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PubMed2000

Large amount of vitamin A has no major effects on thyroidal hormone synthesis in two-stage rat thyroid carcinogenesis model using N-bis(2-hydroxypropyl)nitrosamine and thiourea.

In our previous investigation, which focused on two-stage carcinogenicity in the thyroid, rats were administered N-bis(2-hydroxypropyl)nitrosamine (DHPN), followed by thiourea (TU) over an experimental period of 19 weeks. Simultaneous treatment with a high level of vitamin A (VA) enhanced the induction of proliferative lesions that originated from the thyroidal follicular epithelium. To examine whether hormone synthesis in the thyroid could be inhibited by simultaneous treatment with a large amount of VA and TU, all of the rats were initially given a single subcutaneous injection of 2,800 mg DHPN/kg followed by a supply of 0% TU + 0% VA (DHPN only, control group), 0.2% TU in their drinking water (DHPN/TU group), 0.1% VA in their diet (DHPN/VA group), or 0.2% TU + 0.1% VA (DHPN/TU + VA group) during an experimental period of 4 weeks. Results obtained indicate that the iodine uptake and organification, namely iodination of tyrosine residue in thyroglobulin, of the thyroid, were significantly decreased in the DHPN/TU group compared to the DHPN control group. The variation in these values was attributable to the inhibitory effect of TU upon thyroid hormone synthesis. Results obtained from the DHPN/TU + VA and DHPN/TU groups were comparable. Therefore, the possibility that modification of hormone synthesis contributes to the enhancing effect of simultaneous treatment with a large amount of VA on thyroidal tumor induction by TU is considered to be very minimal.

Adenoma↗
PubMed2001

Dose-threshold for thyroid tumor-promoting effects of orally administered kojic acid in rats after initiation with N-bis(2-hydroxypropyl) nitrosamine.

In order to evaluate the threshold dose of thyroid tumor-promoting effects of KA, male F344 rats were initiated with N-bis(2-hydroxypropyl) nitrosamine (DHPN; 2000 mg/kg body wt., single s.c. injection) and, starting 1 week later, received pulverized basal diet containing 0%, 0.002%, 0.008%, 0.03%, 0.125%, 0.5% or 2%KA for 20 weeks. Five rats each in the 0%, 0.125%, 0.5% and 2%KA groups were sacrificed at week 12, and 10 rats each in all groups at week 20. As an additional experiment, three groups without DHPN initiation received basal diet, a diet containing 0.5% or 2%KA for 20 weeks. The serum T4 levels were significantly decreased in the DHPN-initiated groups given 0.125%KA or more at week 12. No significant decreases in serum T3 levels were observed in the groups treated with DHPN + KA and a significant increase was evident in the 2%KA-alone group at week 20. Some rats in the DHPN + 2%KA group at weeks 12 and 20 and the 2%KA-alone group at week 20 showed pronounced elevation of serum TSH. Thyroid weights were significantly increased in the DHPN-initiated groups receiving 0.5% and 2%KA at weeks 12 and 20 and in the 2%KA-alone group at week 20. Histopathologically, the incidences of focal thyroid follicular cell hyperplasias in the DHPN-initiated groups treated with 0.125%, 0.5% and 2%KA at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20, adenomas were observed in 7/10 rats in the DHPN + 0.5%KA group and 8/8 rats in the DHPN + 2%KA group, and carcinomas were observed in 6/8 rats in the DHPN + 2%KA group. In the groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rats in the 2%KA-alone group. These results suggest that the no-observed-adverse effect for the thyroid tumor-promoting effect of KA is 0.03% (15.5 mg/kg/day) under the present experimental conditions, and that KA possesses weak tumorigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism.

Animals↗
PubMed1991

Analytical studies on tobacco-specific N-nitrosamines in tobacco and tobacco smoke.

Chemical-analytical studies have led to the identification of approximately 3000 compounds in tobacco and 4000 in tobacco smoke. These include carcinogens in processed tobacco as well as tumor initiators, tumor promoters, cocarcinogens, and organ-specific carcinogens in tobacco smoke. The latter group includes N-nitrosamines, in particular those that derive from nicotine and other tobacco alkaloids, the TSNA. In vitro nitrosation of nicotine yields NNN, NNA, and NNK. Nitrosation of other tobacco alkaloids leads to the formation of NAT, and NAB. Our analytical studies using GC-TEA have led to the identification of seven TSNA in tobacco and tobacco smoke. In addition to NNN, NAT, NAB, and NNK, we also identified NNAL, iso-NNAL, and, most recently, iso-NNAC. Their levels range from 0.01 to 92 ppm in tobacco and from 6 to 530 ng/cigarette in tobacco smoke. The high levels observed in snuff are primarily due to fermentation and aging. Technological methods exist today to reduce the levels of TSNA in both tobacco and cigarette smoke.

Animals↗
PubMed1991

Nicotine-derived N-nitrosamines (TSNA) and their relevance in tobacco carcinogenesis.

Biochemical studies and bioassays support the concept that the increased risk for cancer of the oral cavity in snuff dippers and cancer of the lung, upper aerodigestive tract, and pancreas in smokers is most likely associated with the exposure to tobacco-specific N-nitrosamines. The doses of TSNA required to induce tumors in the oral cavity in rats and tumors in the lungs of rats and hamsters are comparable to the total doses of TSNA to which a long-term snuff dipper, respectively a cigarette smoker, are exposed over 4 decades. The carcinogenic NNN and NNK are metabolized to highly reactive electrophiles which react with nucleophilic centers of DNA and with proteins. The DNA-adducts are known to cause miscoding which can activate K-ras proto-oncogenes. K-ras oncogenes have been detected in adenocarcinomas of the lung of smokers. TSNA also form globin adducts in the blood of laboratory animals as well as of snuff dippers and smokers. Such adducts are currently being evaluated for their significance as biochemical markers of exposure to TSNA. These biomarkers may also serve as indicators for the possible endogenous formation of TSNA in tobacco chewers and smokers. Additional research needs in TSNA carcinogenesis include the development of modified methods for the reduction of TSNA in tobacco and smoke, inhibition of TSNA carcinogenesis by nutrients and micro-nutrients and the testing of chemopreventive agents.

Animals↗
PubMed1996

Formation and analysis of tobacco-specific N-nitrosamines.

Chemical-analytical studies during the past 4 years led to several new observations on the formation of tobacco-specific N-nitrosamines (TSNA) and their occurrence in smokeless tobacco, mainstream smoke (MS), and sidestream smoke (SS) of American and foreign cigarettes. When snuff was extracted by means of supercritical fluid extraction with carbon dioxide containing 10% methanol, analysis of this material confirmed that the extraction with organic solvents had been partially incomplete. Epidemiological studies in the northern Sudan showed a high risk for oral cancer for users of toombak, a home-made oral snuff. Toombak contains 100-fold higher levels of TSNA than commercial snuff in the U.S. and Sweden. The TSNA content in the saliva of toombak dippers is at least ten times higher than that reported in the saliva of dippers of commercial snuff. Biomarker studies have shown corresponding high levels of hemoglobin adducts with metabolites of NNN and NNK as well as for urinary metabolites of NNK. These data supported the epidemiological findings. The analyses of MS of U.S. and foreign cigarettes smoked under FTC conditions revealed comparable data for the smoke of nonfilter cigarettes and filter cigarettes except in the case of low- and ultralow-yield cigarettes, which showed reduced TSNA yields. The MS of cigarettes made from Burley or dark tobacco is exceptionally high in TSNA, primarily because of the high nitrate content of those tobacco types. Taking puffs of larger volume and drawing puffs more frequently, practices observed among most smokers of cigarettes with low nicotine yield, results in high TSNA values in the MS. The formation of the lung carcinogen NNK is favored during the smoldering of cigarettes, between puffs, when SS is generated. Consequently, in most samples from indoor air polluted with environmental tobacco smoke (ETS), the highest concentration of an individual TSNA is that of NNK. When nonsmokers had remained for up to 2 h in a test laboratory with high ETS pollution, they excreted measurable amounts of NNK metabolites in the urine, indicative of the uptake of TSNA.

Air Pollution, Indoor↗
PubMed1996

Synthesis of tobacco-specific N-nitrosamines and their metabolites and results of related bioassays.

Tobacco-specific N-nitrosamines (TSNA) are the most abundant, strong carcinogens in tobacco smoke. Seven TSNA have been identified in tobacco products: N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), and 4-(methylnitrosamino)-4-3-pyridyl)butyric acid (iso-NNAC). The syntheses of these compounds are reviewed. The syntheses of 14C- and 3H-labeled NNK as well as metabolites of NNK and NNN are also discussed. Comparative assays for lung tumorigenesis in female A/J mice were carried out for six of the TSNA and for two related compounds, N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR). They yielded the following ranking of potency: NDMA > NNK > NNAL > NPYR > NNN > NAB. Iso-NNAL and iso-NNAC were inactive. These results are also compared with previous assays of TSNA carcinogenicity in rats and hamsters.

Adenoma↗
PubMed2000

Activation of voltage-operated Ca2+-channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

The nicotine-derived tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung cancer in all animal species tested and is thought to contribute significantly to the high lung cancer burden associated with smoking. NNK has recently been identified as a high affinity ligand for neuronal nicotinic acetylcholine receptors comprised of alpha7 subunits (alpha7 nAChR), and expressed in human small cell lung carcinoma (SCLC). As agonist-binding to this receptor in mammalian cells often results in membrane depolarization and activation of voltage-operated Ca2+-channels (VOCCs), we hypothesized that NNK may exert similar effects in SCLC. Using flow cytometry to monitor the influx of Ca2+, reverse transcription polymerase chain reaction (RT-PCR) to determine the expression of VOCC-specific messenger RNA, as well as analysis of DNA synthesis or determination of cell number, our data demonstrate that binding of NNK to the alpha7 nAChR in SCLC cells caused influx of Ca2+ via VOCCs of the L-, N-, and P-type. In turn, this led to a significant increase in DNA synthesis and cell number which was inhibited by a site-selective antagonist for the alpha7 nAChR and by Ca2+-channel blockers of the L-, N-, or P-types of VOCCs. Our findings suggest that the chronic activation of VOCC-mediated Ca2+ influx by NNK in smokers is an important event that may affect numerous Ca2+-dependent signal transduction pathways, thus contributing significantly to the development of SCLC.

Calcium Channels↗
PubMed1976

Mass spectrometry of nitrosamines: rearrangement of nitrosobenzylmethylamine molecular ions with loss of OH-radicals investigated by deuterated derivatives.

Nitrosamines (R1R2NO) containing a certain R groups yield mass spectra with M+-OH fragments which can be accounted for by intramolecular hydrogen shift with subsequent cleavage of OH-radicals. As can be shown with mass spectra of specifically deuterated derivatives of nitrosobenzylmethylamine - nitrosobenzyltrideuteriomethylamine, alpha,alpha-nitrosodideuteriobenzylmethylamine and o,o',p-nitrosotrideuteri0-benzylmethylamine - hydrogen transfer within the molecular ion of nitrosobenzylmethylamine occurs selectively onto the oxygen of the nitroso group from the benzylethylene group, probably via a five-membered cyclic transition state. Cleavage of OH radicals leads to formation of M+-17 ions, the stability of which can be explained by mesomerically stabilized cyclic diazirinium ions.

Chemical Phenomena↗
PubMed1976

Lung carcinomas induced by oral administration of N-bis(2-hydroxypropyl)nitrosamine in rats.

The oral administration of N-bis(2-hydroxypropyl)nitrosamine (DHPN) in drinking water induced lung tumors in high incidence in rats at 25 weeks. Histologically, they were adenoma, adenocarcinoma, squamous cell carcinoma, and combined squamous cell and adenocarcinoma. Metastases of adenocarcinoma were observed in regional lymph nodes. The development of tumors in other sites was seen in the liver, thyroid, kidney, ureter, urinary bladder, and pancreas. The incidence of lung tumor was distinctly higher than that of other sites. These results indicate that the target organ of DHPN was the lung and that oral administration of this chemical carcinogen was responsible for the development of lung carcinomas in rats.

Adenocarcinoma↗
PubMed1975

Epidemiology and aetiology of cancer of the uterine cervix including the detection of carcinogenic N-nitrosamines in the human vaginal vault.

Cancer of the uterine cervix occurs with high frequency in black females of several populations of Southern Africa. It accounts for 40-50% of all cancers in Black females in the Johannesburg area and for over 40% of those in women in the rural lowveld area of the Transvaal. The aetiology of this cancer has several distinct features, almost all of which concern some or other aspect of coitus. Age at first coitus and at first marriage, and promiscuity, are very strongly associated with the development of the disease, and age, race, religion, culture, socio-economic status, extent of genital hygiene and venereal disease also play a major role. In spite of current belief, circumcision of the male partner is at best weakly associated with the development of the disease, and so are menstruation, coital habits and pregnancy. Certain aetiological features are selectively discussed; these include Herpesvirus type II, 'rogue' spermatozoa and the recent isolation of a group of potent carcinogens, the nitrosamines, in infected discharge samples taken from the vaginal vault of patients attending gynaecological clinics.

Black or African American↗
PubMedDate not supplied

Effects of citrus phytochemicals on liver and lung cytochrome P450 activity and on the in vitro metabolism of the tobacco-specific nitrosamine NNK.

NNK is a potent environmental carcinogen to which both smokers and nonsmokers are exposed. The response to NNK may be affected by factors including nutrition. We investigated the effects of five citrus phytochemicals on the in vitro metabolism of the tobacco-specific nitrosamine NNK and on the dealkylation of methoxyresorufin (MROD) and pentoxyresorufin (PROD) in liver and lung microsomes of the Syrian golden hamster. In the NNK metabolism experiments in vitro incubations contained 3 microCi [5-H3] NNK, 0.5 mg microsomal protein and 0.5 mumole of the citrus phytochemical diosmin, naringin, naringenin, quercetin or rutin. In the dealkylation studies incubations contained 0.5 microM methoxyresorufin or pentoxyresorufin, 0.5 mg microsomal protein and 0.5 mumole of citrus phytochemical. The major NNK metabolism pathway in hamster liver microsomes was NNK-reduction while in lung microsomes it was alpha-hydroxylation. The alpha-hydroxylation pathway produces metabolic products that methylate and pyridyloxobutylate DNA. Naringenin, a metabolite of naringin, and quercetin were the most potent inhibitors of alpha-hydroxylation of NNK in both liver and lung microsomes. This inhibition correlated with a potent inhibition of MROD and PROD activity in liver but not in lung microsomes. The metabolic activation of NNK is associated with cytochrome P450 isoforms 1A1, 1A2, 2B1, 2D6 and 2E1. Our results suggest that naringenin and quercetin from citrus fruits inhibit the activity of cytochrome P450 (CYP) isoforms that activate NNK and may afford protection against NNK-induced carcinogenesis.

Animals↗
PubMed2001

[Ground and first singlet excited dissociation constants of 4-methylumbelliferone: application for indirect spectrofluorimetry of nitriles and nitrosamines].

The light adsorption process provides important changes in the electronic configuration of molecules. For phenolic derivatives, light adsorption contributes to acidity in the excited state. In aqueous medium, excitation of the molecular form (ArOH) undergoes dissociation at the first singlet excited state and subsequent fluorescence emission occurs from the excited ionized form (ArO-*). The emission is higher than from the molecular form and exhibits a shift to the red. The combination of these two phenomena allowed simultaneous increase in selectivity and sensitivity. In addition this method allowed an easy quantification of 4-methylumbelliferone at the nanomolar level and consequently trace levels of nitrates and N-nitrosamines after diazotization and/or denitrozation.

Chemical Phenomena↗
PubMed1999

[Malignant transformation of HPV-18 immortalized human bronchial epithelial cells induced by tobacco-specific nitrosamine NNK].

The malignant transformation of HPV-18 immortalized human bronchial epithelial cell(BEP2D) induced by tobacco-specific nitrosamine NNK and its biological characteristics were investigated. BEP2D cells treated with NNK at the concentration of 500 micrograms/ml for 24 hours could be subcultured continuously in vitro. The 15th passage cells in soft agar (0.038%) increased 11 fold compared with that of control cells (0.0033%). The 25th passage cells could grow into tumor in nude mice. The tumor was a squamous cell carcinoma in morphology confirmed by histopathological examination. The results indicated that the malignant transformation induced by NNK was a sequential process. This culture system provides a potential tool for the study of cell and molecular mechanism in the multistage carcinogenesis of human bronchial epithelial cells.

Animals↗
PubMed1976

Histological classification of urinary bladder cancers in rats induced by N-butyl-n-(4-hydroxybutyl)nitrosamine.

Histological types and grades of 613 urinary bladder cancers induced in rats by N-butyl-N-(4-hydroxybutyl) nitrosamine(BBN) were analyzed. Most of them (95.1%) were transitional cell carcinomas, the remainder being squamous cell carcinomas (3.3%), undifferentiated carcinomas (2.5%), and carcinosarcomas (0.3%). Among the transitional cell carcinomas, 23.3% were Grade I anaplasia, 55.2% Grade II, and 21.5% Grade III. Among the squamous cell carcinomas, 20% each were Grade I and II, and 60% Grade III. Most of the undifferentiated carcinomas were Grade III. Some of the cases of transitional cell carcinoma had areas of squamous metaplasia and/or glandular metaplasia, and the incidence of metaplasia increased with the grade of anaplasia. Approximately 36% of the cases of transitional cell carcinoma were of the invasive type. Invasive types were twice as numerous among cases of squamous cell carcinoma as among those of transitional cell carcinoma and all of undifferentiated carcinomas were invasive. The incidence of invasive type was closely related to the grade of anaplasia. These results show that the morphological characteristics of urinary bladder carcinomas induced by BBN in rats are similar to those seen clinically in humans.

Animals↗
PubMed1992

Comparison of cytochrome P-450- and peroxidase-mediated activations of carcinogenic azo dyes and N-nitrosamines.

Carcinogenic azo dyes (dimethylaminoazobenzene, Sudan I) and N-nitrosamines (N-nitrosomethylaniline, N-nitrosomethylbenzylamine) are oxidized by cytochrome P-450 isoenzymes and peroxidase yielding metabolites which in vitro bind to DNA and transfer RNA (tRNA). The parallelism and differences in oxidative reactions are described. Peroxidase is more effective than P-450 in activating reactions of some carcinogens studied. The presence of either of these enzymes is supposed to be responsible for the organ and/or cell type specific effects of the carcinogens studied.

Animals↗
PubMedDate not supplied

Effects of different inducers of cytochrome P450 on the mutagenesis of the tobacco-specific nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) in Salmonella typhimurium TA1535.

The effects of six inducers of isoenzymes of cytochrome P450 on the mutagenicity of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Salmonella typhimurium strain TA1535 by hamster liver S9 and microsomes were investigated. Comparisons of the effects of dimethylsulfoxide (DMSO) as solvent for NNK were also made. The inducing agents were Aroclor 1254 (AROC), 3-methylcholanthrene (MC), phenobarbital (PB), dexamethasone (DXM), ethanol (ETOH) and isosafrol (ISF). The number of histidine-independent colonies induced by NNK in saline mediated by S9 from the inducing agents was as follows: ISF = AROC greater than PB greater than MC greater than DXM greater than ETOH. AROC-induced microsomes produced the most revertants by NNK (saline) greater than MC greater than PB = DXM and ISF greater than ETOH. The number of revertant colonies induced by NNK in DMSO was significantly less than that by NNK in saline for both hamster liver S9 and microsomes irrespective of the inducing agent. The greatest inhibitory effect of DMSO was observed with ISF-induced S9.

Animals↗
PubMed2004

The relative risks of a low-nitrosamine smokeless tobacco product compared with smoking cigarettes: estimates of a panel of experts.

A nine-membered panel of experts was asked to determine expert opinions of mortality risks associated with use of low-nitrosamine smokeless tobacco (LN-SLT) marketed for oral use. A modified Delphi approach was employed. For total mortality, the estimated median relative risks for individual users of LN-SLT were 9% and 5% of the risk associated with smoking for those ages 35 to 49 and > or =50 years, respectively. Median mortality risks relative to smoking were estimated to be 2% to 3% for lung cancer, 10% for heart disease, and 15% to 30% for oral cancer. Although individual estimates often varied between 0% and 50%, most panel members were confident or very confident of their estimates by the last round of consultation. In comparison with smoking, experts perceive at least a 90% reduction in the relative risk of LN-SLT use. The risks of using LN-SLT products therefore should not be portrayed as comparable with those of smoking cigarettes as has been the practice of some governmental and public health authorities in the past. Importantly, the overall public health impact of LN-SLT will reflect use patterns, its marketing, and governmental regulation of tobacco products.

Adult↗