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PubMed1987

Evaluation of porous polymer traps for analysis of four volatile N-nitrosamines using thermal desorption injection coupled with a gas chromatograph-thermal energy analyzer.

Three porous polymer adsorbents, Tenax-TA, Chromosorb 102, and Chromosorb 103 were investigated as potential gas phase, trapping agents for volatile N-nitrosamines using a thermal desorption injector coupled with a gas chromatograph-thermal energy analyzer. N-Nitrosodimethylamine was used as the model N-nitrosamine for determining break-through volume, the effect of temperature on retention volume, and collection efficiency at 25 degrees C for each adsorbent. Results from these three parameters indicated that Chromosorb 103 exhibited the best adsorbent characteristics for the pre-concentration of volatile N-nitrosamines. A mixture of three dialkyl N-nitrosamines (dimethyl, diethyl, and dipropyl), and N-nitrosopyrrolidine were analyzed using a high-temperature mineral oil purge and trap procedure. Recoveries ranged from 82.2 to 102.8% at levels of 10 and 100 ng of each N-nitrosamine added.

Chromatography, Gas↗
PubMed1981

Effect of cimetidine on gastric juice N-nitrosamine concentration.

Total extractable N-nitroso compounds, pH, and nitrite levels were measured in, and microorganisms were cultured from, the fasting gastric juice of 140 patients taking the H2-receptor antagonist cimetidine and from 267 subjects, including 50 healthy volunteers, not taking cimetidine. Significantly higher mean N-nitrosamine concentrations and pH levels were demonstrated in the cimetidine-treated patients; N-nitrosamine concentration increased with pH. In 30 patients studied, cimetidine treatment significantly increased gastric pH and N-nitrosamine concentrations, while in 23 patients withdrawal of cimetidine treatment resulted in a significant reduction of pH but not of N-nitrosamine concentrations. The gastric juice nitrite level was often raised and nitrate-reducing bacteria cultured were similar to those associated with other causes of hypochlorhydria. These results demonstrate for the first time a relation between gastric juice N-nitrosamine concentration, pH, and cimetidine treatment, and the findings are discussed in relation to gastric cancer induction.

Achlorhydria↗
PubMed1998

Volatile N-nitrosamines in gastric juice of patients with various conditions of the gastrointestinal tract determined by gas chromatography-mass spectrometry and related to intragastric pH and nitrate and nitrite levels.

Gastric juice samples of 71 patients undergoing upper gastrointestinal endoscopy were collected as well as saliva samples from 40 of these patients. Age, sex, endoscopic diagnosis and medication were recorded. The gastric juice samples were analyzed for the presence and quantity of individual volatile N-nitrosamines, which were detected by gas chromatography-mass spectrometry, without prior derivatization. The samples were screened for eight nitrosamines, i.e. N-nitrosodimethylamine, N-nitrosoethylmethylamine, N-nitrosodiethylamine, N-nitrosodi-n-propylamine, N-nitrosodi-n-butylamine, N-nitrosopyrrolidine, N-nitrosopiperidine and N-nitrosomorpholine. The pH of the fresh gastric juice as well as nitrate and nitrite levels of gastric juice and saliva were determined. The mean total level of volatile N-nitrosamines in gastric juice was found to be 4.84 nmol/l (range 0-17.7 nmol/l). The main N-nitrosamines found were N-nitrosodiethylamine (mean concentration 3.1 nmol/l), N-nitrosodimethylamine (mean concentration 0.90 nmol/l) and N-nitrosopyrrolidine (mean concentration 0.38 nmol/l). Significant correlations between mean intragastric pH values and mean N-nitrosodi-n-butylamine level (P = 0.005) and total volatile N-nitrosamine contents (P = 0.009) were observed.

Adolescent↗
PubMed2026

Differential Mutagenic Response of Rat Liver and Lung to Nicotine-Derived Nitrosamine Ketone (NNK).

Nitrosamines (NA) are chemical impurities that are present in tobacco, foods, more recently in some pharmaceuticals and are associated with genotoxicity and carcinogenicity. We evaluated the in vivo mutagenicity of nicotine-derived nitrosamine ketone (NNK) or 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone, a model compound used as an anchor molecule to estimate carcinogenic potency of unknown nitrosamine impurities. Big Blue rats were treated with NNK at doses ranging from 0.001 to 30 mg/kg for 28 days, following which liver and lung tissue were harvested 3 days later for nuclear genomic DNA isolation. Mutations in liver and lung were assessed with the cII transgene assay and endogenous genomic loci using Duplex Sequencing (DupSeq), a highly validated error-corrected sequencing (ECS) technology. The no genotoxic effect level (NOGEL) was 1 mg/kg in liver and 0.1 mg/kg in lung while the benchmark dose (BMD) analysis for cII mutagenicity determined a BMDL50 of 1.3 mg/kg in liver and 0.12 mg/kg in lung, consistent with lung being the more sensitive target organ for carcinogenicity for NNK. ECS-derived mutagenicity was highly correlated with cII-derived mutagenicity. Interestingly, the types of mutations formed appeared to be tissue-specific with higher C > T transitions and lower T > G transversions in lung compared to liver, differences that may reflect tissue-specific DNA repair capacity and/or metabolic differences. Collectively, these data support the use of in vivo mutagenicity data─from both TGR cII and ECS methods─for human health and cancer risk characterization of nitrosamines and for estimating acceptable daily intakes for unknown nitrosamine drug substance related impurities.

Animals↗
PubMed2005

Novel amorphous functional materials for trapping nitrosamines.

Novel amorphous functional materials are designed to modify amorphous silica with alumina. They are first presented as efficient adsorbents to trap both volatile nitrosamines and bulky tobacco specific nitrosamines in the environment. Selective adsorption, temperature programmed surface reaction (TPSR), and FTIR methods are employed to study the impact of alumina modification on the ability of silica to adsorb and catalytically degrade nitrosamines. Due to the special interaction between the N-NO group of nitrosamines and the aluminum ion in the composite, nitrosamines can be very easily trapped by the composite. Moreover, this cost-efficient material first shows a remarkable adsorptive capability and catalytic activity in reduction of NNN (N-nitrosonornicotine) in the liquid phase. The new concept of designing a multifunctional trap for carcinogenic pollutants, which combines the amorphous silica's pore structure with the specific adsorbing/catalyzing features of metal ions, proves feasible.

Adsorption↗
PubMed2001

Structural features of aliphatic N-nitrosamines of 7-azabicyclo[2.2.1]heptanes that facilitate N-NO bond cleavage.

N-Nitrosamines can be considered as potential nitric oxide (NO)/nitrosonium ion (NO(+)) donors. However, the relation of the structures of N-nitrosamines, in particular of aliphatic N-nitrosamines, to the characteristics of release of NO or NO(+) remains unclear. Here we show that aliphatic N-nitrosoamines of 7-azabicyclo[2.2.1]heptanes can undergo heterolytic N-NO bond cleavage. On the basis of the observation of reduced rotational barriers of the N-NO bonds in solution and nitrogen-pyramidal structures of the N-nitroso group in the solid state, we postulate that N-NO bond cleavage of N-nitrosamines is enhanced by a reduction of the resonance in the N-NO group. Computational studies suggest that these structural features of the N-nitrosamines of 7-azabicyclo[2.2.1]heptane are derived from angle strain imposed on the CNC angles.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1977

Ultrastructural and metabolic determinants of resistance to azo-dye susceptibility to nitrosamine carcinogenesis of the guinea-pig.

During diethylnitrosamine (DEN) administration, a distinctive difference was observed between rats and guinea-pigs in the sequence of ultrastructural changes in the hepatic endoplasmic reticulum (ER). In DEN-induced hepatic tumour cells in the guinea-pig there was extensive proliferation of the rough ER, while the smooth ER was quite sparse; in the premalignant liver the opposite was noted. This is in contrast to the rat, in which administration of either DEN or 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) brings about, in both premalignant and malignant hepatic tissue, proliferation of the smooth ER and sparsity of the rough ER. Yet, as in the rat, the number of ribosomes on the outer surface of the guinea-pig liver rough ER is greatly reduced and this is paralleled by a 49% decrease of the RNA/protein ratio as early as 4 weeks of nitrosamine administration. The decrease of RNA/protein ratio and ultrastructurally observed loss of ribosomes from the ER, following nitrosamine administration, correlate with a decrease of photometric response of microsomal suspensions to the sulphydryl probe, p-chloromercuribenzoate. While azo-dye-reductase activity is higher in untreated rats than in untreated guinea-pigs, feeding 3'-Me-DAB for 6 weeks brings about a 76% decrease in the rat, but no significant decrease in the guinea-pig, which is refractory to azo-dye carcinogenesis. Thus, the ability of the liver to inactivate the dye is greatly decreased in the rat, but not in the guinea-pig, as administration progresses toward the threshold dose for tumorigenesis. On the other hand, constitutive levels of nitrosamine dealkylase are identical in the 2 species and remain essentially unchanged following administration of DEN for 10 weeks. Inasmuch as nitrosamine dealkylation represents activating metabolism, this provides a rationale for the comparable susceptibility of the rat and guinea-pig to DEN carcinogenesis. Of the 2 enzymes in the 2 species, it is only azo-dye reductase in the guinea-pig which appears to be unregulated by glucose repression, since starvation brings about no change in this activity. Starvation-induced increase of azo-dye reductase in the rat is not influenced by administration of 3'-Me-DAB and only slightly by DEN. The starvation-induced increase of nitrosamine dealkylation is abolished, however, in both species by administration of DEN but only slightly decreased by 3'-Me-DAB.

Animals↗
PubMed1992

N-nitrosamine generation by urinary tract infections in spine injured patients.

Urine was collected from 33 patients resident at the Welsh Spinal Injuries Unit and analysed for volatile N-nitrosamines by gas chromatography. N-nitrosodime-thylamine, N-nitrosopiperidine or N-nitrosopyrrolidine was detected in 32 of the samples. Thirty-one of the samples were infected by one or more microbial species. Nitrate and N-nitrosamines were not found in the sterile urines of a group of 10 control individuals exposed to the same dietary and environmental influences as the spinal patients. Although N-nitrosamines were found in some of the catheter drainage system products, they did not elute into urine on 24-h exposure. In addition, 6 of the nitrosamine-containing urines had no contact with drainage systems as they were collected from spinal patients who were capable of independent voiding. It was concluded that the nitrosamines detected in the urines arose from the bacterial nitrosation of urinary amines. These results support the hypothesis that chronic urinary tract infection may have a role in the aetiology of bladder cancer in spine injured patients.

Humans↗
PubMed1998

Formation of nitrosamines during consumption of nitrate- and amine-rich foods, and the influence of the use of mouthwashes.

We studied the formation of carcinogenic nitrosamines during consumption of food rich in nitrate and amines, and its possible inhibition by use of an antibacterial mouthwash. Twelve volunteers were fed a diet containing the high-nitrate vegetables lettuce or spinach during two periods of four consecutive days, in combination with fish products containing high levels of amines as nitrosatable precursors. During the two periods, the subjects used an antibacterial mouthwash containing chlorhexidine or a control mouthwash without antibacterial activity. Twenty-four-hour urine samples were collected after consumption of the meals, and saliva samples were collected 1 h after each meal. The nitrate and nitrite contents of the urine and saliva samples were determined by spectrophotometry (for nitrite) and HPLC (for nitrate). The concentrations of volatile nitrosamines in the urine samples were determined by gas chromatography-mass spectrometry. Significant increases in mean urinary nitrate levels (from 59 to 135 mg/24 h) and in mean salivary nitrate levels (from 10 to 56 microg/ml) and salivary nitrite levels (from 2 to 11 microg/ml) were observed during the consumption of food rich in nitrate and amines, as well as a significant increase in the mean urinary excretion of total examined volatile nitrosamines (from 2 to 7 nmol/24 h) and of N-nitrosodimethylamine (from 1.2 to 2.9 nmol/24 h). Use of the antibacterial mouthwash resulted in a decrease in mean salivary nitrite levels from 16 to 3 microg/ml and a decrease in mean urinary excretion of N-nitrosomorpholine (from 7.0 to 0.3 nmol/24 h). For the whole data set, significant correlations were observed between nitrate intake in food and urinary nitrate (p = 0.01; r2 = 0.07) and between urinary nitrate and urinary N-nitrosodimethylamine (p = 0.002; r2 = 0.11). In conclusion, consumption of a diet rich in nitrate and amines increases the risk of formation of carcinogenic nitrosamines. Use of an antibacterial mouthwash containing chlorhexidine can result in inhibition of nitrosamine formation.

Adult↗
PubMed1993

Metabolism of carcinogenic nitrosamines in the rat and human esophagus and induction of esophageal adenocarcinoma in rats.

The mechanism is discussed by which certain nitrosamines induce esophageal papillomas and squamous cancer in rats, and some evidence is presented for the view that nitrosamines also induce the same cancer in humans, especially in China and South Africa. Studies on the metabolism of nitrosamines by cytochrome P450 isozymes in rat and human esophagus, including the activation reactions of formaldehyde and pentaldehyde formation from methyl-n-amylnitrosamine (MNAN), are reviewed. These reactions are catalyzed by microsomes from the rat and human esophagus, probably because these microsomes contain specific cytochrome P450 isozymes. Evidence is reviewed for the occurrence of nitrosamines related to MNAN in fungus-infected corn. The incidence of esophageal adenocarcinoma is rising in Western countries. The precursor lesion, Barrett's esophagus, is associated with colon cancer, suggesting a role for bile salts in the induction of the esophageal tumor. Studies are described in which rats were subjected to esophago-duodenostomy (joining the duodenum to the esophagus) and then treated with nitrosamines that normally induce esophageal squamous cancer. Adenocarcinomas of the lower esophagus were induced as well as Barrett's esophagus (under one set of conditions). Feeding a high-fat diet with this system increased the incidence of esophageal adenocarcinoma. This tumor was not induced when the operation was changed to esophago-gastroplasty (widening the lower esophageal sphincter). These results support a role of reflux of duodenal contents (including bile and pancreatic juice) rather than of gastric contents in the etiology of human esophageal adenocarcinoma.

Adenocarcinoma↗
PubMed2001

Release of nitric oxide together with carbon-centered radicals from N-nitrosamines by ultraviolet light irradiation.

Solutions of N-nitrosamines, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosomorpholine and N-nitrosopyrrolidine in phosphate buffer (pH 7.4) were irradiated by ultraviolet (UV) light at room temperature. The N-nitrosamines were extensively degraded due to irradiation for 120 min in a time-dependent fashion as monitored by UV-absorption or high performance liquid chromatographic analysis. Carbon-centered radicals were generated from four N-nitrosamines during the short time irradiation of 10-60 s as monitored by electron spin resonance (ESR) technique using 5,5-dimethyl-1-pyrroline N-oxide and N-tert-butyl-alpha-phenylnitrone as spin traps. Nitric oxide (NO) was generated during the short time irradiation as monitored by ESR technique using cysteine-Fe(II) complex, N-methyl-D-glucamine dithiocarbamate and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Significant amounts of nitrite (4-16%) from four N-nitrosamines and also a significant amount of nitrate (4%) was produced from N-nitrosodimethylamine during the irradiation time of 120 min. Released NO from the N-nitrosamines must be converted into nitrite through intermediary reactive nitrogen oxide species including nitrogen dioxide and dinitrogen trioxide in contact with dissolved oxygen.

Carbon↗
PubMed1980

Aqueous extraction of N-nitrosamines from elastomers.

Elastomers compounded with accelerators or stabilizers derived from dialkylamines have been found to contain the corresponding N-nitrosodialkylamines. Previous work showed that the N-nitrosamines are evolved from heated elastomers; we have not found they are also extractable in water. In the absence of the dialkylamino compound in the elastomer, no N-nitrosodialkylamines were detected. Generally, less than 250 parts of N-nitrosamine per billion parts of elastomer was detected after extracting for one or five days at room temperature or 100 degrees C. Compounded and cured polychloroprene, ethylene-propylene-diene terpolymer, chlorosulfonated polyethylene, and natural rubber, as well as several commercial rubber articles, were included in this study. Controls were run to determine the background levels of N-nitrosamines and the recovery of N-nitrosamines from the extraction solvent. N-nitrosamines were quantitated using gas chromatography with thermal energy analyzer detection.

Chromatography, Gas↗
PubMed2002

Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: application of genetically engineered Salmonella expressing human CYP.

The role of human cytochrome P450 (CYP) in the metabolic activation of tobacco-related N-nitrosamines was examined by Salmonella mutation test using a series of genetically engineered Salmonella typhimurium YG7108 strains each co-expressing a form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) together with human NADPH-cytochrome P450 reductase. Seven tobacco-related N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine, N-nitrosonornicotine, N-nitrosoanabasine, and N-nitrosoanatabine were used. The CYP2A6 was found to be responsible for the mutagenic activation of essentially all tobacco-related N-nitrosamines examined. On the basis of the evidence, genetic polymorphism of the CYP2A6 gene appeared to be one of the factors determining cancer susceptibility caused by smoking. Previously, we found the whole deletion of the CYP2A6 gene (CYP2A6*4C) as a type of genetic polymorphism in Japanese. We hypothesized that individuals possessing the gene homozygous for CYP2A6*4C were incapable of activating tobacco-related N-nitrosamines and showed lower susceptibility to lung cancer induced by tobacco smoke. Thus, the relationship between the CYP2A6*4C and the susceptibility to the lung cancer was evaluated. The frequency of the CYP2A6*4C was significantly lower in the lung cancer patients than healthy volunteers, suggesting that the subjects carrying the CYP2A6*4C alleles are resistant to carcinogenesis caused by N-nitrosamines because of the poor metabolic activation capacity. Taking these results into account, CYP2A6 is an enzyme enhancing lung cancer risk.

Aryl Hydrocarbon Hydroxylases↗
PubMed1982

Metabolic nitrite formation from N-nitrosamines: evidence for a cytochrome P-450 dependent reaction.

Nitrite was formed on incubation of N-nitrosamines with a reconstituted monooxygenase system, consisting of cytochrome P-450 (P-450) and NADPH P-450 reductase from pig liver. Nitrite was not obtained when the nitrosamines were incubated with NADPH P-450 reductase alone or when molecular oxygen or NADPH were omitted. Interaction of nitrosamines with the reconstituted P-450 system or with hemoglobin under reducing conditions resulted in optical spectra identical with those obtained with nitrite. It is proposed that N-nitrosamines are denitrosated by electron transfer from the hemoprotein iron to the nitrosamine molecule.

Animals↗
PubMed1987

Combination experiments with very low doses of three genotoxic N-nitrosamines with similar organotropic carcinogenicity in rats.

The study was designed to assess the syncarcinogenic activity of very low doses of N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR) and N-nitrosodiethanolamine (NDElA) in the liver of 1800 male Sprague-Dawley rats. The N-nitrosamines were administered throughout the rats' lives individually and in combination at three logarithmically spaced dose levels contained in drinking water. The dose levels in the individual dose-response experiments ranged from the lowest concentrations of previous experiments (NDEA, 0.1 mg/kg; NPYR, 0.4 mg/kg; NDElA, 2.0 mg/kg) to dosages 10 times lower and comprised a high, medium and low dose (escalation factor: 3.16). The high dose of the combination contained the three nitrosamine concentrations used as the medium doses of the individual nitrosamines. The medium combination dose resulted from the combined administration of the three lowest dosages, and the low combination dose consisted of three nitrosamine dosages which amounted to one-third of the low dosages respectively. Administration of these dosages was associated with a dose-dependent incidence of liver cancer: NDEA induced 45, 3.8 and 2.5%; NPYR caused 21.3, 5 and 1.3%; NDElA generated 7.5, 1.3 and 2.5%; and the combinations induced 16, 4.2 and 1.7% respectively. Untreated controls showed 0.6% liver cancer incidence. Besides the liver, the gastrointestinal tract, the neurogenic tissue, the urinary tract and the hematopoietic and lymphatic tissue were affected by tumor incidences increased over that of controls. There was, however, no well-defined dose dependency as with the liver tumors. These results indicate dose dependency of liver tumor formation even at very low exposure levels of the individual agents. The carcinogenic effects of the hepatotropic N-nitrosamines summed up in combination. The observed additivity was linear. Dose levels, which alone would presumably not have been carcinogenic, effected a significant cancer risk in combination.

Animals↗
PubMed1977

Metabolism of acyclic and cyclic N-nitrosamines in cultured human bronchi.

The metabolism of carcinogenic N-nitrosamines was studied in normal-appearing bronchial specimens obtained from 4 patients. Explants of bronchi were cultured in a chemically defined medium for 7 days. N-Nitrosamines [N-nitrosodimethylamine (DMN), N-nitrosodiethylamine (DEN), N,N'-dinitrosopiperazine (DNP), N-nitrosopyrrolidine (NPy), and N-nitrosopiperidine (NPd)] labeled with 14C were each then added at 100 mumoles for 24 hours. Measurable CO2 was formed by bronchial explants from: 1) DMN, DEN, and NPy in all 4 patients; 2) DNP in 3 of 4 patients; and 3) NPd in only 1 of 4 patients. In all bronchial specimens, these N-nitrosamines and/or their metabolites bound to bronchial mucosal DNA and protein. Binding levels were higher to protein than to DNA. Binding levels of DNP were as high as those with the two acyclic N-nitrosamines DMN and DEN, but binding levels of NPy and NPd were lower. Human bronchus was shown to metabolize and bind acyclic and cyclic N-nitrosamines found in the environment and in tobacco smoke.

Bronchi↗
PubMed1989

Volatile N-nitrosamines in urinary catheters.

Levels of volatile N-nitrosamines were measured in 10 brands of latex and 2 brands of silicone catheters using high performance liquid chromatography. The cytotoxicity of catheters from identical batches was determined by measuring the inhibitory effect of catheter extracts on the uptake of 3H-labelled thymidine into L-929 fibroblasts in culture (IC50). The most frequently encountered nitrosamines were N-nitrosodi-n-butylamine and N-nitrosodiethylamine. Total N-nitrosamine levels in excess of 100 ng/g were found in 6 of the 16 catheters tested. When compared with the cytotoxicity of the catheters a significant correlation was found, with increasing nitrosamine content being associated with greater cytotoxicity. In view of the reported toxic and carcinogenic effects of these compounds it is suggested that the nitrosamine content of catheters be routinely monitored and safe regulatory limits be imposed.

Cells, Cultured↗
PubMed1991

Effect of vitamin C on endogenous formation of N-nitrosamines in ureterosigmoidostomy patients.

The bacterially catalyzed formation of nitrosamines in the rectosigmoid is a favorite theroy for the increased risk of colon carcinomas following ureterosigmoidostomy. The urine/feces mixtures of 20 ureterosigmoidostomy patients were analyzed for nitrate, nitrite, volatile and nonvolatile nitrosamines prior to, and after, oral administration of vitamin C, a known nitrosation inhibitor. Following a 4-week period of daily ingestion of 2 g vitamin C (1 g in children) there was a slight, but not significant, decrease of volatile and nonvolatile nitrosamines and nitrite, as well as a nonsignificant increase in nitrate in the urine/feces of these patients. No correlation between the vitamin C concentration in serum or urine/feces mixture and the nitrosamine excretion was observed. These results suggest that the administration of vitamin C is not a suitable method for prophylaxis of endogenous nitrosation in ureterosigmoidostomy patients. Clinical and experimental findings implicate that factors other than nitrosamines play an important role in colon carcinogenesis of patients with ureterosigmoidostomies or other forms of urinary diversions using the small or large bowel.

Ascorbic Acid↗