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PubMed1994

Adenine.methylthymine base-pairs enhance non-uniformity in DNA helices.

Nitroso compounds are known to induce mutations and cancer. Here we study the effect of methylation of O4 of thymine by nitroso compounds on the structure and dynamics of DNA helices. Four dodecamers, for which there exist experimental data obtained by NMR techniques, are studied using very long (approximately 1 ns) molecular dynamics simulations. The conformations obtained are in good agreement with the NMR data. A statistical analysis indicates that DNA in solution adopts conformations which are intermediate between those of the ideal DNA families, such as A and B-DNA. Also, the structures obtained in these molecular dynamics simulations possess a greater degree of non-uniformity than the crystal structures. Most importantly, the helices containing adenine.methylthymine base-pairs show a further enhancement in non-uniformity. A biological role for the enhanced nonuniformity is suggested.

Adenine↗
PubMed1987

HRP-catalyzed bioactivation of carcinogenic hydroxamic acids. The greater reactivity of glycolyl- versus acetyl-derived hydroxamic acids.

An analysis of the hydroxamic acid oxidation reaction by H2O2 and horseradish peroxidase (HRP) was made with three pairs of hydroxamic acids. Each pair consisted of the aceto- and glycolhydroxamic acid derivatives from one of three different arylhydroxylamines. The parent arylhydroxylamines were the known carcinogens, N-hydroxy-2-aminofluorene and N-hydroxy-4-aminobiphenyl and the noncarcinogen 4-chlorophenyl-hydroxylamine. All the hydroxamic acids appeared to be converted to products that were expected on the basis of the previously-proposed mechanism of this peroxidative reaction. Each acetohydroxamic acid gave the corresponding nitroso compound and O-acetyl ester of the starting material in approximately equal amounts. The glycolhydroxamic acids gave the corresponding nitroso compound and a relatively unstable product that was proposed, by analogy, to be the O-glycolyl ester of the starting material. A comparison of the initial rates of reaction of each hydroxamic acid pair showed that the glycolhydroxamic acid was much more susceptible to the peroxidation reaction than was the corresponding acetohydroxamic acid. The initial rate of the reaction was also highly dependent upon the nature of the aromatic ring in the order fluorene greater than biphenyl greater than 4-chlorophenyl. The relative degree of HRP-catalyzed covalent binding to DNA of the aceto- and glycolhydroxamic acids in the fluorene series was studied and found to parallel the relative rates of reaction of these substrates in the H2O2/HRP system. It was proposed that glycolhydroxamic acids are likely to be more genotoxic than are acetohydroxamic acids when subjected to peroxidative bioactivation conditions.

Biotransformation↗
PubMed1991

Urinary excretion of N-nitrosoproline in relation to consumption of raw and cooked vegetables in a Danish rural population.

Several recent case-control studies of gastric cancer have demonstrated the protective effect of consumption of vegetables. According to Correa's model of gastric carcinogenesis, the initiating agent is N-nitroso compounds either ingested or formed in vivo. In our study of endogenous nitrosation, we measured intragastric formation of N-nitroso compounds in 285 individuals by the nitrosation of proline; in this presentation we analysed the effect of consumption of vegetables on urinary excretion of N-nitrosoproline (NPRO). When adjustment was made for the dominating determinants of NPRO excretion (total nitrate intake and tobacco smoking), a marked difference in the effects of consumption of raw and cooled vegetables was seen: consumption of cooked vegetables increased endogenous nitrosation of proline, while consumption of raw vegetables had only a marginal effect. We suggest that the difference between raw and cooked vegetables is due to destruction of ascorbate in the cooking of the vegetables. The lack of a protective effect of consumption of raw vegetables on the rate on endogenous nitrosation of proline indicates, however, that the determinants of nitrosation of proline and the determinants of gastric cancer risk may be different.

Cooking↗
PubMed1981

Quantitative estimation of endogenous nitrosation in humans by monitoring N-nitrosoproline excreted in the urine.

Endogenous formation of N-nitrosoproline (NPRO) was demonstrated by monitoring its excretion in the urine of a male volunteer who had ingested vegetable juice, as a source of nitrate, and proline. The resulting NPRO was analyzed after derivatization by combined gas-liquid chromatography thermal energy analysis. The amount of total NPRO excreted in the urine was found to be proportional to the proline dose and increased exponentially with the nitrate dose ingested. Neither nitrate nor proline, when taken alone, led to a detectable increase in NPRO in urine. The amounts of NPRO formed (as estimated from the amounts excreted within 24 hr) after dosing 325 mg nitrate (NO3-) followed by 500 mg proline, ranged from 16.6 to 30.0 (mean, 23.3) micrograms per person. The simultaneous intake of ascorbic acid or alpha-tocopherol inhibited nitrosation of proline in vivo. Monitoring of NPRO or other N-nitroso compounds excreted in the urine thus appears to be a suitable procedure for estimating daily human exposure to endogenously formed N-nitroso compounds.

Ascorbic Acid↗
PubMed1981

Nitrite-induced volatile mutagens from normal human feces.

Volatile mutagens (putative carcinogens) were produced from normal human and animal feces upon incubation with sodium nitrite in saline at 37 C for 48 hours. The mutagens were detected by using Ames' Salmonella typhimurium tester strain TA1535 without microsomes, on plates inverted over samples in sealed containers. Mutagenicity was maximal at 0.2 to 0.6 M NaNO2 and at pH 6.2 to 6.8. Reversions per plate varied from approximately 30 to 450 (1.5 to 25 x background) within the normal human population. Sodium ascorbate and alpha-Tocopherol (at one-half [NaNO2]) each reduced the mutagenicity by approximately 30%. Two standard N-nitroso-compounds were mutagenic in the system. We propose that the mutagenicity in our system is probably caused by the formation of volatile N-nitroso-compounds and that addition of nitrite to human feces in vitro enhances a process that occurs in vivo.

Ascorbic Acid↗
PubMed1991

Volatile and nonvolatile nitrosamines in beer.

The occurrence of N-nitroso compounds was investigated at different stages in the production of four different beer types and in 14 retail beer samples. Only two N-nitroso compounds, namely N-nitrosodimethylamine (0.17 +/- 0.18 microgram/kg; not detected to 0.60 microgram/kg) and N-nitrosoproline (1.51 +/- 1.01 micrograms/kg; range 0.5-3.60 micrograms/kg) were detected. For moderate beer drinkers, the N-nitrosodimethylamine exposure levels are unlikely to present a significant health risk while the presence of noncarcinogenic N-nitrosoproline does not pose any hazard to human health.

Beer↗
PubMed2005

Kinetics of RDX degradation by zero-valent iron (ZVI).

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a common groundwater contaminant at military facilities. The current research has been conducted to evaluate the use of zero-valent iron (ZVI) for the remediation of water contaminated with RDX. RDX was found to degrade rapidly in the presence of ZVI. The observed first-order kinetic constant for RDX reduction follows an enzymatic-like kinetic model with respect to the ZVI concentration. At low ZVI concentrations, RDX reduction follows pseudo first order kinetics with respect to ZVI concentration; while at high ZVI concentrations the RDX reduction is zero-order. Nitroso compounds (MNX, DNX, and TNX), nitrate, nitrite and nitrous oxide were identified as the main by-products for the RDX reduction by ZVI. The nitroso compounds were found to undergo reduction by ZVI.

Iron↗
PubMed2005

Hemin potentiates nitric oxide-mediated nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline.

Heme has been reported to be an important contributor to endogenous N-nitrosation within the colon and to the enhanced incidence of colon cancer observed with increased intake of red meat. This study uses the heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) as a target to evaluate hemin potentiation of nitric oxide (NO)-mediated nitrosation. Formation of 14C-2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) was monitored by HPLC following incubation of 10 microM IQ with the NO donor spermine NONOate (1.2 microM NO/min) at pH 7.4 in the presence or absence of hemin. N-NO-IQ formation due to autoxidation of NO was at the limit of detection (0.1 microM) and increased 22-fold in the presence of 10 microM hemin and an in situ system for generating H2O2 (glucose oxidase/glucose). A linear increase in N-NO-IQ formation was observed from 1 to 10 microM hemin. Significant nitrosamine formation occurred at fluxes of NO and H2O2 as low as 0.024 and 0.25 microM/min, respectively. Potentiation by hemin was not affected by a 400-fold excess flux of H2O2 over NO or a 4.8-fold excess flux of NO over H2O2. Reactive nitrogen species produced by hemin potentiation had a 46-fold greater affinity for IQ than those produced by autoxidation. Azide inhibited autoxidation, suggesting involvement of the nitrosonium ion, NO+. Hemin potentiation was inhibited by NADH, but not azide, suggesting oxidative nitrosylation with NO2* or a NO2*-like species. IQ and 2,3-diaminonaphthylene were much better targets for nitrosation than the secondary amine morpholine. Apc(min) mice with dextran sulfate sodium-induced colitis demonstrated increased levels of urinary nitrite and nitrate consistent with increased expression of iNOS and NO synthesis. As reported previously, identical conditions increased fecal N-nitroso compounds. Thus, hemin potentiation of NO-mediated nitrosation of heterocyclic amines provides a testable mechanism by which red meat consumption can generate N-nitroso compounds and initiate colon cancer under inflammatory conditions, such as colitis.

Animals↗
PubMed1992

Action profiles of nitric oxide, S-nitroso-L-cysteine, SNP, and NANC responses in opossum lower esophageal sphincter.

Circular muscle strips from opossum lower esophageal sphincter were suspended in organ baths for measurement of isometric tension. Nonadrenergic noncholinergic (NANC) inhibitory nerves were stimulated by means of transmural field stimulation. This induced frequency-dependent relaxations of the muscle strips. Methylene blue (3 x 10(-6) M; inhibits guanylate cyclase) and pyrogallol (10(-4) M; generates superoxide anions) had no influence on relaxations, whereas oxyhemoglobin [10(-5) M; binds nitric oxide (NO) and other nitroso compounds extracellularly] inhibited relaxations at all frequencies. NO concentration dependently relaxed the muscle strips. Pyrogallol (10(-4) M) and methylene blue (3 x 10(-6) M) inhibited and oxyhemoglobin (10(-5) M) nearly abolished relaxation induced by NO. S-nitroso-L-cysteine caused concentration-dependent relaxations of the muscle strips, which were inhibited by pyrogallol (10(-4) M), whereas methylene blue (3 x 10(-6) M) augmented the action of S-nitroso-L-cysteine. Methylene blue (3 x 10(-6) M) had no influence on the concentration-dependent relaxations caused by sodium nitroprusside (SNP). Oxyhemoglobin (10(-5) M), and to a lesser extent pyrogallol (10(-4) M), both inhibited the effects of SNP. The action profiles for S-nitroso-L-cysteine, NO, and SNP differed from the action profile for NANC nerve-mediated response. Although pyrogallol inhibited the effects of SNP, the action profile generally resembled the action profile for NANC responses more closely than did the profiles for S-nitroso-L-cysteine or NO. In conclusion, of the nitroso compounds studied, SNP most closely resembled the response to NANC nerve stimulation. Neither NO nor S-nitroso-L-cysteine individually mimicked the NANC response.

Animals↗
PubMed1981

Gastric juice N-nitrosamines in health and gastroduodenal disease.

The concentrations of total extractable N-nitroso compounds, pH, and nitrite levels were measured in fasting gastric juice, which was also cultured for bacteria, from 50 healthy volunteers and 217 patients with common upper gastrointestinal complaints. The concentrations of N-nitroso compounds and pH levels rose significantly with age. Sex and cigarette smoking had no significant effect. There was a positive correlation between pH and N-nitroso concentration, and between pH and an increase in the concentration of nitrites. A significant relation was demonstrated between raised N-nitroso and nitrite levels and growth of nitrate reductase-positive microorganisms. These results demonstrate for the first time in man the interrelations of N-nitrosamine concentration, pH, gastric juice nitrite, and nitrate-reducing bacteria. The findings are considered in relation to the risks of development of gastric cancer in man.

Adolescent↗
PubMed1986

The biochemistry of nitrates, nitrites, nitrosamines and other potential carcinogens in human saliva.

Human whole saliva protects the oral environment in many different ways from invading pathogenic microorganisms. Human saliva is also capable of inactivating mutagenic and carcinogenic agents by various mechanisms. The peroxidation of these agents is likely to be one of the degrading reactions. However, under certain circumstances some potentially carcinogenic compounds, such as N-nitrosamines, may be generated in whole saliva or--even more likely--in the saliva-gastric juice mixture after swallowing. The formation of N-nitroso compounds requires relatively high intake of nitrate e.g. from vegetable juices. Nitrate is partly reduced to nitrite by oral bacterial enzymes. The nitrosation of various secondary amines is favoured by high salivary (or gastric) concentration of thiocyanate and by low pH. The endogenous generation of N-nitroso compounds may be causally related to the development of oral or gastric cancer.

Carcinogens↗
PubMedDate not supplied

N-nitrosamine and mutagenicity formation in Chinese salted fish after digestion.

Salted and dried fish (Nemipterus virgatus), acquired from Hong Kong, was treated with 0.43-110 mM nitrite during in vitro digestion using gastric enzymes and the volatile N-nitrosamine content and mutagenicity on Salmonella typhimurium TA100 assayed without concentration. N-Nitrosodimethylamine (NDMA; the only nitrosamine detected) formation was second order in nitrite concentration. When 10 g of fish was treated with 6.96 mM nitrite, 394 nM NDMA was formed. Thiocyanate was catalytic for NDMA formation at nitrite concentration greater than 0.87 mM and when the ratio of thiocyanate to nitrite was greater than 1. Approximately a 50% inhibition in NDMA formation by ascorbic acid was seen when the ratio of ascorbate to nitrite was approximately 2 or greater and the nitrite concentration was 1.74 mM. Mutagenicity increased with increasing nitrite concentration but the addition of thiocyanate did not increase mutagenicity over nitrite alone. Ascorbate increased mutagenicity even though NDMA formation was inhibited. Even at nitrite concentrations greater than 100-fold higher than expected in vivo, there was insufficient NDMA formed to account for the observed mutagenicity. These data do not exclude the possibility that the observed mutagenicity was due to non-volatile N-nitroso compounds, however, this possibility seems unlikely given the effects of ascorbate and thiocyanate which would be expected to inhibit and enhance non-volatile N-nitroso compound formation.

Animals↗
PubMed1992

Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines. XII. Enantioselectivity and temperature dependence in microsomes and reconstituted cytochrome P-450 systems from rat liver.

Formation of metabolic intermediate (MI) complexes was studied with the enantiomers of amphetamine, 1-phenyl-2-pentanamine, N-hydroxyamphetamine, and 2-nitroso-1-phenylpropane (the C-nitroso analogue of amphetamine). Three different enzyme systems were used; liver microsomes from phenobarbital pretreated rats and two reconstituted systems containing the P450 2B1 and P450 2C11 forms of cytochrome P-450. Enantioselective complex formation in microsomes was shown for the amines and the nitroso compound, but not for the hydroxylamine. The highly purified P450 2B1 system formed the MI complex with all substrates tested, and the enantioselectivity observed with the microsomal system was reproduced. In the P450 2C11 system the nitroso compounds were completely inactive, whereas the enantiomers of N-hydroxyamphetamine still produced the complex at a high rate. Changes in temperature were shown to affect (R)-2-nitroso-1-phenylpropane more than its enantiomer. Both enantiomers showed biphasic Arrhenius plots for MI complex formation in microsomes (breaks around 22 degrees C), but the activation energies of the (R)-isomer were about five times higher than those of the (S)-isomer. A theory is presented which suggests different modes of interaction with the active site of P-450 to account for the different behaviour of the various substrates.

Amphetamines↗
PubMed1987

2-(N-nitroso-N-methylamino)propiophenone, a direct acting bacterial mutagen found in nitrosated Ephedra altissima tea.

A new N-nitroso compound identified in a nitrosated tea extract made from the plant Ephedra altissima and shown to be formed under in vivo conditions was identified as 2-(N-nitroso-N-methylamino)propiophenone (NMAP). N-Nitrosoephedrine (NEP), another N-nitroso compound detected in nitrosated Ephedra altissima tea and NMAP are shown to exert mutagenic activity in the Salmonella/mammalian microsome mutagenicity (Ames) test. Base-pair substitution mutation-detecting strains (TA100 and TA1535) showed both compounds to be weak direct-acting mutagens without the addition of S9-mix. The identification, synthesis and mutagenicity of NMAP are discussed.

Mutagenicity Tests↗
PubMed1991

The anomalous biological activity of nitroso-2-oxopropyl compounds.

The carcinogenic action of a set of N-nitroso compounds containing the 2-oxopropyl group was considered in relation to their metabolism and their activity as alkylating agents for DNA. In contrast with the great carcinogenic potency of methylnitrosourea and ethylnitrosourea, comparable with the corresponding dialkylnitrosamines, 2-oxopropylnitrosourea is a weak carcinogen with a limited range of target organs in rats and hamsters. 2-Oxopropylnitrosochloroethylurea was somewhat weaker than 2-oxopropylnitrosourea and similarly induced spleen hemangiosarcomas in hamsters, but few tumors of any kind in rats. The relatively much more potent carcinogenicity of nitrosobis-(2-oxopropyl)amine, nitroso-(2-hydroxypropyl) (2-oxopropyl) amine and methylnitroso-2-oxopropylamine suggests that the activity of an oxopropylating agent is not involved in carcinogenesis by nitroso-2-oxopropylamines. The nitrosamines are likely to undergo extensive metabolism to form proximate carcinogenic moieties, probably including the methyldiazonium ion, which are responsible for the induction of a broad range of tumors in rats and hamsters. These include tumors of the liver, pancreas ducts, lung and nasal mucosa in hamsters, and esophagus, liver, lung, thyroid, kidney, trachea, bladder and nasal mucosa in rats.

Animals↗
PubMed1984

Species differences in nitrosamine carcinogenesis.

The carcinogenic action of approximately 50 N-nitroso compounds, nitrosamines, and nitrosoalkylamides has been compared in rats and in Syrian golden hamsters. The compounds were administered PO, as far as possible at comparable dose rates. The relative potencies of the treatments were assessed mainly by the time to death of the animals with tumors. The esophagus and other parts of the upper gastrointestinal tract were the most common sites for tumor induction in rats, but the esophagus was hardly ever affected in hamsters, although several compounds induced tumors of the forestomach in both rats and hamsters. No conclusion could be drawn about the relative susceptibility of the rat and hamster to these N-nitroso compounds, which varied with different compounds. Few generalizations can be made about these results, although it appeared that the 2-hydroxypropyl group was usually necessary for the induction of pancreas tumors in hamsters.

Alkylation↗
PubMed1984

Detection of N-nitrosamines in the saliva of habitual chewers of tobacco.

The saliva of habitual chewers of tobacco and of non- chewers was examined using high-performance liquid chromatography and gas-liquid chromatography-thermal energy analysis. N-Nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosonornicotine and N- nitrosohydroxyproline were detected in the saliva from the tobacco chewers . These N-nitroso compounds are probably leached from the tobacco itself and/or are formed in situ by the nitrosation of tobacco alkaloids as well as that of secondary amines. No N-nitroso compounds were detected in the saliva of non- chewers .

Adult↗
PubMed1998

Effect of gastric secretion on penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine into gastric mucosa of rats.

Clinical conditions with low gastric acid secretion have been associated with increased risk of gastric cancer. There has also been concern about gastric acid inhibition and N-nitroso compound formation in the stomach. This study investigates the effect of gastric acid secretion on the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine, an N-nitroso compound and gastric carcinogen, into the gastric mucosa of rats. Gastric acid secretion was stimulated by pentagastrin (40 microg/kg/hr) and inhibited by omeprazole (40 micromol/kg) before mucosal exposure to N-3H-methyl-N-nitro-N-nitrosoguanidine. Penetration of the carcinogen was evaluated by light microscopic identification of cells in the S-phase labeled with N-3H-methyl-N-nitro-N-nitrosoguanidine. This population of double-labeled cells is considered at risk from N-methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis. The percentage of double-labeled cells was significantly higher in antrum than in corpus mucosa (P < 0.0001). Stimulation or inhibition of gastric acid secretion did not affect the penetration of N-3H-methyl-N-nitro-N-nitrosoguanidine in antrum or corpus mucosa. We conclude that modulation of gastric acid secretion does not affect the penetration of the carcinogen into the gastric mucosa nor does it explain the different penetration of the carcinogen into corpus and antrum mucosa.

Animals↗