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At least 721 records · Page 40Linked to original sources
PubMed1979

Carcinogenic effect of N-bis(2-hydroxypropyl)nitrosamine by a single administration in rats.

The carcinogenic effect of a single intraperitoneal injection of N-bis)2-hydroxypropyl)nitrosamine (BHP) was studied in male Wistar rats. Lung tumors (adenomas and adenocarcinomas) had the highest incidence (100%). Fewer neoplasms were induced in the thyroid (adenomas and adenocarcinomas, 36%), kidney (renal cell carcinomas, 8%), and the sigmoid colon (adenomas and adenocarcinomas, 9%). No pancreatic neoplasms were found.

Adenocarcinoma↗
PubMed1979

Intranuclear rodlets in undifferentiated carcinomas of salivary glands in strain A mice in a study involving a tobacco specific nitrosamine, N-nitrosonornicotine.

Undifferentiated carcinomas of the salivary glands were found in 2 of 44 (4.5%) strain A mice injected intraperitoneally with a tobacco specific nitrosamine, N-nitrosonornicotine (NNN). The presence of intranuclear rodlets (INR) in the salivary carcinomas provided the first demonstration of such structures in a non-neuronal tumor in mice. Two types of rodlets were exhibited; one was composed of fibrillar filaments arranged in bundles, and the other was much thicker, branching in form. These INR appeared to be closely associated with nuclear chromatin or nucleoli.

Animals↗
PubMed1984

Enhancement of N-bis(2-hydroxypropyl)nitrosamine-initiated lung tumor development in rats by bleomycin and N-methyl-N-nitrosourethane.

Potential modification of N-bis(2-hydroxypropyl)nitrosamine (DHPN)-induced lung carcinogenesis by bleomycin and N-methyl-N-nitrosourethane (MNUT) was investigated in male F344 rats. Rats were given 0.2% DHPN for 1 week followed by a weekly i.p. injection of either bleomycin at 2.0 mg/kg body wt or of MNUT at a dose of 1.0 mg/kg body wt for 35 weeks. Animals given DHPN followed by solvent administration alone, either saline or 0.02% ethanol and animals given bleomycin or MNUT without DHPN pretreatment were served as controls. Bleomycin treatment increased the incidence of cancer, whereas hyperplasia, adenoma and cancer of the lung were all significantly elevated after MNUT administration. MNUT alone induced low incidences of lung tumors. Bleomycin also increased the incidence of papillary or nodular hyperplasia of the urinary bladder while it inhibited the development of thyroid tumors. MNUT, however, did not affect tumor development in other organs.

Adenocarcinoma↗
PubMed1997

Oxidative DNA damage in tissues of pregnant female mice and fetuses caused by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induces the promutagenic oxidative-damage DNA lesion, 8-oxo-2'-deoxyguanosine (8-oxo-dG), in adult animals. To investigate whether this alteration occurs in DNA after transplacental exposure, pregnant Swiss mice were administered single or multiple doses of NNK. The 8-oxo-dG was quantified in placenta, and maternal and fetal tissues. In maternal lungs, single and multiple doses of NNK significantly increased levels of 8-oxo-dG by 23% and 32%, respectively. In maternal liver, a significant 38% increase was observed after multiple dose treatment. In the fetuses, a significant 45% increase in 8-oxo-dG levels was observed in liver after multiple doses of NNK. This is the first demonstration of oxidative DNA damage after transplacental exposure to NNK, and supports the concept of maternal smoking as a contributor to the development of childhood cancer.

Animals↗
PubMed1998

Effects of pycnogenol on the microsomal metabolism of the tobacco-specific nitrosamine NNK as a function of age.

NNK is a potent environmental carcinogen to which smokers and non-smokers are exposed. The response to NNK can be altered by various factors including nutrition. In this study, we examined the effects of pycnogenol on the in vitro metabolism of the tobacco-specific nitrosamine NNK by liver and lung microsomes from 6- and 20-month-old male F344 rats. The major NNK metabolic pathway in liver microsomes was carbonyl reduction, while alpha-hydroxylation was the major pathway in lung microsomes irrespective of age. Pycnogenol (40 and 120 microg/ml) exhibited a statistically significant inhibition of carbonyl reduction and alpha-hydroxylation pathways in liver microsomes from both age groups and in addition to these pathways, pycnogenol inhibited the N-oxidation pathway in lung microsomes. The liver and lung microsomes from 20-month-old rats were less active than from 6-month-old rats although the difference was not statistically significant.

Aging↗
PubMed1999

Tumor-promoting activity of 2,6-dimethylaniline in a two-stage nasal carcinogenesis model in N-bis(2-hydroxypropyl)nitrosamine-treated rats.

The potential promotion activity on nasal carcinogenesis of 2,6-dimethylaniline (DMA), an alpha2-adrenergic agonist metabolite of xylazine which is used for food-producing animals as a sedative agent, was examined. Male F344 rats received diet containing 0 or 3000 ppm DMA for 52 weeks after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Histopathological assessment showed the incidence of carcinomas in the DHPN+DMA group (33%) to be significantly elevated as compared with that for the DHPN-alone group (5%). Incidences and/or multiplicity of epithelial hyperplasias and dysplastic foci were also increased in the DHPN+DMA group. These lesions were exclusively observed in the olfactory mucosa. The lowest plasma levels of DMA in tumor- and dysplastic foci-bearing rats were 0.05 and 0.20 microg/ml, respectively. These results indicate that DHPN acts as an appropriate initiator for nasal carcinogenesis and that DMA exerts a tumor-promoting effect on the olfactory mucosa in the rat nasal cavity.

Adenoma↗
PubMed1986

Analysis of human blood for volatile N-nitrosamines by gas chromatography-chemiluminescence detection.

A method was developed to separate and measure trace levels of volatile N-nitrosamines (NAs) in human blood that either eliminated or accounted for in vitro artifactual formation of N-nitrosodimethylamine (NDMA) through the use of water blanks, added inhibitor (ascorbic acid) and added morpholine. The absolute minimum detectable limit was 8 pg; minimum level of reliable measurement was 0.05 microgram/kg for a 20-g blood specimen. Recovery of NDMA from blood was 93 +/- 5%. Coefficient of variation was 25%. Bloods from 242 people were analyzed for volatile NAs. NDMA was the only NA found. Positive specimens were presumptively confirmed by their non-detection after ultraviolet photolysis and/or mass spectrometry. This paper presents additional evidence that in vivo NA formation occurs.

Adult↗
PubMed2002

Automated in-tube solid-phase microextraction coupled with HPLC for the determination of N-nitrosamines in cell cultures.

An automated in-tube solid-phase microextraction (SPME) HPLC analysis method for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and several metabolites has been developed. NNK is one of the tobacco-specific N-nitrosamines (TSNA), which has been linked to cancers associated with the use of or exposure to tobacco products. In-tube SPME is an on-line extraction technique in which analytes are extracted and concentrated from the sample directly into a coated capillary by repeated draw/eject steps. In this study, a tailor-made polypyrrole (PPY)-coated capillary and several commercially available capillaries (capillary GC columns) were used to evaluate their extraction efficiencies for NNK and several metabolites in cell cultures. Compared with commercial capillaries that were currently used for in-tube SPME, the PPY-coated capillary showed better extraction efficiency for all of the compounds studied. After optimization of the extraction conditions, NNK and five metabolite compounds were analyzed in spiked cell cultures, confirming the applicability of the developed method. Excellent linearity was observed for all compounds (av R2 = 0.9942) and detection limits that ranged from 20 to 250 ng/mL. The average within-day and between day variations (% RSD) were 2.9 and 3.6%, respectively. This automated extraction and analysis method simplified the determination of the TSNA, requiring a total sample analysis time of only approximately 30 min.

Animals↗
PubMed2003

Simultaneous determination of five tobacco-specific nitrosamines in mainstream cigarette smoke by isotope dilution liquid chromatography/electrospray ionization tandem mass spectrometry.

Tobacco-specific nitrosamines (TSNAs) have been previously implicated as a source of carcinogenicity in tobacco and cigarette smoke. Accurate quantification of these chemicals is needed to help assess public health risk. We have developed and validated a specific and sensitive method to simultaneously measure five TSNAs in the particulate phase of mainstream tobacco smoke. Cigarette smoke particulate, produced using standardized machine smoking protocols, was collected on a Cambridge filter pad. The particulate matter was extracted using methylene chloride, back extracted into aqueous solution, further purified by solid-phase extraction, and analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry using isotopically labeled analogues as internal standards. Limits of detection for this method ranged from 0.05 to 1.23 ng/mL using an injection volume of 20 microL. A linear calibration range spanning 2.5-2500 ng/mL was adequate to measure TSNA levels in cigarette smoke. The method achieved excellent reproducibility and accuracy. The identity of each TSNA was established by chromatographic retention time, analyte-specific fragmentation patterns, and relative peak area ratios of two product/precursor ion pairs. This new method provides higher sensitivity, specificity, and throughput than earlier methods for TSNA determination.

Calibration↗
PubMed2005

Development of a quantitative method for the analysis of tobacco-specific nitrosamines in mainstream cigarette smoke using isotope dilution liquid chromatography/electrospray ionization tandem mass spectrometry.

An improved method has been developed for the determination of the four major tobacco-specific nitrosamines (TSNA) in mainstream cigarette smoke. The new method offers decreased sample preparation and analysis time as compared to traditional methodologies. This method uses isotope dilution liquid chromatography coupled to a tandem mass spectrometer with electrospray ionization and is significantly more sensitive than traditional methods. It also shows no evidence of artifactual formation of TSNA. Sample concentrations were determined for four TSNA in mainstream smoke using two isotopically labeled TSNA analogues as internal standards. Mainstream smoke was collected on an industry standard 44-mm Cambridge filter pad, extracted with an aqueous buffer solution, and analyzed without further sample cleanup. This method has been validated through intra- and interlaboratory studies and has shown excellent recoveries, sensitivity, and repeatability. The limits of detection of each TSNA varied from 0.01 to 0.1 ng/mL, and the linear calibration range of the instrument in sample matrix spanned 0.5-200 ng/ mL, which allowed for the determination of the TSNA levels in cigarettes with a wide range of deliveries. Data are also reported from two commercially available industry reference cigarettes and show excellent agreement and reproducibility over a six-month time period (n > 50).

Artifacts↗
PubMed1999

Supercritical fluid extraction and gas chromatography/mass spectrometry for the analysis of tobacco-specific nitrosamines in cigarettes.

A method for measuring four tobacco-specific nitrosamines (TSNAs), an important group of compounds in tobacco products, was developed. These compounds were extracted using supercritical fluid extraction (SFE) and purified by a sodium hydroxide wash of the ethyl acetate eluting solvent and solid-phase extraction. Quantitation was performed using gas chromatography/mass spectrometry (GC/MS). Spiking experiments were carried out to determine the recovery, precision, and limits of detection of this method. The detection limits were 0.04 microgram per sample for N'-nitrosonornicotine and N'-nitrosoanatabine and 0.02 microgram for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosoanabasine. This method was used to measure TSNAs in various brands of cigarette tobacco with excellent reproducibility. The variation of TSNA levels among the cigarettes of different packs and types was significantly smaller than that among different brands. Comparable TSNA levels were obtained with SFE and liquid extraction methods. Signal-to-noise levels were similar for GC/MS and GC/thermal energy analysis when low-level tobacco samples were analyzed.

Gas Chromatography-Mass Spectrometry↗
PubMed2004

Decreased levels of tobacco-specific N-nitrosamines in moist snuff on the Swedish market.

Moist snuff, or snus, on the Swedish market in 2001 and 2002 was analyzed for tobacco-specific N-nitrosamines (TSNAs) using a recently developed LC-MS/MS method. All samples of moist snuff analyzed were found to contain detectable levels of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB), and 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In the survey in 2001, all samples except for one were produced by Swedish Match (n = 14), which is the dominating manufacturer on the Swedish snuff market. In the survey in 2002, samples from both Swedish Match (n = 7) and seven smaller manufacturers (n = 20) were analyzed. Total TSNA levels of between 0.15 and 3.0 microg/g wet weight were found. In the survey in 2001 and 2002, the mean level of the total TSNA content in moist snuff was 1.1 microg/g (n = 14) and 1.0 microg/g (n = 27), respectively. The result of the survey shows that the level of TSNAs in moist snuff on the Swedish market has been greatly reduced since the middle of the 1980s. Clearly, efforts have been made by the manufacturers to reduce the level of TSNAs in snuff.

Nitrosamines↗
PubMed2005

Comparative analysis of tobacco-specific nitrosamines and total N-nitroso compounds in moldovan cigarette tobacco.

While previous studies have evaluated levels of tobacco-specific nitrosamines (TSNA) and total N-nitroso compounds (NOC) in tobacco, there are no reports in the literature on TSNA and total NOC in the same tobacco products. We compared levels of TSNA, total NOC, and NOC precursors (NOCP) in tobacco of cigarettes purchased in Moldova and in some tobacco types commonly used for the manufacturing of Moldovan cigarettes. Cigarette tobaccos included those from non-Moldovan, traditional Moldovan, and blended Moldovan cigarettes. The results demonstrate that tobacco of non-Moldovan cigarettes contains higher TSNA and NOC levels (mean, 16 and 63 nmol/g tobacco, n = 6) than that of Moldovan cigarettes (mean, 5 and 23 nmol/g tobacco, n = 25). TSNA and NOC levels were also generally higher in tobacco of blended than in traditional Moldovan cigarettes. NOCP levels in Moldovan and non-Moldovan cigarette tobacco were similar as follows: 29000 +/- 30000 and 33000 +/- 28000 nmol/g tobacco (mean +/- SD). Total NOC were strongly correlated with total TSNA levels (r = 0.66; P < 0.0001). These findings demonstrate that current technologies involved in the manufacture of some blended cigarettes create conditions that favor N-nitrosation of alkaloids and other tobacco constituents.

Moldova↗
PubMed1999

Antimutagenic effect of fruit and vegetable ethanolic extracts against N-nitrosamines evaluated by the Ames test.

The inhibitory effect of nine fruit and vegetable ethanolic extracts against the mutagenicity of N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR), N-nitrosodibutylamine (NDBA), and N-nitrosopiperidine (NPIP) was evaluated by means of the Ames test. Licorice ethanolic extract was the only one that showed an inhibitory effect (ranging from moderate to strong) against mutagenicity of all N-nitrosamines tested. This ethanolic extract showed the greatest inhibition effect against NPIP (72%), NDMA (45%), and NPYR (39%). The greatest inhibition effect (51%) of the mutagenicity of NDBA was shown by kiwi ethanolic extract. Vegetable and fruit ethanolic extracts that exhibited an antimutagenic effect (at the range 50-2000 microg/plate), in decreasing order, against NDMA and NPYR were as follows: licorice > kiwi > carrot and licorice > broccoli > pineapple > kiwi, respectively. Decreasing orders against NDBA and NPIP were, respectively, kiwi > onion > licorice = garlic > green pepper > carrot and licorice > garlic > pineapple > carrot.

Antimutagenic Agents↗
PubMed2005

Nitrosation chemistry of pyrroline, 2-imidazoline, and 2-oxazoline: theoretical Curtin-Hammett analysis of retro-ene and solvent-assisted C-X cleavage reactions of alpha-hydroxy-N-nitrosamines.

The results are presented of a theoretical study of the nitrosation chemistry of pyrroline 1 (X = CH2), imidazoline 2 (X = NH), and 2-oxazoline 3 (X = O). Imines 1-3 are converted to the alpha-hydroxy-N-nitrosamines 7-9 via the N-nitrosoiminium ions 4-6. The NN-cis isomers of 7-9 may undergo retro-ene reactions to the delta-oxoalkyl diazotic acids 10-12. With the opportunity for microsolvation, C-X cleavage becomes possible for 8 and 9 and leads to the formation of N-(2-aminoethyl)- and N-(2-hydroxyethyl)-N-nitrosoformamides 15 and 16, respectively. The NN-isomerization barriers are comparable to the barriers for the ring-opening reactions, and the consideration of two Curtin-Hammett scenarios is required: CH-I for the NN-trans-rotamers of 7-9 to undergo C-X cleavage or NN-isomerization and CH-II for the NN-cis-rotamers to undergo C-X cleavage, C-N cleavage, or NN-isomerization. We determined all stereoisomers of the substrates, the products, and of all transition states structures for the retro-ene reactions of 7-9, the C-X cleavages of microsolvated 8 and 9, and the NN-isomerizations of 8 and 9. The potential energy surfaces were explored at the B3LYP/6-31G level, and the results are discussed with emphasis on the comparison of the kinetics and thermodynamics of C-N versus C-X cleavage. The study shows all decompositions to be very fast with activation barriers below 21 kcal.mol(-1), and the comparative analysis predicts that the chemical toxicologies of 1 and 3 should be similar and remarkably different from that of 2.

Hydrolysis↗
PubMed2006

Kinetics and mechanisms of the reactions of hydroxyl radicals and hydrated electrons with nitrosamines and nitramines in water.

Absolute rate constants for hydroxyl radical, *OH, and hydrated electron, e(aq)(-), reactions with low-molecular-weight nitrosamines and nitramines in water at room temperature were measured using the techniques of electron pulse radiolysis and transient absorption spectroscopy. The bimolecular rate constants obtained, k (M(-1) s(-1)), for e(aq)(-) and *OH reactions, respectively, were as follows: methylethylnitrosamine, (1.67 +/- 0.06) x 10(10) and (4.95 +/- 0.21) x 10(8); diethylnitrosamine, (1.61 +/- 0.06) x 10(10) and (6.99 +/- 0.28) x 10(8); dimethylnitramine, (1.91 +/- 0.07) x 10(10) and (5.44 +/- 0.20) x 10(8); methylethylnitramine, (1.83 +/- 0.15) x 10(10) and (7.60 +/- 0.43) x 10(8); and diethylnitramine, (1.76 +/- 0.07) x 10(10) and (8.67 +/- 0.48) x 10(8), respectively. MNP/DMPO spin-trapping experiments demonstrated that hydroxyl radical reaction with these compounds occurs by hydrogen atom abstraction from an alkyl group, while the reaction of the hydrated electron was to form a transient radical anion. The latter adduct formation implies that the excess electron could subsequently be transferred to regenerate the parent chemical, which would significantly reduce the effectiveness of any free-radical-based remediation effort on nitrosamine/nitramine-contaminated waters.

Aniline Compounds↗
PubMedDate not supplied

Differences in DNA-guanine alkylation between male Sprague-Dawley rats and Syrian hamsters following exposure to a single dose of pancreatic nitrosamine carcinogens.

N-Nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) are potent pancreatic carcinogens for the Syrian hamster, while in rats they primarily target the esophagus and respiratory tract. Both species metabolize these carcinogens to yield methylating and 2-hydroxypropylating agents. Ratios of N7-methylguanine (N7-MeG) to N7-(2-hydroxypropyl)guanine (N7-HPG) in hepatic DNA of BOP- and HPOP-treated hamsters are 84 and 7, respectively. Similar ratios are observed in DNA of rat liver and hamster kidney, while in the lung and pancreas of both species and also in rat kidney, such ratios are significantly lower. Differences between hamsters and rats regarding the extent of DNA alkylation are observed with either BOP or HPOP. At 50 mg/kg BOP levels of N7-MeG are 3428, 1907, 457, and 260 mumol/mol of guanine in hamster liver, kidney, lung, and pancreas, respectively. In rats treated with the same dose of BOP, levels of this adduct in corresponding tissues are 4616, 451, 372, and 105 mumol/mol of guanine. HPOP like BOP alkylates kidney and pancreas DNA more extensively in hamsters than in rats while levels of N7-MeG in liver and lung DNA are similar in both species. Levels of the O6-methylguanine (O6-MeG) are 3.6 and 5.5 times greater in the DNA of hamster pancreas than in that of the rat after an injection of 50 mg/kg BOP and HPOP, respectively. Such differences suggest that initial alkylation of hamster pancreas is a critical factor in the induction of pancreatic cancer in this species by the above nitrosamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed2001

Preparation of pyridine-N-glucuronides of tobacco-specific nitrosamines.

Nicotine and cotinine are metabolized to pyridine-N-glucuronides in humans. This suggests that the analogous metabolites of the carcinogenic nicotine-related nitrosamines N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) should also be formed in people exposed to these compounds via tobacco products. We describe the synthesis of the appropriate pyridine-N-glucuronides: pyridyl-N-beta-D-glucopyranuronosyl-N'-nitrosonornicotinium inner salt (NNN-N-Gluc, 8), 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanonium inner salt (NNK-N-Gluc, 9), and 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanolonium inner salt (NNAL-N-Gluc, 10). The starting material, methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate (1), is prepared in two steps from glucuronolactone. Reactions of 1 with racemic NNN (2), NNK (3), or racemic NNAL (4) are carried out with no solvent and the crude products are deprotected by treatment with base, giving the desired N-glucuronides 8-10 in 5-7% overall yield after HPLC purification. The N-glucuronides were characterized by (1)H NMR, including COSY and NOESY spectra, and by MS and MS/MS. NNN-N-Gluc exists as a 52:48 ratio of (E)- and (Z)-rotamers, which were partially separated by HPLC. This ratio was surprisingly similar to the (E):(Z) ratio for NNN itself suggesting hydrogen bonding of the (Z)-nitroso oxygen atom to the 2' '-hydroxyl group of the glucuronide moiety. Partial HPLC separations of the (E)- and (Z)-rotamers of NNK-N-Gluc and the (E)- and (Z)-rotamers as well as the (R)- and (S)-diastereomers of NNAL-N-Gluc were also achieved. The standards prepared in this study as well as the HPLC conditions developed for their separation will be important for analysis of these compounds in human urine.

Chromatography, High Pressure Liquid↗