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At least 613 records · Page 34Linked to original sources
PubMed1984

N-nitrosamine formation by intestinal bacteria.

N-Nitrosamine formation by various intestinal bacteria was investigated. N-Nitroso-dimethylamine (NDMA) formation by viable resting cells of Escherichia coli A10 was proportional to the incubation time and the enzyme concentration, while boiled cells were incapable of nitrosation. The enzyme was optimal at pH 7.5 and showed about the same specificities for dimethylamine, diethylamine, dibutylamine, di-isobutylamine, piperidine and pyrrolidine, but high specificity for morpholine. The intestinal bacteria harbouring nitrosating enzyme were mainly aerobic, i.e., Escherichia coli, Proteus morganii, Klebsiella pneumonia and Pseudomonas aeruginosa. Only one of the 32 anaerobic intestinal bacterial species, i.e., Peptococcus asaccharolyticus, was positive. The enzyme activities of these nitrosating bacteria covered a range of 0.06-0.90 nmol NDMA formed per hour per mg protein. These results support the theory of enzymatic catalysis of N-nitrosamine formation by microorganisms and suggest the possibility of endogenous nitrosation in the digestive tract.

Dimethylnitrosamine↗
PubMed1983

High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting.

In order to elucidate the enzymic basis of nitrosamine metabolism, the in vitro metabolism of nitrosamines by rat liver microsomes and the effects of fasting on the microsomal enzymes have been studied. Fasting for 1 to 3 days causes a 2- to 3-fold enhancement of the reduced nicotinamide adenine dinucleotide phosphate-dependent nitrosodimethylamine demethylase (NDMAD) activity. The cytochrome P-450 content and the activities of reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase and benzphetamine demethylase, however, are only modestly increased. Gel electrophoretic analysis reveals the induction of a 50,000-dalton protein band during fasting. The induction of this protein band as well as the enhancement of NDMAD activity are inhibited by CoCl2 and inhibitors of protein and RNA biosynthesis. The involvement of cytochrome P-450 in the NDMAD is supported by the fact that microsomal reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase is required for the demethylase activity. Kinetic analysis indicates that a low-Km form of NDMAD (apparent Km, 0.07 mM) is markedly induced by fasting. With microsomes of control rats, there are at least three apparent Km values (0.07, 0.38, and 38.6 mM) for NDMAD; but with microsomes of fasting rats, the low-Km (0.07 mM) form is predominant. These results suggest that rat liver microsomes contain a cytochrome P-450 isozyme which has high affinity for nitrosodimethylamine, and this isozyme is induced by fasting. In addition to nitrosodimethylamine, the oxidative demethylation of N-nitroso-N-methylethylamine, N-nitroso-N-methylbutylamine, N-nitroso-N-methylaniline, and N-nitroso-N-methylbenzylamine is also enhanced by fasting. The extent of enhancement and substrate dependency of these reactions, however, is different from that of NDMAD.

Animals↗
PubMed1984

Nitrosamine-induced colonic carcinogenesis in rats after jejuno-ileal bypass.

In the present experiment the influence of the exclusion of approximately 50% of the small bowel on chemically induced colonic carcinogenesis was investigated. For tumor induction the nitrosamine derivative acetoxymethyl-methyl-nitrosamine was applied intrarectally weekly for 8 weeks in 72 male Sprague-Dawley rats. The animals were randomized into 3 groups; in one group, small bowel exclusion was performed before the tumor induction, in the other group after the induction period. The control group received explorative laparotomy only. Tumor development was examined endoscopically and at autopsy 40 weeks after the start of the experiment. No differences occurred regarding number, shape and size of tumors in the operated versus the control group.

Animals↗
PubMed1999

Mutations of the p53 gene in oral squamous-cell carcinomas from Sudanese dippers of nitrosamine-rich toombak and non-snuff-dippers from the Sudan and Scandinavia.

Using PCR-SSCP/DNA sequencing methods, we analyzed 14 oral squamous-cell carcinomas (OSCCs) and 8 pre-malignant oral lesions from different Sudanese patients for prevalence of mutations in exons 5 to 9 of the p53 gene in relation to toombak-dipping status. OSCCs (14 from Sudan, 28 from Scandinavia), and 3 pre-malignant oral lesions from Sudanese non-dippers were used as controls. A statistically significant increased incidence in mutations of the p53 gene was found in OSCCs from toombak dippers (93%; 13/14), as compared with those from non-dippers in Sudan (57%; 8/14) and in Scandinavia (61%; 17/28) respectively. In OSCCs from dippers, mutations were found in exons 5 to 9, while in those from non-dippers they were found in exons 5, 7, 8, 9, and no mutations were found in exon 8 in any of the OSCCs from Sudan. Certain types of mutations, however, were similar with respect to exposure to toombak. OSCCs from dippers showed 15 transversions, 9 transitions, 3 insertions and one deletion, compared with 7 transversions, 2 transitions and one deletion found in OSCCs from Sudanese non-dippers, and 9 transversions, 17 transitions and 2 insertions found in those from non-dippers in Scandinavia. No mutations were found in any of the non-malignant oral lesions in relation to dipping or non-dipping status. These findings suggest that (i) the use of toombak plays a significant role in induction of increased p53 gene mutations, (ii) mutations observed were similar to those induced by tobacco-specific N-nitrosamines (TSNAs) in experimental animal models and those already reported in toombak dippers, (iii) types of mutations associated with TSNAs were similar in the exposed and the control groups, (iv) a novel mutation in exon 6 was found in the OSCCs from toombak dippers, (v) the p53 exons 5 (codon 130), 6 (codons 190, 216) and 7 (codons 229, 249, 252) mutations are probable hot spots for toombak-related OSCCs. Further studies are necessary to validate the increased incidence and exon locations of the p53-gene mutations as a biomarker of malignant transformation in populations in which the oral use of tobacco is habitual.

Base Sequence↗
PubMed1984

Effects of intravesical instillation of antitumor chemotherapeutic agents on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effects of intravesical instillation of Adriamycin (doxorubicin) (ADR), and mitomycin C (MMC), as inhibitors of development of rat bladder tumors, were examined in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Intravesical instillation of ADR or MMC once a week for 12 weeks into rats pretreated with BBN for 4 weeks markedly enhanced development of bladder tumors. That is, one week after the end of intravesical instillation of these compounds the incidence of papillary or nodular hyperplasias, namely preneoplastic lesions, was significantly increased, and at the end of the experiment the incidence of not only papillary or nodular hyperplasias but also of papillomas and cancers was significantly increased. These results indicate that the intravesical instillation of ADR or MMC promotes two-stage bladder carcinogenesis in rats.

Animals↗
PubMed2006

Determination of tobacco-specific N-nitrosamines in rabbit serum by capillary zone electrophoresis and capillary electrophoresis-electrospray ionization-mass spectrometry with solid-phase extraction.

In this paper, we propose a new strategy for separation and determination of tobacco-specific N-nitrosamines (TSNAs), a group of strong carcinogens found only in tobacco products, by using CZE and CE-MS associated with SPE. Six TSNAs: N'-nitrosonornicotine, N'-nitrosoanatabine, N'-nitrosoanabasine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol were simultaneously separated by either of two CZE methods, one of which worked with ammonium formate buffer (pH 2.5) and another with citrate buffer (pH 2.4), as well as a CE-MS method. The CZE conditions including pH and concentration of running buffer, capillary length, applied voltage, and capillary temperature were systematically optimized. For CE-MS method, an optimized sheath liquid consisted of methanol-water was used at a flow rate of 10 muL/min. With SPE procedure, our proposed CE-MS method was successfully applied to determine TSNAs after 15 min metabolism in rabbits. A comparison study between CZE and CE-MS methods for quantitative purposes was carried out, showing that both methods provided similar separation efficiency, selectivity, repeatability, linearity, and recovery. However, CE-MS method was better suited for the analysis of TSNAs in complicated biological samples for its sensitivity and extra information on molecular structure. Having good accordance with our previous work by using LC-MS, the new CE-MS method is expected to be an alternative to the LC-MS method and applied to study the metabolism of TSNAs.

Animals↗
PubMed2004

Effect of XPD/ERCC2 polymorphisms on chromosome aberration frequencies in smokers and on sensitivity to the mutagenic tobacco-specific nitrosamine NNK.

Polymorphisms in DNA-repair genes could contribute to the interindividual differences in cancer susceptibility in smokers. By reducing DNA-repair capacity, these polymorphisms may influence the net level of smoking-induced genetic damage significantly, a critical step in the cascade of events leading to cancer. In this biomonitoring study, we examined the relationship between polymorphisms in the DNA-repair gene XPD/ERCC2 and genetic damage. We tested the hypothesis that coding polymorphisms in XPD/ERCC2 limit DNA-repair efficiency in humans leading to increased frequencies of chromosome aberration (CA) in their lymphocytes. We also used the mutagen-sensitivity assay, with the tobacco-specific nitrosamine NNK as a model mutagen, to determine whether lymphocytes from individuals with the variant XPD alleles are more sensitive to this tobacco-specific carcinogen. We calculated odds ratios (ORs) as estimates of relative risk of increased frequencies of CA associated with two XPD polymorphisms (Asp312Asn in exon 10 and Lys751Gln in exon 23). We observed a 2.57-fold (95% confidence limit [CL] = 0.88-7.50; P = 0.10) increase in risk of elevated in vivo frequencies of CA associated with the variant 312Asn allele in the total population. The relative risk was more pronounced in smokers (OR = 4.67; 95% CL = 1.04-20.90; P = 0.04) and in all subjects >48 years old (OR = 7.33; 95% CL = 1.53-35.10; P = 0.01). Similarly, elevations in NNK-induced aberrations were significantly associated with the 312Asn allele (OR = 3.69; 95% CL = 1.29-10.56; P = 0.02). The risk was higher in smokers (OR = 4.62; 95% CL = 1.14-18.70; P = 0.04) and in subjects >48 years old (OR = 5.76; 95% CL = 1.30-25.41; P = 0.03). No significant effect was observed with the 715Gln variant allele in relation to either in vivo or NNK-induced CA. These data suggest that the Asp312Asn polymorphism may alter the phenotype of the XPD protein, resulting in reduced DNA-repair capacity.

Adult↗
PubMed2005

Gender differences in genetic damage induced by the tobacco-specific nitrosamine NNK and the influence of the Thr241Met polymorphism in the XRCC3 gene.

The rapid increase in adenocarcinoma of the lung and mortality amongst women strongly suggests that gender differences exist in sensitivity to certain tobacco carcinogens. In the current study, we performed the mutagen-sensitivity assay, with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to test the hypothesis that women are more sensitive to the genotoxic effects of NNK than men. Chromosome aberration (CA) frequencies in peripheral blood lymphocytes (PBLs) from 99 patients were evaluated before and after in vitro exposure to NNK. Because the Thr241Met polymorphism in the DNA-repair gene XRCC3 is associated with increased risk of tobacco-related cancers, especially among women, we also tested the hypothesis that individuals who inherit the homozygous variant 241Met allele are more sensitive to the genotoxic effects of NNK. CA frequency was significantly higher 1 hr after NNK treatment in women, compared with men (P = 0.02). When smoking and gender were considered together, a significant interaction was observed. PBLs from female smokers had significantly higher frequencies of NNK-induced CA, compared with female nonsmokers 1 hr after treatment (P = 0.02). We observed no overall effect of the Thr241Met polymorphism on NNK-induced CA in men, women, smokers, or nonsmokers. Overall, our data indicate that women are more sensitive to the genotoxic effects of NNK than men. Because in past years smoking among women has increased, and in view of the close correlation between NNK exposure and adenocarcinoma of the lung, our data provide a plausible explanation for the recent increase in the incidence of this cancer among women.

Adult↗
PubMed2005

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenocarcinomas in Syrian golden hamsters contain beta 2-adrenergic receptor single-nucleotide polymorphisms.

Cigarette smoking contributes to the development of lung cancer throughout the world, with cases of pulmonary adenocarcinoma (PAC) the most numerous. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is formed from nicotine, has been demonstrated to cause mutations in genes that affect cell regulation and proliferation. Moreover, NNK has been shown to interact directly with and stimulate beta adrenergic receptor (ADRB) signal transduction pathways. Our goal was to determine whether single-nucleotide polymorphisms (SNPs) in the Adrb2 from PAC tumors were induced in golden hamsters by the injection of NNK. Here we report the cloning and sequencing of Adrb2 clones from either dissected lung tumors from NNK-injected animals or whole-lung tissue from water-injected controls. Both sets of animals contained SNPs; however, we found significantly more SNPs in the Adrb2 from NNK-injected animals than in the controls. The majority of these SNPs were novel, nonsynonymous mutations found in regions of the Adrb2 known to be involved in ligand binding, G-protein coupling, and desensitization/down-regulation. Our data verified the mutagenic effects of NNK as well as demonstrated that this animal model provides an outstanding way of identifying mutations not only in the Adrb2, but also in other genes that may play essential roles in the regulation and growth of pulmonary adenocarcinomas.

Adenocarcinoma↗
PubMed1992

Localized formation of micronuclei in the oral mucosa and tobacco-specific nitrosamines in the saliva of "reverse" smokers, Khaini-tobacco chewers and gudakhu users.

"Reverse"-cigar smokers (who hold the burning end of cigars within the mouth), dippers (who place a mixture of Khaini-tobacco and slaked lime into the lower gingival groove) and users of tobacco-containing toothpaste (gudakhu) in Orissa, India, were examined for precancerous oral lesions, the frequency of micronucleated cells at 3 different intra-oral sites, and levels of tobacco-specific nitrosamines (TSNA) in the saliva. Among reverse-cigar smokers, a high incidence of leukokeratosis nicotina palati, an elevated frequency of micronucleated cells in the palate (2.5% as compared to 0.6% in non-smokers and non-chewers of tobacco) and tongue (2.1%) from which carcinomas preferentially develop, and up to 5890 ppb nitrosonornicotine and up to 1880 ppb N-nitrosoanatabine in the saliva were found. Among Khaini-tobacco chewers, the frequency of micronucleated cells was elevated to 2.1% in the gingival groove, and up to 1580 ng N-nitrosonornicotine, 690 ng N-nitrosoanatabine, 90 ng N-nitrosoanabasine, and 180 ng 4-(methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone) per ml of saliva were observed. The localized elevation of the frequency of micronuclei and cancer development is probably due to a synergistic effect of hyperthermia and tobacco-related carcinogens among reverse-cigar smokers, and to the close, prolonged contact between the mucosa and tobacco among Khaini-tobacco/slaked lime dippers. Neither pre-cancerous lesions nor an elevated frequency of micronuclei were seen in the oral mucosa of users of gudakhu, a tobacco-containing toothpaste, which may be due to the low amount of TSNA released from the gudakhu and the short exposure time, which is restricted to the period of tooth brushing.

Adult↗
PubMed2003

Liquid chromatographic/tandem mass spectrometric method for the determination of the tobacco-specific nitrosamine metabolite NNAL in smokers' urine.

A specific and rapid liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method was developed and validated for NNAL, a metabolite of the tobacco-specific nitrosamine metabolite NNK. The metabolite was detected in smokers' urine with a limit of quantitation (LOQ) of 20 pg ml(-1) and a linear range up to 1000 pg ml(-1). The method features a single solid-phase extraction step and MS/MS monitoring following electrospray ionization. Fragmentation pathways for the protonated molecular ion are proposed. The sample preparation is simpler than that for gas chromatographic methods reported in the literature and maintains sensitivity adequate for determining NNAL in smokers' urine. By using enzyme hydrolysis to determine total NNAL in urine, the amount of NNAL-glucuronide was calculated. A standard pooled smokers' urine sample used for development gave values of 176 +/- 8 pg ml(-1) free NNAL and 675 +/- 26 pg ml(-1) total NNAL following enzyme hydrolysis. The method was applied to a group of seven smokers; the free NNAL level for the group was 101-256 pg ml(-1) with NNAL-glucuronides at 247-566 pg ml(-1). The ratio of conjugated to free NNAL was in the range 0.98-2.95. The variability in total daily amount of NNAL excreted (ng per 24 h) had RSDs of 6-21% for free NNAL, 7-22% for conjugated NNAL and 6-20% for total NNAL excreted. When normalized to the number of cigarettes smoked, the amounts of NNAL excreted per cigarette smoked were in the range of amounts of NNK yields reported for cigarettes in the literature.

Adult↗
PubMed1983

Streptozotocin prevents development of nitrosamine-induced pancreatic cancer in the Syrian hamster.

Administration of the nitrosamine carcinogen N-nitroso-bis (2-oxopropyl) amine (BOP) by subcutaneous injection (5 mg/kg/week) led to the development of invasive pancreatic ductular adenocarcinoma in 100% of normal Syrian hamsters by 24 weeks. Pretreatment of a second group of hamsters with the beta-cell toxin streptozotocin in a diabetogenic dose (50 mg/kg i.p. X 3) completely prevented the development of pancreatic cancer when BOP was subsequently administered. The mechanism of blockade by streptozotocin is unknown. This study suggests the potential importance of the endocrine pancreas in exocrine pancreatic carcinogenesis.

Adenocarcinoma↗
PubMed1977

Ultrastructural alterations of APUD cells during nitrosamine-induced lung carcinogenesis.

Groups of Syrian golden hamsters were treated twice weekly for life with 1/10 LD50 DEN, or once weekly for life with 1/5 LD50 DBN. The sequential alterations in the ultrastructure of Apud cells in their bronchial lining were examined. Both carcinogens caused pronounced proliferation of this cell type during the initial treatment period. Thereafter, the formation of increasing numbers of filamentous bundles was observed in the cytoplasm of the Apud cells, whereas their neurosecretory granules decreased in number. The present findings suggest that after an initial phase of proliferation, the Apud cells undergo squamous metaplasia when treated with the two nitrosamines investigated.

Animals↗
PubMed1979

Oesophageal neoplasia in male Wistar rats due to parenteral di(2-hydroxypropyl)-Nitrosamine (DHPN): a combined histopathological, histochemical and electron microscopic study.

Intraperitoneal di(2-hydroxypropyl)-Nitrosamine (DHPN) caused a high incidence of oesophageal squamous carcinoma in male Wistar rats, particularly in rats killed 11 or more months after the start of injections. No control rats (injected intraperitoneally with saline) developed an oesophageal neoplasms. Histopathologically, the tumours were moderately well differentiated. Histochemical studies showed minor increases in mucin staining and mast cell population and a marked increase in bacteria in tumour-bearing oesophaguses. Electron microscopy showed the tumours to be similar to, but to differ in some respects from squamous carcinomas at other sites in humans. The possible implications of this work for human disease are twofold. It could provide a model for further study of aspects of oesophageal carcinoma and it serves to remind us that all potential oesophageal carcinogens need not act during swallowing.

Animals↗
PubMed2004

Development, validation and transfer of a hydrophilic interaction liquid chromatography/tandem mass spectrometric method for the analysis of the tobacco-specific nitrosamine metabolite NNAL in human plasma at low picogram per milliliter concentrations.

A highly sensitive bioanalytical method based on a simple liquid/liquid extraction and hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC/MS/MS) analysis has been developed, validated and transferred for the determination of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a tobacco-specific nitrosamine metabolite. Deuterated NNAL (NNAL-d(4)) was synthesized and used as the internal standard. This method can be used for the analysis of free and total NNAL (free NNAL plus NNAL-gluc) in K(3)-EDTA human plasma. Free NNAL and NNAL-d(4) are extracted from human plasma by liquid/liquid extraction. To analyze for total NNAL and the internal standard, a separate aliquot of the K(3)-EDTA human plasma is treated with beta-glucuronidase to deconjugate the NNAL-gluc; the total NNAL and internal standard are then extracted using liquid/liquid extraction. After drying down under nitrogen, the residue is reconstituted with acetonitrile and analyzed using positive ion electrospray and HILIC/MS/MS at a flow rate of 1.0 mL/min. The chromatographic run time is 1.0 min per injection, with retention time for both NNAL and NNAL-d(4) of 0.75 min with a capacity factor (k') of 2. The standard curve range for this assay is from 5.00-1000 pg/mL for both free and total NNAL, using a total plasma sample volume of 1.0 mL. The interday precision and accuracy of the quality control (QC) samples demonstrated <7.6% relative standard deviation (RSD) and <3.3% relative error (RE) for free NNAL. For total NNAL, the interday precision and accuracy of the QC samples demonstrated <11.7% RSD and <2.8% RE. Optimization of enzyme hydrolysis of NNAL-gluc is discussed in detail. The overall recoveries for free and total NNAL and IS were 68.2 and 71.5% (free) and 70.7 and 65.5% (total). No adverse matrix effects were noticed for this assay.

Chromatography, High Pressure Liquid↗
PubMed1979

Influence of drugs on activation and inactivation of hepatocarcinogenic nitrosamines.

The alkylation of liver macromolecules following in vivo administration of dimethylnitrosamine (DMN) was diminished after phenobarbital or 3-methylcholanthrene induction of the microsomal monooxygenase system, but increased after SKF 525 A pretreatment. Determination of CH2O and CH3+formation in microsomal incubation systems revealed the same results for low DMN concentrations. An interpretation is given on the basis of spectrophotometric data and electron spinresonance (EPR) measurements, by proposing that metabolic inactivation of nitrosamines is catalysed by a reduction process in which cyt. P 450 seems to be involved.

Alkylation↗