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PubMed1985

Effect of streptozotocin on the glutathione S-transferases of mouse liver cytosol.

Streptozotocin (STZ) increased the activity of mouse hepatic glutathione (GSH) S-transferases assayed with 1-chloro-2,4-dinitrobenzene. Nicotinamide administered prior to STZ prevented the hyperglycemia indicative of STZ-induced diabetes, but had no effect on the increase in GSH S-transferase activity caused by the drug. Another diabetogenic agent, alloxan, did not alter GSH S-transferase activity. Thus, streptozotocin may be increasing GSH S-transferase activity directly, and not as a result of the diabetic state the drug induces. Two transferases were characterized from mouse liver cytosol. One was a homodimer with a subunit molecular weight of about 28,000 and a pI of about 8.2. The other was also a homodimer with a subunit molecular weight of about 27,500 and a pI of about 9.2. The pI 8.2 GSH S-transferase was induced by STZ, while the pI 9.2 transferase was decreased by the drug. At least one other transferase appeared to be induced by STZ. Two other nitroso compounds, chlorozotocin and diethylnitrosamine, also increased GSH S-transferase activity, suggesting that this effect may be nitroso related.

Animals↗
PubMed1993

Tea and cancer.

Tea is one of the most popular beverages consumed worldwide. The relationship between tea consumption and human cancer incidence is an important concern. This topic has been studied in different populations by many investigators, but no clear-cut conclusion can be drawn. Whereas some studies have shown a protective effect of tea consumption against certain types of cancers, other studies have indicated an opposite effect. Our purpose is to provide a critical review of this topic, covering basic chemistry and biochemical activity of tea, epidemiologic investigations, and laboratory studies, as well as possible directions for future research. Studies have demonstrated either a lack of association between tea consumption and cancer incidence at specific organ sites or inconsistent results. On the other hand, many laboratory studies have demonstrated inhibitory effects of tea preparations and tea polyphenols against tumor formation and growth. This inhibitory activity is believed to be mainly due to the antioxidative and possible antiproliferative effects of polyphenolic compounds in green and black tea. These polyphenolics may also inhibit carcinogenesis by blocking the endogenous formation of N-nitroso compounds, suppressing the activation of carcinogens, and trapping of genotoxic agents. The effect of tea consumption on cancer is likely to depend on the causative factors of the specific cancer. Therefore, a protective effect observed on a certain cancer with a specific population may not be observable with a cancer of a different etiology. On the basis of this concept, we suggest future laboratory and epidemiologic studies to elucidate the relationship between tea consumption and human cancer risk.

Animals↗
PubMed1990

Hemoglobin-carcinogen adducts as molecular biomarkers in epidemiology.

The goal of our work is to determine the exposure of people to the ultimate form of both environmental and endogenous mutagens and carcinogens. The scientific approach is to develop methods of analysis of chemically-defined adducts of protein and DNA. Our research to date has encompassed a wide variety of compounds known or suspected to cause cancer in people: aromatic amines, heterocyclic amines, polycyclic aromatic hydrocarbons (PAH), aflatoxins, N-nitroso compounds, and urethane. The most advanced of those problems is that of aromatic amines in which several different types of studies on human populations have already been completed using hemoglobin (Hb) adducts of 4-amino-biophenyl (ABP) as the biomarker. These studies have revealed a correlation between the level of amine adduct and risk of bladder cancer, and most important, the role of a metabolic polymorphism, the acetylator phenotype, as an important determinant of adduct level. In the case of PAH we have developed a useful human dosimeter based upon release of bay region tetrols from Hb esters. This method is now being applied to analyze the internal dose of benzo[a]pyrene (BaP) diolepoxide and to determine the range of PAH structures subject to conversion to ultimate carcinogenic forms. Together, these studies open the door to a new era in which we will be able to examine the overall influence of metabolic polymorphisms on the internal dose of many carcinogens in individuals.

Amines↗
PubMed1978

Nitrosamine carcinogenicity: a quantitative Hansch-Taft structure-activity relationship.

Statistically significant correlations have been demonstrated between carcinogenic activity, water-hexane partition coefficients and electronic factors for an extensive series of N-nitroso compounds. Electronic factors were expressed by the Taft sigma* values of substituents on the carbon atoms alpha to the N-nitroso group. Such correlations indicate that transport of the carcinogen to its active site has an important effect on its potency. The correlations also implicate reactivity at the alpha-carbon in the determination of carcinogenic activity and point out various structural types which do not follow the general rule.

Animals↗
PubMed1985

Susceptibilities of drugs to nitrosation under simulated gastric conditions.

Drugs of differing structures and pharmacological actions have been incubated at 37 degrees C and pH 2.0 under conditions simulating those within the normal fasting stomach. The nitrite concentration (25 microM) was kept as constant as possible for 3 hr in an attempt to mimic its in vivo replenishment from the saliva. The extents of N-nitrosation varied widely, but were less than those observed by Gillatt et al. (Fd Chem. Toxic. 1984, 22, 269) using the WHO Nitrosation Assay Procedure, in which the initial nitrite concentration is 40 mM, 1600 times greater, and the pH (3.0) is close to the optimum for the N-nitrosation of secondary amines. The highest yield of N-nitroso compound was obtained with the benzathine salt of penicillin G whereas some drugs, including hydrochlorothiazide and chlorthalidone, produced no detectable N-nitroso derivative. The degree of N-nitrosation was consistently reduced when the initial nitrite concentration of 25 microM was not replenished during the incubations, underlining the importance of simulating the continuous supply of nitrite from the saliva. In all instances, the reactions of the drugs with nitrous acid were inhibited and, in most cases, completely prevented by the presence of ascorbic acid (125 mg).

Chemical Phenomena↗
PubMed2000

Protein degradation in the large intestine: relevance to colorectal cancer.

Colorectal cancer is the second most common form of cancer death in Western countries. Diet has been implicated in the aetiology of this disease. Epidemiological evidence suggests that diets high in meat and fat and low in fermentable carbohydrate increase colorectal cancer risk. One mechanism that could explain the association with meat is increased colonic protein metabolism due to increased protein intake from high meat diets. Products of colonic protein degradation and metabolism include ammonia, phenols, indoles and amines which have been shown to exert toxic effects in vitro and in animal models. These compounds are present in faecal samples suggesting that they may exert gut mucosal effects. Human studies have shown that colonic protein metabolism via the gut microflora is responsive to dietary protein as faecal ammonia and urinary phenolic compound concentrations increase in response to increased intake of protein rich foods. Other toxic metabolites from dietary protein precursors such as N-nitroso compounds and sulphides are also formed. Recent work has shown that diets high in meat, fat and low in fibre increase human faecal water genotoxicity. It is likely that metabolites from colonic protein metabolism contribute to this increase in genotoxicity during high meat intakes.

Adult↗
PubMed1977

Chromosome tests with 134 compounds on Chinese hamster cells in vitro--a screening for chemical carcinogens.

Chromosomal aberration tests in vitro were carried out on Chinese hamster cells grown in culture with various chemicals, including carcinogenic N-nitroso compounds and their related derivatives, food additives, medical drugs, pesticides and other chemicals commonly used in laboratories or industries. Sixty-three of the 134 chemicals gave negative results in our test system even with doses at which the cell growth was markedly inhibited. Nearly all compounds known to be mutagenic in bacteria were also positive in our tests. Both urethane and diethylstilbestrol were positive, even though they are known to be carcinogenic but not mutagenic in bacteria. Compounds such as N-alkyl-N'-nitroguanidines, barbital, sodium benzoate, saccharin sodium, sodium nitrite, sodium nitrate and 4-aminoquinoline-1-oxide were positive in our chromosome tests, but they have not been conclusively tested for their carcinogenicity.

Animals↗
PubMed1995

Potential chemotherapeutic activity of 4-iodo-3-nitrobenzamide. Metabolic reduction to the 3-nitroso derivative and induction of cell death in tumor cells in culture.

A C-nitroso prodrug, 4-iodo-3-nitrobenzamide, was synthesized, and its action on a variety of tumor cells of human and animal origin tested. This prodrug was reduced transiently by tumor cells to 4-iodo-3-nitrosobenzamide at a very low rate, which was, however, sufficient to kill tumor cells. The final reduction product was 4-iodo-3-aminobenzamide, and no intermediates accumulated. No toxicity could be observed in hamsters even at 200 mg/kg, given i.p. daily for 7 days. The chemical reactivity of both 4-iodo-3-nitrosobenzamide and its noniodinated homolog with reduced ascorbate yielded the hydroxylamines. With glutathione, 4-iodo-3-aminobenzamide was formed, suggesting glutathione sulfinic acid formation. Confirming earlier studies, 4-iodo-3-nitrosobenzamide inactivated poly(ADP-ribose) polymerase by zinc ejection from the first zinc finger of this nuclear protein. The iodinated nitroso compound was more effective than its iodine-free analog. Selective tumoricidal action appeared to correlate with the reduction of the nitro group to nitroso in tumor cells, and with the previously described subsequent induction of tumor apoptosis by the C-nitroso intermediate. These processes were accelerated by buthionine sulfoximine, which diminishes cellular GSH.

Animals↗
PubMed1983

The bacterial mutagenicity of three naturally occurring indoles after reaction with nitrous acid.

Three naturally occurring indoles were evaluated for potential nitrosatability using the Nitrosation Assay Procedure (NAP test) as recommended by the World Health Organisation. All three indoles i.e. tryptophan, tryptamine and 5-hydroxy-tryptamine were nitrosated to products which were directly mutagenic for S. typhimurium TA1537. In addition, the products of nitrosation of tryptamine and 5-hydroxytryptamine were also mutagenic for strains TA1538, TA98 and TA1535 without the need for metabolic activation. The sensitivities of the frameshift-detecting strains TA1537, TA1538 and TA98 were of particular interest, since nitroso compounds are characteristically base-substitution mutagens. The mutagenic effects of the products formed after nitrosation of each indole at pH 3.6, were eliminated in the presence of S9 mix. This was not the case when the nitrosation assay was carried out at pH 2.6. At this pH the mutagenicity of the nitrosated products varied in the presence of S9 mix and depended upon the nature of the indole undergoing nitrosation, and the bacterial test strain utilised for the mutagenicity assay. This indicated that more than one mutagenic product was responsible for the observed effects. As well as pH, a number of other factors influenced the formation of mutagenic nitroso products. Most notably, the concentrations of precursor compounds (sodium nitrite, and indole) present in the NAP test were of critical importance. As the sodium nitrite concentration was reduced from that recommended by the W.H.O. (40 mM), so the mutagenicity decreased. For all three compounds significant mutagenic effects were lost at sodium nitrite concentrations below 15 mM. In conclusion the data presented in this paper clearly demonstrates that individuals are chronically exposed to naturally occurring substances which readily nitrosate in excess nitrous acid and yield bacterial mutagens.

Biotransformation↗
PubMed2001

Electrodes modified with nitrofluorenone derivatives as a basis for new biosensors.

We report about the electrocatalytic properties of electrodes modified by adsorption of nitro-fluorenone derivatives. The stable, adherent monolayer of these catalyst precursors can be transformed electrochemically into the corresponding hydroxylamine compounds (R-NO(2)+4e+4H(+)-->R-NHOH+H(2)O). The completely reversible two electron oxidation of the hydroxylamine leads to the nitroso compounds (R-NHOH-->R-NO+2e+2H(+)) that exhibit high catalytic activity in the electrooxidation of NADH at low overpotentials (-30 mV vs. Ag/AgCl) and therefore constitute a new family of efficient redox mediators for biosensor applications. A significant increase in catalytic activity (up to 500%) is observed after addition of calcium ions to the electrolyte. This is explained by a specific and bridging complexation between the coenzyme's phosphate groups and a carboxyl group present in the catalyst molecule. The interaction favours the contact between NADH and the surface confined catalyst, leading to a higher electron transfer efficiency. This interaction can be used in an approach of molecular level design for controlled monolayer deposition of catalyst, Ca(2+), NAD+ and enzyme. A very simple and inexpensive modification scheme, essentially based on electrostatic attraction, leads to electrodes that can be employed as reagentless biosensors for the electrochemical detection of common and commercially interesting analytes like glucose.

Biosensing Techniques↗
PubMed1985

The metabolism and cellular interactions of some aliphatic nitrogenous carcinogens.

The alkylation of nucleic acids of the liver of rats and Syrian hamsters was measured in relation to carcinogenesis by a number of nitrosamines and azoxyalkanes, most of which induce tumors of the liver in both species following chronic treatment. Two compounds, nitroso-2,6-dimethylmorpholine and nitrosobis(2-hydroxypropyl)amine were not liver carcinogens in rats, but did induce liver tumors in hamsters; there was much less alkylation by these compounds in the rat than in the hamster. In both rats and hamsters, azoxymethane produced a greater extent of alkylation, both at N-7 and O-6 guanine, than did nitrosodimethylamine, although the former is no more potent than the latter as a carcinogen in either species. Both methyl groups of azoxymethane gave rise to N-7 methylation. Nitrosobis(2-oxopropyl)amine (BOP) and nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) produced considerable methylation of liver nucleic acids in both species, comparable with that by nitrosodimethylamine, and they induce liver tumors in both rats and hamsters. However, in male rats the extent of alkylation by BOP was much smaller than in females and no O-6-methylation was detected in the former; this correlates with the failure of BOP to induce liver tumors in male rats by gavage, whereas liver tumors are induced in females.

Alkylation↗
PubMed2004

Formation of unidentified nitrogen in plants: an implication for a novel nitrogen metabolism.

Plants take up inorganic nitrogen and store it unchanged or convert it to organic forms. The nitrogen in such organic compounds is stoichiometrically recoverable by the Kjeldahl method. The sum of inorganic nitrogen and Kjeldahl nitrogen has long been known to equal the total nitrogen in plants. However, in our attempt to study the mechanism of nitrogen dioxide (NO(2)) metabolism, we unexpectedly discovered that about one-third of the total nitrogen derived from (15)N-labeled NO(2) taken up by Arabidopsis thaliana (L.) Heynh. plants was converted to neither inorganic nor Kjeldahl nitrogen, but instead to an as yet unknown nitrogen compound(s). We here refer to this nitrogen as unidentified nitrogen ( UN). The generality of the formation of UN across species, nitrogen sources and cultivation environments for plants has been shown as follows. Firstly, all of the other 11 plant species studied were found to form the UN in response to fumigation with (15)NO(2). Secondly, tobacco ( Nicotiana tabacum L.) plants fed with (15)N-nitrate appeared to form the UN. And lastly, the leaves of naturally fed vegetables, grass and roadside trees were found to possess the UN. In addition, the UN appeared to comprise a substantial proportion of total nitrogen in these plant species. Collectively, all of our present findings imply that there is a novel nitrogen mechanism for the formation of UN in plants. Based on the analyses of the exhaust gas and residue fractions of the Kjeldahl digestion of a plant sample containing the UN, probable candidates for compounds that bear the UN were deduced to be those containing the heat-labile nitrogen-oxygen functions and those recalcitrant to Kjeldahl digestion, including organic nitro and nitroso compounds. We propose UN-bearing compounds may provide a chemical basis for the mechanism of the reactive nitrogen species (RNS), and thus that cross-talk may occur between UN and RNS metabolisms in plants. A mechanism for the formation of UN-bearing compounds, in which RNS are involved as intermediates, is proposed. The important broad impact of this novel nitrogen metabolism, not only on the general physiology of plants, but also on plant substances as human and animal food, and on plants as an integral part of the global environment, is discussed.

Fumigation↗
PubMed2002

Diet and risk of adult glioma in eastern Nebraska, United States.

OBJECTIVE: To investigate potential associations between diet and adult glioma. METHODS: We conducted a population-based case-control study of adult glioma in eastern Nebraska. Nutrient and food group intakes were estimated for 236 glioma cases and 449 controls using information obtained from a food-frequency questionnaire. RESULTS: After adjusting for potential confounders, inverse associations with risk of adult glioma were observed for intakes of dark yellow vegetables (highest quartile versus lowest: OR = 0.6, Ptrend = 0.03) and beans (OR = 0.4, Ptrend = 0.0003), but no associations were seen for dietary sources of preformed nitrosamines or high-nitrate vegetables. Our nutrient analysis revealed significant inverse associations between risk of adult glioma and dietary intake of pro-vitamin A carotenoids (highest quartile versus lowest: OR = 0.5, Ptrend = 0.005), a-carotene (OR = 0.5, Ptrend = 001), beta-carotene (OR = 0.5, Ptrend = 0.01), dietary fiber (OR=0.6, Ptrend = 0.048) and fiber from beans (OR = 0.5, Ptrend = 0.0002). We observed no significant associations with risk of adult glioma for intakes of other nutrients or compounds including nitrate, nitrite, vitamin C, vitamin E, saturated fat, cholesterol, dietary fiber from grain products, or fiber from fruit and vegetables. CONCLUSION: Our study does not support the N-nitroso compound hypothesis, but suggests potential roles for carotenoids and possibly other phytochemicals in reducing risk of adult glioma.

Adult↗
PubMed1979

Reactions of N-methyl-N-nitrosobenzylamine and related substrates with enzyme-containing cell fractions isolated from various organs of rats and mice.

Incubation of the following N-nitroso compounds with microsomes from mouse liver and an NADPH-generating system formed the products stated: benzaldehyde from N-methyl-N-nitrosobenzylamine (MNBA), acetone and formaldehyde from N-methyl-N-nitroso-(alpha-phenyl)-ethylamine (MNPE) and formaldehyde from N-methyl-N-nitroso-(2-phenyl)-isopropylamine (MNPI). Enzymes isolated from mouse liver showed more activity towards MNBA by comparison with rat liver preparations. Microsomes from the organs of female rats showed decreasing activity in the following sequence: esophagus greater than forestomach greater than liver and for female mice: liver greater than forestomach.

Animals↗
PubMed1990

Rat, mouse and hamster isozyme specificity in the glutathione transferase-mediated denitrosation of nitrosoguanidinium compounds.

The major isozymes from affinity column-purified glutathione transferases isolated from Sprague-Dawley rat liver, kidney, and testis cytosol and also from BALB/c mouse and Syrian golden hamster liver cytosol have been resolved by chromatofocusing and tested for their ability to denitrosate and thus detoxicate the DNA-methylating agents and potential carcinogens nitrosocimetidine and 1,3-dimethyl-2-cyano-1-nitrosoguanidine (CyanoDMNG). The isozymes have been kinetically characterized using a battery of substrates permitting, in the rat and mouse cases, subunit composition identification. It has been found that the rat and mouse isozymes belonging to the mu class are uniquely and highly active in the denitrosation of nitrosocimetidine and CyanoDMNG. A specific set of hamster glutathione transferase isozymes were also found to be active in these reactions. We have identified the reaction products produced by the rat liver 3-4 isozyme activity. The glutathione transferase-mediated degradations of 1-methyl-2-nitro-1-nitrosoguanidine and CyanoDMNG generate one molecule of S-nitrosoglutathione per molecule of denitrosated guanidinium compound produced. In the CyanoDMNG incubations essentially all degradation was via denitrosation; nitrite and glutathione disulfide were minor products. In the 1-methyl-2-nitro-1-nitrosoguanidine case nonenzymic degradation of the nitroso compound in the presence of reduced glutathione was evident but little of this decomposition produced S-nitrosoglutathione or 1-methyl-2-nitroguanidine. In the presence of rat transferase 3-4 isozyme, glutathione-dependent 1-methyl-2-nitro-1-nitrosoguanidine degradation was shifted markedly towards denitrosation with the concomitant production of S-nitrosoglutathione.

Animals↗
PubMed1982

Resistance of Salmonella typhimurium TA 1535 to O6-guanine methylation and mutagenesis induced by low doses of N-methyl-N'-nitro-N-nitrosoguanidine: an apparent constitutive repair activity.

Salmonella tester strains which are reverted by base-pair substitution mutagens are relatively insensitive to the mutagenic effects of N-methyl-N-nitroso compounds. One reason for this insensitivity is the ability of these strains to withstand low doses of these compounds before they become sensitive to their mutagenic effects. In this report it is shown that mutagenesis induced by treatment of Salmonella typhimurium TA 1535 with N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) in buffer is biphasic with a low sensitivity range at low doses where little mutagenesis occurs, followed by a high sensitivity range whose onset begins after an apparent threshold dose has been exceeded. levels of O6-methylguanine (O6-MeG) in the DNA extracted from the bacteria follow a similar dose-response curve suggesting a dependency of mutagenesis on O6-MeG. In contrast, levels of 7-methylguanine (7-MeG) in the DNA increase linearly with dose. O6-MeG was undetectable at the lowest dose of MNNG whereas 7-MeG was readily detectable. Although such resistance to O6-alkylation has been demonstrated in MNNG- pretreated (adapted) E. coli, it has not been reported in unpretreated cells. Then isolated DNA was treated with MNNG a linear dose-response in the generation of O6-MeG was observed. The lack of O6-MeG in DNA isolated from MNNG treated cells after low doses is attributed to a saturable, constitutive repair activity in the bacteria. An attempt to observe the removal of O6-MeG from the bacteria after exposure to a short challenge dose of N-nitroso-N-methylurea (NMU) followed by a subsequent incubation in buffer was unsuccessful, probably because all the repair occurred within the time necessary to treat and lyse the cells.

Chromatography, High Pressure Liquid↗
PubMed1992

An evaluation of the E. coli K-12 uvrB/recA DNA repair host-mediated assay. II. In vivo results for 36 compounds tested in the mouse.

The aim of this study was to further evaluate the E. coli K-12 DNA repair host-mediated assay, as a short-term in vivo genotoxicity test, to be used as a complement to the micronucleus test in the routine testing of chemicals and drugs. The assay involves the administration of the test substance to mice by the route of choice, followed by the intravenous administration of a mixture of DNA repair deficient and proficient derivatives of E. coli K-12. After an incubation period the relative survival of the two strains was determined in blood, liver, lungs, kidneys and testes of the host. A significant preferential reduction of the DNA repair deficient strain in any organ indicates that the test substance possesses genotoxic properties. A total of 36 substances, 26 carcinogens, 4 weak or non-carcinogens and 6 unclassified substances, were tested in this assay. Positive results were obtained for 23 compounds. Of the carcinogens 18 were positive and of the non-carcinogens 3 were negative. The overall concordance between the assay and carcinogenicity was 72%. In general, alkylating agents and direct-acting nitroso compounds showed genotoxic activity in all organs tested, while the other substances were positive in a limited number of organs. With oral administration, which was the most commonly used administration route in the study, the organ showing a positive response most often was the blood. The results from the present study were compared with results from the micronucleus test, which were available for 26 of the substances. Results were in agreement for 15 of the substances, while 8 substances were positive in the present assay and negative in the micronucleus test: 4-aminobiphenyl, 2-anisidine, epichlorohydrin, formaldehyde, 1- and 2-naphthylamine, 2-nitrophenylenediamine and 4-nitroquinoline-N-oxide. The substances negative in the E. coli DNA repair host-mediated assay, but positive in the micronucleus test were: benzene, catechol and cyclophosphamide. It is concluded from this evaluation that the E. coli K-12 DNA repair host-mediated assay detects a number of carcinogens that are negative in the micronucleus test, while detecting most of the compounds that are positive in the latter. The advantages of this test are that differential DNA repair measures a broad spectrum of genetic damage, an in vitro/in vivo comparison is possible with the same test organisms, results can be obtained from various organs and the test is rapid.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

Degradation of dimethylnitrosoamine catalysed by physical and chemical agents.

Decomposition of dimethylnitrosoamine (DMNA) by chemical and physical agents was further investigated. Both photoirradiation with sunlight or ultraviolet ray and reductive reactions under acid conditions (likely occurring in the stomach) led to the formation of formaldehyde, formic acid, and N-methydrazine, in addition to denitrosated compounds such as methylamine, dimethylamine, and N-methylhydroxylamine. N-Methylhydrazine was the only compound which was not detected by photoirradiation under neutral conditions. The agreement between physiochemical and metabolic degradation products and the possible biological meaning are discussed together with the problem of environmental contamination by the nitroso compound.

Dimethylnitrosamine↗