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PubMed2002

DNA adducts from N-nitrosodiethanolamine and related beta-oxidized nitrosamines in vivo: (32)P-postlabeling methods for glyoxal- and O(6)-hydroxyethyldeoxyguanosine adducts.

The mechanism by which environmentally prevalent N-nitrosodiethanolamine (NDELA) and related 2-hydroxyethyl- or other beta-oxidized nitrosamines initiate the carcinogenic process has remained obscure. (32)P-Postlabeling assays for the pH sensitive glyoxal-deoxyguanosine (gdG) and the O(6)-2-hydroxyethyldeoxyguanosine (OHEdG) DNA adducts have been developed as probes in this mechanistic investigation and used in both in vitro and in vivo experiments. The ready cleavage of the glyoxal fragment from gdG at pH 7 and greater has required methods of optimization in order to achieve a detection limit of 0.05 micromol/mol of DNA. Nuclease P1 treatment enhances the detection of gdG adducts but does not increase the detection limit for OHEdG. For OHEdG, best results were achieved using fraction collection from HPLC (0.3 micromol/mol of DNA). Using radiochemical methods, both adducts could be detected either by HPLC or 2D TLC. NDELA, N-nitrosomorpholine (NMOR), N-nitrosomethyethanolamine (NMELA), and N-nitrosoethylethanolamine (NEELA) all produce both gdG and OHEdG adducts in rat liver DNA in vivo and are called bident carcinogens because fragments from both chains of the nitrosamine are incorporated into DNA. N-Nitroso-2-hydroxymorpholine (NHMOR), a metabolite of NDELA and NMOR, generates gdG in DNA in vitro and in vivo. gdG DNA adducts were found in the range 1.1-6.5 micromol/mol of DNA. OHEdG DNA adducts were produced from equimolar amounts of nitrosamines in rat liver in vivo over the range 4-25 micromol/mol of DNA and in the order NMELA > NEELA > NDELA > NMOR. Deuterated isotopomers of NDELA showed a marked isotope effect on DNA OHEdG adduct formation. alpha-Deuteration markedly decreased OHEdG adduct formation while beta-deuteration had the opposite effect. These data support the hypothesis that NDELA and related nitrosamines are activated by both enzyme mediated alpha-hydroxylation and beta-oxidation. The formation of OHEdG adducts from NDELA requires alpha-hydroxylation of the 2-hydroxyethyl chain, and formation of gdG necessitates a beta-oxidation as well. The bident nature of these carcinogens may explain why they are relatively potent carcinogens despite the fact that major proportions of doses are excreted unchanged.

Animals↗
PubMed1997

The source of urinary nitrosamines in patients with enterocystoplasties.

OBJECTIVE: To assess the factors influencing urinary nitrosamine production in patients with enterocystoplasties. PATIENTS, SUBJECTS AND METHODS: The study comprised 100 patients with an enterocystoplasty, 20 patients with interstitial cystitis, 30 with infective cystitis and 120 control subjects drawn from hospital staff and out-patients. Urinary nitrosamine levels were measured and the urine samples cultured for microorganisms. RESULTS: Nitrosamine levels were significantly higher only in patients with enterocystoplasties who also had higher urinary white cell counts or significant bacteriuria. CONCLUSION: Patients with an enterocystoplasty and significant bacteriuria are most at risk from potential nitrosamine-induced epithelial injury.

Bacteriuria↗
PubMedDate not supplied

Removal of nitrosamines from waste water by potassium ferrate oxidation.

Potassium ferrate (K2FeO4) is useful in the advanced treatment of waste water. Additional evidence of this capability is presented in this study. Potassium ferrate is a very strong oxidant and is highly soluble in water. The nitrosamine studied in this work was toxic and was a potent pancreatic tumorigen in laboratory animals. Nitrosamines, which are potent carcinogens, are widespread throughout the environment and can be eliminated from waste water effluent by the action of potassium ferrate. Potassium ferrate and the nitrosamine was placed in aqueous solution and allowed to react to completion. Analysis by photospectroscopy revealed that the nitrosamine was completely degraded. This result suggests that potassium ferrate is useful for decontamination of some waste water collections.

Iron↗
PubMedDate not supplied

Assay of N-nitrosamines in foodstuffs produced in the USSR by gas-liquid chromatography with a thermal energy analyser.

The content of volatile N-nitrosamines in over 4000 samples of domestic foodstuffs of plant and animal origin were studied. It was found that 88% of the samples studied contained N-nitrosamines, the greatest amounts being detected in some samples of malt and beer, fish products and some meat products. The impact of food processing technologies on the formation of N-nitrosamines is discussed. Possibilities of preventing the accumulation of N-nitrosamines during the process of food production are discussed.

Calorimetry↗
PubMed1987

Gas chromatographic/mass spectrometric analysis of extracts of workplace air samples for nitrosamines.

Three capillary gas chromatography/mass spectrometry (GC/MS) procedures were developed to confirm the presence of N-nitrosamines in workplace air sample extracts, which were previously analyzed by gas chromatography with a thermal energy analyzer. In the first procedure, high resolution ion monitoring of NO+ was used to confirm the presence of eight N-nitrosamines and to screen the samples for other N-nitroso compounds. In the second procedure, high resolution monitoring of parent ions was used for confirmation of specific N-nitrosamines; and in the third procedure, full-scan GC/MS was used for identification of compounds above the level of 2 ng per injection. Detection limits of the three procedures and retention time precision of both selected ion monitoring techniques are given. Typical examples in the use of these techniques for confirmation of N-nitrosamines in sample extracts also are described.

Air Pollutants, Occupational↗
PubMed1992

Increased 8-oxodeoxyguanosine levels in lung DNA of A/J mice and F344 rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone.

Evidence for the involvement of free radicals in nitrosamine carcinogenesis comes mainly from increased lipid peroxidation as a result of nitrosamine treatment. More direct evidence for nitrosamine-induced oxidative DNA damage has been lacking. In this study we examined the levels of 8-oxodeoxyguanosine or 8-hydroxydeoxyguanosine (8-OH-dG) in tissue DNA of mice and rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Multiple doses of NNK (0.25 or 0.50 mg/mouse, 3 times weekly for 3 weeks) administered by gavage resulted in a significant elevation of 8-OH-dG in lung DNA, from 2.1 to 3.8 adducts/10(5) dG for the lower dose or to 6.6 adducts/10(5) dG for the higher dose, 2 h after the last NNK administration. A single dose treatment of NNK by gavage (4 mg/mouse) also resulted in an increase of this lesion in the lung DNA, however, the increase was not statistically significant. In liver, however, the increase was only significant by multiple doses at the higher dose, from 2.3 to 3.4 adducts/10(5) dG. This lesion appeared to be repaired efficiently. At 4 and 24 h after NNK treatment, the 8-OH-dG levels declined to the basal levels in both liver and lung. A single dose of NNK (20 mg/rat) also caused a significant increase of 8-OH-dG from 3.0 to 5.1 adducts/10(5) dG in rat lung DNA. An increase of 8-OH-dG in liver DNA was also seen, however, it was not statistically significant. Unlike the liver and the lung, the 8-OH-dG levels in rat kidney, a non-target tissue, were inert to NNK treatment. These results provide for the first time direct evidence supporting the role of oxidative DNA damage in NNK lung tumorigenesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Evidence for endogenous formation of tobacco-specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite.

Carcinogenic tobacco-specific nitrosamines are present in tobacco products and are believed to play a significant role in human cancers associated with tobacco use. Additional amounts of tobacco-specific nitrosamines could be formed endogenously. We tested this hypothesis by treating rats with nicotine and sodium nitrite and analyzing their urine. Initially, we treated groups of rats with (S)-nicotine (60 micromol/kg) and NaNO2 (180 micromol/kg), (S)-nicotine alone, NaNO2 alone or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 12 nmol/kg) by gavage twice daily for 4 days. We collected urine and analyzed for two metabolites of NNK; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide. We did not detect these metabolites in the urine of rats treated with nicotine alone or nicotine plus NaNO2, indicating that endogenous conversion of nicotine to NNK did not occur. However, the urine did contain N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB) and N'-nitrosoanatabine (NAT). Analysis of the (S)-nicotine used in this experiment demonstrated that it contained trace amounts of nornicotine, anabasine and anatabine. In a second experiment, we used an identical protocol to compare the endogenous nitrosation of this (S)-nicotine with that of synthetic (R,S)-nicotine, which did not contain detectable amounts of nornicotine, anabasine or anatabine. NNN (0.53 x 10(-3)% of nicotine dose), NAB (0.68%) and NAT (2.1%) were detected in the urine of the rats treated with the (S)-nicotine and NaNO2. NNN (0.47 x 10(-3)% of dose), but not NAB or NAT, was present in the urine of the rats treated with synthetic (R,S)-nicotine and NaNO2. NNN probably formed via nitrosation of metabolically formed nornicotine. These results demonstrate for the first time that endogenous formation of tobacco-specific nitrosamines occurs in rats treated with tobacco alkaloids and NaNO2. The potential significance of the results with respect to nitrosamine formation in people who use tobacco products or nicotine replacement therapy is discussed.

Alkaloids↗
PubMed1987

Identification and analysis of a new tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol.

A new tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL) was isolated from snuff tobacco. Structural characterization of this N-nitrosamine was confirmed by mass spectral analysis. Five popular US brands of moist snuff and three popular US brands of dry snuff tobacco were analyzed for moisture, nicotine and tobacco-specific N-nitrosamines. The moisture content varied from 20 to 53% in moist snuff and from 4.7 to 5.6% in dry snuff. The nicotine levels in these samples varied from 0.6 to 3.2%. The newly identified iso-NNAL was present in concentrations ranging from 0.07 to 2.5 p.p.m. whereas other tobacco-specific N-nitrosamines, N-nitrosonornicotine, N-nitrosoanatabine, N-nitrosoanabasine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone were found to range from 0.1 to 178 p.p.m. Iso-NNAL was not detected in mainstream and sidestream smoke of cigarettes. Iso-NNAL is genotoxic in primary rat hepatocytes; its tumorigenic properties are currently being tested in mice and rats.

Carcinogens↗
PubMedDate not supplied

Volatile nitrosamine levels in rubber teats and pacifiers available in New Zealand.

Samples of rubber baby bottle teats and pacifiers available in New Zealand were analyzed for nitrosamines by HPLC-TEA. These products, which were manufactured in the USA, Singapore, West Germany, England, and Japan contained one to three nitrosamines. All but one product, which was made of synthetic polyisoprene rubber complied with the US Food and Drug Administration regulatory limit of 60 ng/g. The mean level of total nitrosamines in 11 of the 12 products was 34 ng/g with a range from 9-63 ng/g. The twelfth product recorded a level of 190 ng/g total nitrosamines.

Chromatography, High Pressure Liquid↗
PubMed1994

Comparison of co-cultivation of V79 cells with rat hepatocytes and rat H4IIE hepatoma cells for studying nitrosamine-induced hprt gene mutations.

The induction of mutations by nitrosamines in the hprt locus of V79 Chinese hamster cells was examined after metabolic activation in a co-cultivation system using either freshly isolated rat hepatocytes or H4IIE rat hepatoma cells and the results obtained were compared with systems which employ the rat liver microsomal fraction (S9-mix). This study was also designed as a first approach to investigating the induction of point mutations by tobacco-specific nitrosamines in mammalian cells in order to obtain information about the significance of these compounds in connection with the carcinogenicity of tobacco smoke. The mutagenicity of two tobacco-specific nitrosamines, 4-(methylnitroso)-1-(3-pyridol)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), were investigated and compared to two extensively investigated nitrosamines, i.e. dimethylnitrosamine (DMN) and diethylnitrosamine (DEN). DMN was activated to mutagenic species by primary hepatocytes at mumolar concentrations, i.e. 1/100 of the concentrations required for mutagenesis by DEN and NNK. NNN was not activated to mutagenic species by liver S9 or primary hepatocytes. The findings shown here on the mutagenicities of NNK and NNN with liver preparations are in agreement with their relative carcinogenic potencies. When the established liver cell line H4IIE was used for metabolic activation, DMN and was found to be mutagenic, whereas the results for NNN were borderline and for DEN and NNK were without effect. The fate of these compounds via different metabolic pathways is discussed in terms of systems for detection of mutagenic metabolites and type of mutation induced.

Animals↗
PubMed1975

Degradation of N-nitrosamines by intestinal bacteria.

A major proportion of bacterial types, common in the gastrointestinal tract of many animals and man, were active in degrading diphenylnitrosamine and dimethylnitrosamine, the former being degraded more rapidly than the latter. At low nitrosamine concentrations (is less than 0.05 micronmol/ml), approximately 55% of added diphenylnitrosamine, 30% of N-nitrosopyrrolidine, and 4% of dimethylnitrosamine were degraded. The route of nitrosamine metabolism by bacteria appears to be different from that proposed for breakdown by mammalian enzyme systems in that carbon dioxide and formate were not produced. In bacteria, the nitrosamines were converted to the parent amine and nitrite ion and, in addition, certain unidentified volatile metabolites were produced from dimethylnitrosamine by bacteria. The importance of bacteria in reducing the potential hazard to man of nitrosamines is discussed.

Animals↗
PubMed1971

A search for nitrosamines in East African spirit samples from areas of varying oesophageal cancer frequency.

Following the report of the presence of nitrosamine-like substances in samples of homemade spirit from Zambia, which had been obtained from an area where cancer of the oesophagus is common, samples of distilled alcoholic drinks were collected throughout western Kenya and southern Uganda from areas where the frequency of cancer of the oesophagus varies from very common to very rare. The 44 samples of spirit were screened by polarography and substances giving a similar response to nitrosamines were indicated at levels as high as 21 ppm. Subsequent analysis by gas chromatography for selected individual nitrosamines showed no evidence for the occurrence of methylethylnitrosamine (MEN), diethylnitrosamine (DEN), dipropylnitrosamine (DPN), ethylbutylnitrosamine (EBN), dibutylnitrosamine (DBN), nor of N nitrosopiperidine (N Pipn), but traces of compounds having a similar retention time as dimethylnitrosamine (DMN) were observed. However, subsequent examination by mass spectrometry showed no evidence of dimethylnitrosamine. There was no apparent association between the levels of unknown constituents indicated by polarography and gas chromatography, nor between either of these levels and the frequency of cancer of the oesophagus. The results by gas chromatography and mass spectrometry confirm that polarography is too unspecific to be a useful indicator of nitrosamines.

Alcoholic Beverages↗
PubMed2005

Tobacco-specific nitrosamines and their pyridine-N-glucuronides in the urine of smokers and smokeless tobacco users.

Tobacco-specific nitrosamines are believed to play a significant role as causes of cancer in people who use tobacco products. Whereas the uptake of one tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, has been shown by analysis of its metabolites in urine, there are no published studies on urinary levels of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), and N'-nitrosoanabasine (NAB) or their metabolites in human urine. We developed a method for quantitation of NNN, NAT, NAB, and their pyridine-N-glucuronides NNN-N-Gluc, NAT-N-Gluc, and NAB-N-Gluc in human urine. Total NNN (NNN plus NNN-N-Gluc) was assayed using 5-methyl-N'-nitrosonornicotine as internal standard. Urine was treated with beta-glucuronidase. Following solvent partitioning and solid-phase extraction, total NNN was determined using gas chromatography with nitrosamine-selective detection. Total NAT and total NAB were quantified in the same samples. Separate quantitation of NNN and NNN-N-Gluc was accomplished by extraction of the urine with ethyl acetate before beta-glucuronidase hydrolysis; NNN was analyzed in the ethyl acetate extract, and after enzyme treatment, NNN released from NNN-N-Gluc was quantified in the extracted urine. Separate analyses of NAT, NAT-N-Gluc, NAB, and NAB-N-Gluc proceeded similarly. Analyte identities were confirmed by gas chromatography-tandem mass spectrometry. Mean levels of total NNN, NAT, and NAB in the urine of 14 smokers were (pmol/mg creatinine) 0.18 +/- 0.22, 0.19 +/- 0.20, and 0.040 +/- 0.039, respectively, whereas the corresponding amounts in the urine of 11 smokeless tobacco users were 0.64 +/- 0.44, 1.43 +/- 1.10, and 0.23 +/- 0.19, respectively. Pyridine-N-glucuronides accounted for 59% to 90% of total NNN, NAT, and NAB. The results of this study show the presence of NNN, NAT, NAB, and their pyridine-N-glucuronides in human urine and provide a quantitative method for application in mechanistic and epidemiologic studies of the role of tobacco-specific nitrosamines in human cancer.

Animals↗
PubMed2006

Genes involved in DNA repair and nitrosamine metabolism and those located on chromosome 14q32 are dysregulated in nasopharyngeal carcinoma.

Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6% of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1. Differentially expressed probe sets within the nitrosamine metabolism pathway were consistently underexpressed (100%), with strong effects observed for NQ01, CYP2B6, and CYP2E1. No significant evidence of increases in rate of differential expression was seen within the immune/inflammatory pathway. A significant elevation in rate of differential expression was noted for chromosome 4p15.1-4q12 (13.0%; P = 0.04); both overexpression and underexpression were evident (38% and 62%, respectively). An elevation in the rate of differential expression on chromosome 14q32 was observed (11.3%; P = 0.06) with a consistent pattern of gene underexpression (100%; P < 0.0001). These effects were similar when excluding late-stage tumors. Our results suggest that nitrosamine activation and DNA repair are important in NPC. The consistent down-regulation of expression on chromosome 14q32 suggests loss of heterozygosity in this region.

Biopsy↗
PubMed1992

Low susceptibility of nude mice to induction of invasive urinary bladder cancers by N-ethyl-N-(4-hydroxybutyl)nitrosamine.

A time- and dose-dependent study of N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) bladder carcinogenesis was performed in nude mice maintained on tap water containing 0.025% EHBN for 4, 12, and 20 weeks ad libitum. A total of 13 invasive tumors, comprising 11 transitional cell carcinomas (TCCs) (84.6%) and 2 squamous cell carcinomas (SCCs) (15.4%), were found. Compared with previous results for B6C3F1 mice exposed to the same EHBN insult, the numbers of invasive carcinomas induced in nude mice, and especially of SCCs, were low. In order to ascertain whether this difference in cancer incidence between nude and B6C3F1 mice was due to variation in urinary excretion, the metabolism of EHBN was also investigated and compared with that of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Respective total urinary excretions over 48 hr of N-ethyl-N-(3-carboxypropyl)nitrosamine (ECPN) or N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), the ultimate carcinogenic species of EHBN or BBN, were 822.4 +/- 41.4 micrograms and 530.4 +/- 81.0 micrograms, respectively, in nude mice, and 800.6 +/- 83.7 micrograms and 407.8 +/- 69.7 micrograms, respectively, in B6C3F1 mice. In conclusion, although it is apparent that nude mice have a low susceptibility to EHBN induction of urinary bladder cancer, this does not appear to be dependent on reduced metabolism to the active form.

Animals↗
PubMed2006

De minimus non curat lex--virtual thresholds for cancer initiation by tobacco specific nitrosamines--prospects for harm reduction by smokeless tobacco.

Whereas the impact of tobacco specific nitrosamines in smokers is obscured by the presence of numerous other carcinogens and promoters, for smokeless tobacco virtually all the carcinogenic potential is associated with 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). In some countries exposure to smokeless tobacco with extremely high nitrosamine concentrations have been found to induce cancers in the head-neck region, whereas three recent large epidemiological studies failed to detect any such risk with respect to Swedish low-nitrosamine snuff. This review deals with quantitative aspects of DNA adduct formation from NNN and NNK in relation to the background levels ubiquitously found in healthy humans without known exposures to either tobacco or alkylating agents. The lack of significant increases of pro-mutagenic O6-methylations and DNA pyridyloxobutylations seen in smokers, as well as the negative outcome of the Swedish epidemiological studies, can be expected on basis of extrapolation of the dose response relationships found in rodents to actual exposures to NNK and NNN in Swedish snuff or from smoking. Sweden has the lowest prevalence of male smokers and smoking related diseases in the Western World, which has been ascribed to the fact that more than 20% of the grown up male population uses snuff. Smokeless tobacco represents an inexpensive and effective alternative to nicotine delivering products like nicotine patch, spray or gum. Considering that all other tobacco products are freely marketed, the ban on low-nitrosamine snuff in all countries in EU except Sweden is difficult to defend on either medical or ethical grounds.

Head and Neck Neoplasms↗
PubMed1982

Nitrite and nitrosamines in gastric juice: risk factors for gastric cancer?

Nitrite and nitrosamine concentrations have been measured in 108 patients undergoing gastroscopy as a part of routine gastrointestinal investigations. The nitrite and nitrosamine values of 20 patients with duodenal and 11 patients with benign gastric ulcer were within the range of the values of 26 normal subjects. The nitrite and nitrosamine concentrations in 32 patients with inflammatory changes of the gastric mucosa were slightly higher than normal values and correlated with the progressive degrees of the severity. In 19 patients with atrophic gastritis the concentrations of nitrite and nitrosamines were significantly elevated in comparison with those of all other groups. Our data suggest a relationship between the constant exposure of an already damaged gastric mucosa to N-nitroso compounds and the known high incidence of gastric cancer in atrophic gastritis.

Atrophy↗
PubMedDate not supplied

Metabolic fate of N-n-butyl-N-(4-hydroxybutyl)-nitrosamine and its analogues. Selective induction of urinary bladder tumours in the rat.

1. The metabolic fates of N-n-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and N,N-di-n-butylnitrosamine (DBN) were investigated in the rat and other animal species, to elucidate a possible relationship between metabolism and organotropic carcinogenicity to the urinary bladder of these N-nitrosamines. 2. The principal urinary metabolite of BBN as well as of DBN in the rat was N-n-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), which was demonstrated to be the active form of these compounds as bladder carcinogen. The species difference in response to BBN or DBN is discussed on the basis of the urinary excretion rate of BCPN. 3. Metabolism in vivo and carcinogenicity of a number of BBN analogues were investigated in the rat and a general scheme for biotransformation of N-alkyl-N-(omega-hydroxyalkyl)nitrosamines is given. 4. A possible correlation of structure and metabolism with organotropic carcinogenicity of BBN analogues is discussed, with special reference to selective induction of bladder tumours. 5. A clear demonstration of overlapping carcinogenic and mutagenic activities is presented for BBN, DBN and related compounds.

Animals↗