant tumors of different localization than did the animals fed on "Stavrida" or control rats. Feeding of rats on the vegetable oil from "stavrida" and "sprat" cans did not have any material effect on the development of tumours. Introduction of these samples of oil together with the food or parenterally to mice did not have any substantial influence on the development in them of skin tumors, induced with benzpyrene. The canned goods under investigation, especially of the "sprat" kinds, demonstrated small amounts of benzpyrene and carcinogenic nitroso-compounds.

Animals↗

PubMed1991

Identification of tetrahydro-beta-carboline-3-carboxylic acid in foodstuffs, human urine and human milk.

1-Methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) and 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (TCCA), both precursors of mutagenic N-nitroso compounds (N-nitrosamines, 1-methyl-2-nitroso-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and 2-nitroso-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid), were detected in various food-stuffs, urine from healthy human subjects and human milk. A purification procedure, involving a chemically-bonded material followed by HPLC combined with fluorometric detection, was used for the quantitative determination of these compounds, allowing the separation of two diastereoisomers of MTCA. An HPLC and mass spectrometry method was also developed for their identification. Comparing the concentration of MTCA and TCCA in fermented products and raw materials suggested that tetrahydro-beta-carbolines may have been produced through fermentation or by condensation of tryptophan and acetaldehyde formed from ethanol added as a food preservative. This is the first report of excretion of tetrahydro-beta-carbolines in human urine and human milk. A comparison of the concentrations of tetrahydro-beta-carbolines in urine from human infants and human milk indicates that tetrahydro-beta-carbolines may be synthesized endogenously in humans. A possible pathway of tryptophan metabolism in plants and animals is presented.

Adult↗

PubMed1978

Characteristics of the TEA detector in use with high pressure liquid chromatography.

It was found that the response of the TEA detector was highly dependent on the operating temperature of the furnace and on the flow rate of gas that is used to purge the furnace. It was also found that the response of the detector was very highly dependent on the volatility of the nitroso compound and the optimum operating conditions were also very different for low and high volatility compounds. When samples containing equal quantities of NDMA, NPYR, NPRO and NPIC were chromatographed at low furnace temperatures, only the peaks for NPRO and NPIC (low volatility) were observed. When a high furnace temperature was used, only NDMA and NPYR (high volatility) were routinely observed. At intermediate temperatures, all four compounds could usually be observed. Under optimum conditions, the sensitivity was 3 microgram/ml for NPRO and 5 microgram/ml for NPIC.

Chromatography, High Pressure Liquid↗

PubMed1984

Dietary phenolics and betel nut extracts as modifiers of N-nitrosation in rat and man.

Polyphenolic compounds (PPC) isolated from betel nuts and some dietary PPC were examined for their modifying effects on N-nitrosation in vitro and in vivo. The formation of N-nitrosodiethylamine (NDEA) and N-nitrosoproline (NPRO) was either enhanced or inhibited by PPC from betel nuts, depending on (1) the structure of the PPC, (2) the pH of the reaction medium, (3) the relative concentrations of nitrite and PPC, and (4) the nature of the nitrosatable amino compounds. Both catalysis and inhibition of endogenous nitrosation of proline were observed in rats, although to a lesser extent than in vitro. Caffeic and ferulic acids, as well as the PPC-containing beverages tea and coffee, exerted inhibitory effects on endogenous formation of NPRO in two human subjects. These results demonstrate that PPC can modify the yield of endogenously formed N-nitroso compounds, and may thus effect the carcinogen burden in man.

Animals↗

PubMed1982

Measurement of endogenous n-nitrosation in rats and humans by monitoring urinary and faecal excretion of N-nitrosamino acids.

N-Nitrosamino acids [N-nitrosoproline (NPRO), N-nitrosohydroxyproline and N-nitrososarcosine] given orally to rats were found to be excreted unchanged in the urine and faeces almost quantitatively. Fasted rats were gavaged with solutions of a nitrosatable amino acid, followed by nitrite or N-nitrosodiphenylamine (NDPhA). The N-nitrosamino acid excreted in the urine and faeces during 24 h was monitored as an index of endogenous N-nitrosation. The results obtained by applying this procedure to the study of endogenous N-nitrosation in rats were all in good agreement with those of in vitro experiments. Endogenous transnitrosation by NDPhA to proline was shown to occur in rats; thiocyanate catalysed this transnitrosation reaction in vivo. Formation of NPRO in a human was demonstrated by monitoring the excretion of NPRO in the urine of one male volunteer who had ingested vegetable juice, as a source of nitrate, and proline. The amounts of NPRO excreted in the 24-h urine appeared to be proportional to the proline dose and increased exponentially with the dose of nitrate ingested. The simultaneous intake of ascorbic acid or alpha-tocopherol inhibited NPRO formation in the human subject. Monitoring of urinary NPRO would appear to be useful for the estimation of the extent of endogenous N-nitrosation in high-risk populations or individuals, in which endogenously formed N-nitroso compounds have been associated with increased risk of cancers, such as those of the stomach and oesophagus.

Amino Acids↗

PubMed1971

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate.

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed.

Alkanes↗

PubMed1984

Liver carcinogenesis in tropical Africa.

The geographical pathology of hepatocellular carcinoma (HCC) was essentially anecdotal until systematic cancer registration was introduced, but it is now clear that sub-Saharan Africa is a high-incidence area. The disease is multifactorial in etiology, the possible etiological agents including hepatitis B virus and a number of chemical carcinogens, among which the most important appear to be the aflatoxins and N-nitroso compounds. Medicinal plants and herbal teas used in the tropics also contain compounds such as furocoumarins that are mutagenic and/or carcinogenic. A modified form of the Ames Salmonella typhimurium assay was used to study the mutagenicity of aflatoxins B1 and M1 and palmotoxin B0, a co-metabolite of aflatoxin B1, and also of chamuvaritin and chamuvarin, two benzyldihydrochalcones derived from the roots of Uvaria chamae, which are used for medicinal purposes in West Africa. The mutagenicity of a number of furocoumarins isolated from Nigerian medicinal plants was studied by means of the same assay as well as with Chinese hamster V79 cells and C3H 10T1/2 cells; in the last two systems the studies were carried out both with and without photoactivation. The same compounds, and 8-methoxypsoralen, were also investigated by means of cell transformation studies.

Aflatoxins↗

PubMedDate not supplied

A rapid and selective method for determining potential nitrosating agents in cosmetic products by chemiluminescence detection of nitric oxide.

A method was developed for rapid and selective determination of potential nitrosating agents at the part-per-billion level in cosmetic products. These compounds are chemically reduced to nitric oxide, which is determined by its chemiluminescent reaction with ozone. Suspended materials and colors in cosmetic products do not interfere. Hence their removal before analysis is not required. A detection limit of 33 ppb, calculated as nitrite, was obtained. No false-positive interferences were observed from antifoaming agents, several N-nitroso compounds, and nitrate up to 20 ppm. Among cosmetic products surveyed, potential nitrosating agents were found at levels ranging from 113 to 5021 ppb. No consistent relationship was found between levels of potential nitrosating agents and N-nitrosamines in the same products. However, the highest levels of nitrosating agents were most often associated with the highest levels of N-nitrosamines known to be present in the products.

Adsorption↗

PubMed1994

Mutagenicity of coal-dust and smokeless-tobacco extracts in Salmonella typhimurium strains with differing levels of O-acetyltransferase activities.

Epidemiological studies have indicated an increased incidence of gastric neoplasia in coal miners. Because smokeless tobacco use is prevalent in the mining industry, nitrites or other components of these products may be etiologically associated with these gastric neoplasms. In this study both nitrosated and non-nitrosated coal-dust (from West Virginia and New Mexico) as well as smokeless-tobacco (snuff and chewing tobacco) extracts were examined for the presence of aromatic amines and nitroarenes by comparing the activities of these extracts in the pre-incubation variant of the Ames assay. Salmonella strains with differing O-acetyltransferase activities (TA98 and YG1024) were utilized in this investigation. The results of the examination of the coal-dust extracts indicated positive activity only in the nitrosated extracts. Both nitrosated extracts elicited an increased number of revertants (2-4-fold) on YG1024 without S9 in comparison to TA98, suggesting the presence of nitroarenes in these extracts. Additionally, the nitrosated West Virginia coal extract showed higher levels of activity on YG1024 with S9, indicating the possible presence of aromatic amines in this complex mixture. The non-nitrosated smokeless-tobacco extracts showed activity only on YG1024 in the presence of S9, with the highest amount of activity occurring in the snuff sample. Except for the chewing-tobacco extract on TA98 without S9, positive activity was found in both nitrosated tobacco extracts on YG1024 and TA98. As with the coal extracts, the presence of nitroarenes was inferred for these nitrosated materials. A comparative study of the non-nitrosated snuff extract across 5 tester strains with varying sensitivities to aromatic amines and nitroarenes (TA98NR, TA98/1,8-DNP6, TA98, YG1021 and YG1024) indicated that aromatic amines were a probable source of the mutagenic activity. The curing process and/or the addition of certain flavorants are potential sources of the mutagenic aromatic amines suggested to be present in the non-nitrosated snuff extract. These findings are consistent with an etiologic role supplementary to the nitroso compounds for mutagenic nitroarenes and aromatic amines in the development of gastric neoplasia in coal miners.

Acetyltransferases↗

PubMed1995

Marked increase in urinary excretion of nitrate and N-nitrosothioproline in the osteogenic disordered syndrome rats, lacking ascorbic acid biosynthesis, by administration of lipopolysaccharide and thioproline.

Urinary excretions of nitrate and N-nitrosothiazolidine-4-carboxylic acid (N-nitrosothioproline; NTPRO) were determined in rats with osteogenic disordered syndrome (ODS, od/od), lacking L-ascorbic acid (ASC) biosynthesis, after i.p. administration of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg) followed by thiazolidine-4-carboxylic acid (thioproline, 20 mg/rat). L-Ascorbic acid-sufficient ODS rats showed the excretion of nitrate and NTPRO at the levels of 20.3 +/- 7.9 mumol/24h and 369 +/- 111 pmol/24 h respectively, whereas the levels of nitrate and NTPRO in ASC-deficient (scorbutic) rats increased to 54.7 +/- 5.6 mumol/24 h (P < 0.01) and 796 +/- 367 pmol/24 h (P < 0.05) respectively. Administration of L-arginine further increased urinary excretion of nitrate and NTPRO while D-arginine showed no effect. NG-Monomethyl-L-arginine, a specific inhibitor of nitric oxide synthase (NOS), strongly inhibited endogenous formation of both nitrate and NTPRO. These results indicate that increased excretion of NTPRO in ODS rats stimulated by LPS involves induction of NOS leading to an increase in endogenous formation of reactive nitrogen oxides such as N2O3, a potent nitrosating agent at physiological pH conditions. Increased NOS activities in the plasma and various tissues of ODS rats were observed 5 h after treatment with LPS. The possibility of extragastric N-nitroso compound formation in inflammation sites is discussed.

Animals↗

PubMed1991

The etiology of gastric cancer.

We review recent evidence concerning risk factors for gastric cancer. An overview of analytical studies shows convincing evidence of a protective effect of fruit and vegetables. The specific protective constituents have not been firmly established, but micronutrients, especially ascorbic acid, are probably of importance. Other dietary factors that show a consistent pattern of effect in different studies are the moderate risks associated with high intake of preserved foods and salt. Evidence also indicates that gastric cancer is associated with tobacco consumption, although even in continuing heavy smokers the risk does not exceed two fold. Another non-dietary factor of potential importance is infection with the bacterium, Helicobacter (Campylobacter) pylori. The model of Correa and co-workers currently offers the best working hypothesis to explain the etiology of gastric cancer. Although the endogenous synthesis of N-nitroso compounds is central to the model, it is not yet clear what the rate-limiting steps are. Exposure to nitrate per se does not directly cause gastric cancer.

Animals↗

PubMed1981

Cellular DNA damage by nitrosocimetidine: a comparison with N-methyl-N'-nitroso-nitrosoguanidine and x-irradiation.

Permanently proliferating lymphoblastoid cell lines (LCLs) and normal unstimulated peripheral blood leukocytes have been used to study the effects of nitrosocimetidine (NC) on cultured human lymphoid cells. The approaches that were used to assess the cells' ability to cope with NC were: (i) determination of cell survival as measured by colony formation in microtiter plates; (ii) quantitation of DNA synthesis and DNA-repair replication by isopyknic sedimentation of DNA density labeled with 5-bromo-2-deoxyuridine (BrdU); (iii) measurement of the induction of alkali labile lesions and strand breaks by NC in 3H-labeled DNA using velocity sedimentation in alkaline sucrose. In summary, treatment with NC was found to inhibit both replicative DNA synthesis and colony formation in LCLs. At the molecular level, NC treatment induced alkali labile lesions in LCL DNA and elicited DNA-repair replication in proliferating LCLs as well as unstimulated lymphocytes. Considered in total, these data indicate that NC is reactive with human DNA in the cellular environment in a manner similar to methylating nitroso compounds which have been shown to be carcinogenic. The significance of these findings will be discussed.

Ataxia Telangiectasia↗

PubMed1998

Genetic toxicity of N-methylcarbamate insecticides and their N-nitroso derivatives.

N-Methylcarbamate esters are an important group of insecticides. They have lower acute toxicity to vertebrates than organophosphates, although their genotoxicity has not been adequately studied. Here we investigate the cytotoxicity and genotoxicity of N-methylcarbamate insecticides and their N-nitroso derivatives in Chinese hamster V79 cells, using the hprt locus as a marker, and also assess inhibition of gap junctional intercellular communication. N-Methylcarbamate insecticides were chemically N-nitrosated to obtain the N-nitroso derivatives. N-Nitrosation greatly increased the cytotoxicity and mutagenicity of N-methylcarbamates at the hprt locus in Chinese hamster V79 cells. The mutagenic potential of N-nitroso-N-methylcarbamates was much higher than those of many other known mutagenic nitroso compounds, as well as some non-nitroso mutagenic alkylating agents. Parental N-methylcarbamates themselves were not mutagenic, however, they inhibited gap junctional intercellular communication half as effectively as the well-studied tumor promoter 12-O-tetradecanoylphorbol-13-acetate. The findings show that N-methylcarbamate insecticides and their N-nitroso derivatives have the potential to act through mediation of epigenetic and genotoxic mechanisms respectively in the multiple stages of chemical carcinogenesis.

Aldicarb↗

PubMed2000

Safety of proton-pump inhibitors: the acid test.

It is well established that atrophic gastritis, pernicious anaemia and partial gastrectomy are associated with an increased risk of gastric carcinoma. These conditions all result in a low acid output state. Although the mechanism of gastric carcinogenesis is not known, the model proposed by Correa has provided the most attractive explanation to date. The suggestion is that prolonged hypochlorhydria predisposes to gastric carcinoma by an increase in the production of carcinogenic N-nitroso compounds. This hypothesis has led to concerns about the safety of long-term acid suppression in the management of a variety of acid-related gastrointestinal conditions.

Achlorhydria↗

PubMed1989

Genotoxicity testing of Maillard reaction products.

Since the development of short-term genotoxicity tests such as the Ames assay, the mutagenicity of Maillard reaction products has been tested extensively. Some products have exhibited strong activity. For example, one of the earliest studies demonstrated some mutagenic activity in a dichloromethane extract of a D-glucose/ammonia Maillard model system. Many researchers have attempted to pinpoint the principal chemical(s) of mutagenicity of the Maillard products using various sugar-amino acid browning model systems over last two decades. However, no mutagenic individual Maillard product has been isolated and identified. Nitrite has been also used as a reactant in browning reaction model systems, primarily to investigate the formation of potentially mutagenic or carcinogenic N-nitroso compounds. Recently some potent mutagens isolated from pyrolyzed amino acids or proteins have begun to receive attention as Maillard reaction products.

Amino Acids↗