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PubMed1982

Geno- and cytotoxicity of nitrosamines, aflatoxin B1, and benzo[a]-pyrene in continuous cultures of rat hepatoma cells.

Two closely related hepatoma cell lines were examined for their response to carcinogens requiring metabolic activation: H5, a dedifferentiated line expressing cytochrome P-448-dependent monooxygenase(s); and HF1-4, a differentiated line which also expresses cytochrome P-450-dependent monooxygenase(s). The hepatocarcinogens dimethyl- and diethylnitrosamine and aflatoxin B1, preferred substrates for cytochrome P-450-dependent monooxygenase(s), and the non-hepatocarcinogen benzo[a]pyrene, which is preferentially metabolized by cytochrome P-448-dependent monooxygenase forms, were used as test agents. Their effects were compared to those of the directly alkylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N-nitrosourea (ENU). The cytotoxicity was evaluated by plating efficiency, the genotoxicity by the appearance of alkaline labile DNA sites. The nitrosamines had a cytotoxic and genotoxic effect on the differentiated HF1-4 cells, but had no effect on H5 cells. Aflatoxin B1 affected both cell lines, but was approximately 10-times more potent in the HF1-4 than in the H5 cells. In contrast to the nitrosamines and the mycotoxin, benzo[a]-pyrene exerted a stronger effect on the dedifferentiated cell line. Pretreatment of cultures with dexamethasone increased both the cytotoxicity and genotoxicity of the hepatotoxic agents. MNNG and ENU induced a similar degree of DNA-damage after short-term (2 h) exposure in the two cell lines. When cells were allowed to recover for 16 h HF1-4 cells, but not H5 cells, regained their full growth potential suggesting a marked capacity for the repair of MNNG- and ENU-induced lesions in the HF1-4 cells. The results indicate that continuous lines of mammalian cells may retain a considerable degree of organ-specific response to chemical carcinogens. Hepatoma cells of the type described above may be useful for screening the wide spectrum of chemicals which are potentially genotoxic in liver and in extrahepatic tissues and for analyzing their metabolic activation and mechanism of action.

Aflatoxin B1↗
PubMed1983

The effect of disulfiram on the carcinogenicity of N-butyl-N-(3-carboxypropyl)nitrosamine in the rat.

N-Butyl-N-(3-carboxypropyl)nitrosamine (BCPN) is a proximate carcinogenic metabolite of the bladder specific carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN). The objective of this study was to determine if disulfiram would inhibit the induction of bladder cancer in rats given BCPN, as reported for BHBN (Cancer Res., 39, 3040, 1979). Two groups of 30 male Wistar rats were given 1.5 mM BCPN (0.028%) in the drinking water for 12 weeks. The total dose of BCPN/rat was 5 mmol (0.95 g). During administration of the BCPN, one group of rats was fed a diet containing 0.5% disulfiram, while the other group was maintained on control diet. At the end of 12 weeks, the animals were maintained on control diet without BCPN for an additional 18 weeks, at which time the animals were sacrificed. It was found that 0.5% disulfiram significantly reduced the incidence of bladder cancer, decreasing from 30/30 (100%) in the group receiving BCPN alone to 3/30 (10%) in the group fed the disulfiram diet. The inhibition of BHBN-induced bladder cancer by disulfiram, previously reported, was also confirmed in these experiments.

Animals↗
PubMed1984

A comparative study of the bioactivation of nitrosamines to mutagens by various animal species including man.

Dimethylnitrosamine, dipropylnitrosamine, methylethylnitrosamine, nitrosopiperidine and nitrosopyrrolidine were assayed for mutagenicity in the Ames test in the presence of hepatic postmitochondrial preparations isolated from the mouse, rat, hamster, pig and man. Prior to each mutagenicity assay all activation systems were fully characterised with respect to monoamine oxidase, mixed-function amine oxidase and mixed-function oxidase activities. The hamster was the most efficient activator for all nitrosamines followed by the mouse. The latter species, however, activated nitrosopyrrolidine only weakly which was the only carcinogen readily activated by the human preparation. None of the aliphatic nitrosamines was activated by the rat or pig. No correlation was observed between efficiency of activation and any of the enzyme activities studied.

Animals↗
PubMed1985

Fluoro-substituted N-nitrosamines. 7. Non-genotoxic N-nitroso-bis(2,2,2-trifluoroethyl)amine and N-nitroso-bis(2,2,3,3,4,4,4-heptafluorobutyl)amine: binding to cytochrome P-450, acidity of alpha-protons and pharmacokinetic investigations.

The biologically inactive fluorinated nitrosamines N-nitroso-bis(2,2,2-trifluoroethyl)amine (NDEA-F6) and N-nitroso-bis-(2,2,3,3,4,4,4-heptafluorobutyl)amine (NDBA-F14) were investigated for binding affinity to cytochrome P-450 and for ease of alkali-induced proton abstraction at the alpha-C atom, in comparison with biologically active analogues (N-nitroso-diethylamine, NDEA; N-nitroso-2,2,2-trifluoroethylethylamine, NDEA-F3; N-nitrosodibutylamine, NDBA; N-nitroso-4,4,4-trifluorobutylbutylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)amine, NDBA-F6). Binding to cytochrome P-450 was studied by spectroscopic measurements (optical difference spectra with microsomal fractions); base-catalyzed deuterium exchange of alpha-hydrogen atoms was followed by 1H n.m.r. measurements. Additionally the excretion of NDEA-F6 and NDBA-F14 in expired air, urine and faeces was studied after oral application to the rat. Compared with the biologically active nitrosamine analogues, NDEA-F6 and NDBA-F14 showed higher binding affinity to cytochrome P-450. N.m.r. spectroscopy showed that NDEA-F6, NDBA-F14 and NDEA-F3 (at the fluorinated alkyl chain) were rapidly deprotonated at the alpha-C-position in sodium perdeutero methylate, in contrast to the other analogues tested. In vivo, NDEA-F6 and NDBA-F14 were excreted unchanged, mainly via exhalation. The biological inactivity of NDEA-F6 and NDBA-F14, together with the observed blocking of their microsomal activation can be reconciled with the experimental findings which indicate that homolytic alpha-C-H bond fission is more likely to be involved in alpha-C-hydroxylation of dialkylnitrosamines, than alpha-proton abstraction.

Animals↗
PubMed1985

Fluoro-substituted N-nitrosamines. 8. N-Nitrosodibutylamine and omega-fluorinated analogues: in vivo metabolism in relation to the induction of urinary bladder cancer in the rat.

Urinary excretion of N-nitrosodibutylamine (NDBA) and of two omega-fluorinated analogues [N-nitroso-4,4,4-trifluorobutyl-butylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)-amine, NDBA-F6] was studied in male Sprague-Dawley (SD) rats. After oral application of equimolar doses (0.44 and 1.32 mmol/kg body wt.) urines were collected (48 h) and analyzed for parent compounds, and for nitrosamine metabolites by gas chromatography/Thermal Energy Analyzer (GC/TEA) and gas chromatography/mass spectrometry (GC/MS). After administration of NDBA the known major metabolites N-nitroso-3- hydroxybutylbutylamine (3-OH-NDBA) and N-nitroso-3-carboxypropylbutylamine (BCPN) were excreted in urine. After application of the omega-fluorinated analogue NDBA-F6, however, urinary and biliary nitrosamine metabolites were detected only in trace amounts. This finding demonstrates a strong inhibitory effect of fluorine substitution on oxidations at omega, (omega-1) and beta-positions. Confirmation of this inhibitory effect of omega-fluorine substitution is given from the excretion profiles of NDBA-F3 which shows metabolic oxidations only at the nonfluorinated chain: N-nitroso-3-hydroxybutyl-4,4,4-trifluorobutylamine (3-OH-NDBA-F3) and N-nitroso-3-carboxypropyl-4,4,4-trifluorobutylamine (BCPN-F3) were excreted as main metabolites. Our results on metabolism together with the available data on carcinogenicity of the compounds in the rat strongly support the hypothesis that omega-oxidation of one butyl-chain is a prerequisite for the induction of urinary bladder tumors with NDBA. For the induction of liver tumors, alpha-C-hydroxylation appears to be the crucial event.

Animals↗
PubMed1988

Summation effect of uracil on the two-stage and multistage models of urinary bladder carcinogenesis in F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Uracil is known to cause reversible urolithiasis and to induce papillomatosis in the urinary bladder of F344 rats. We examined whether the marked urothelial cell proliferation caused by uracil, given in the middle of the post-initiation stages, enhances the promoting activity of a promoter in the two-stage model or the promoting and/or carcinogenic activity of a low-dose carcinogen in the multistage model of urinary bladder carcinogenesis. Rats were initiated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks, and then 2% butylated hydroxyanisole (BHA) or 0.002% N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) were given during experimental weeks 4-9 and weeks 12-20. Uracil was given during weeks 9-12 at a level of 3% of the diet. Rats in the control group were treated with BBN and uracil. Rats were killed at weeks 16 and 20. At week 16, higher occurrences of papillary or nodular (PN) hyperplasia and papilloma were observed in uracil-BHA-treated rats than in the controls. At week 20, significantly higher incidences of PN hyperplasia and papilloma were observed in both uracil-EHBN- and uracil-BHA-treated groups, and a summation effect of uracil was observed. These results indicate that uracil given in the middle of the post-initiation stage enhanced the promoting activity of the compound through marked proliferation of the bladder epithelium.

Animals↗
PubMed1991

The application of solid phase extraction to the analysis of tobacco-specific nitrosamines.

A new isolation and separation method has been developed for the alkaloid-related nitrosamines in tobacco, called tobacco-specific nitrosamines (TSNA). The improved isolation procedure involves the extraction by sonication of TSNA from cured tobacco with toluene and an aqueous citrate buffer solution, while purification is achieved by solid phase extraction on small silica cartridges. Interfering extract materials are eluted from the silica cartridges with the toluene and a chloroform-methylene chloride solvent, while subsequent elution with chloroform yields the TSNA in a purified fraction. Gas chromatographic analyses on an SE-54-coated glass capillary column and detection by a nitrogen-phosphorous detector produce very good data on the four TSNAs, which include N-nitrosanatabine (NATB), N-nitrosoanabasine (NAB), 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (called NNK), and N-nitrosonornicotine (NNN). The method is shown to be quantitative, reproducible, and applicable to the determination of TSNA in various tobacco samples, such as stems and lamina of cured tobacco leaves, as well as to smokeless tobacco.

Chromatography, Gas↗
PubMedDate not supplied

Chemical studies on tobacco-specific N-nitrosamines in the smoke of selected cigarettes from the U.S.A., West Germany, and France.

Studies on the variations of biologically important smoke constituents of popular cigarettes in several European countries and in the United States include investigations on the types and levels of volatile (VNA) and tobacco-specific nitrosamines (TSNA). GLC-TEA and HPLC-TEA methods are used to determine the VNA and TSNA in mainstream and sidestream smoke of cigarettes. This report presents data on the smoke of some West German cigarettes which demonstrate that the VNA levels are about the same as those in the smoke of U.S. cigarettes; but that they are lower than those in the smoke of French cigarettes, made of dark tobacco types. The tobacco-specific nonvolatile N-nitrosamines determined in the mainstream smoke of commercial U.S. blended cigarettes (N-nitrosoanatabine, N-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone together) ranged from 680 to 830 ng per cigarette, while those for commercial West German products ranged from 340 to 780 ng per cigarette in nonfilter brands and from 180 to 450 ng in filter-tipped cigarettes. The analyzed French products contained 1010 to 1380 ng of these compounds in the smoke of each cigarette.

Chromatography, Gas↗
PubMed2004

Development of a food database of nitrosamines, heterocyclic amines, and polycyclic aromatic hydrocarbons.

Some nitrosocompounds that are formed during food preservation, as well as polycyclic aromatic hydrocarbons (PAH) and heterocyclic amines (HA) formed during cooking, may have carcinogenic activity. An accurate assessment of dietary intake of such compounds is difficult, mainly because they are not naturally present in foods, and they are not included in standard food composition tables. Our objective was to develop a food composition database of nitrates, nitrites, nitrosamines, HA, and PAH. We conducted a literature search on the food content of these compounds using the Medline and EMBASE databases. We gathered the following information: 1) Food information: name, cooking methods, preservation methods, cooking doneness, temperature, and time; 2) compound information: type, quantity, value type, analytic method, and sampling methods; and 3) publication information: year, author, and country. We developed a table that includes 207 food items with information concerning the concentration of nitrites, nitrates, and nitrosamines, 297 food items with information about HA concentration and 313 food items with information about PAH. The database is based on 139 references from 23 different countries. It is arranged according to compounds and food groups to facilitate its practical use. The potential limitations are due to the quality of the information we could obtain through Medline and EMBASE databases. This database will allow investigators to quantify dietary exposure to several potential carcinogens, and to analyze their relation to the risk of cancer.

Carcinogens↗
PubMed1976

Efficient photolytic degradation of nitrosamines.

The principles and practice of nitrosamine degradation by photochemical means were described. Two types of apparatus were constructed for this purpose. A nitrosamine waste solution containing 10-3-10-1 N in hydrochloric acid and about 10 mole-equivalents of an HNO2 scavenger (i.e., urea, guanidine, or hydrazoic acid) was efficiently and irreversibly degraded to the parent amines and N2 (and/or N2O) by irradiation. Efficiency of the degradation depended on the type of apparatus used. With the use of one apparatus, about 11 g N-nitrosodimethylamine was photolytically converted to dimethylamine, N2, and N2O in 24 hours. Protonated guanidine catalyzed the photohydrolysis processes.

Carcinogens↗
PubMed1995

Five leading U.S. commercial brands of moist snuff in 1994: assessment of carcinogenic N-nitrosamines.

BACKGROUND: Moist snuff is the only tobacco product in the United States with increasing sales (an increase of 38.4% between 1981 and 1993) and with increased consumption, primarily by male adolescents aged 12-18 years old and young adults aged 19 years old or older. It is known from previous studies that levels of nicotine and the proportion of unprotonated (free) nicotine, as well as the pH, which affects nicotine delivery, vary considerably among the leading snuff brands. Whether concentrations of major carcinogens, such as the nicotine-derived tobacco-specific N-nitrosamines (TSNAs), like N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), also vary among these brands has not been determined previously. PURPOSE: Our purpose was threefold: 1) to determine the concentrations of major carcinogenic nicotine-derived N-nitrosamines in each of the five most popular moist snuff brands; 2) to analyze the quantitative differences in the various snuff components (e.g., NNN) between two major brand categories: a category comprising the brands known to have high levels of unprotonated nicotine (Copenhagen, Skoal fine cut, and Kodiak) versus a category comprising the brands known to have low levels (Hawken and Skoal Bandits); and 3) to compare the differences in the concentrations of nicotine (previously determined), NNN, NNK, and total TSNAs between these two major brand categories. METHODS: Three boxes of each of the five leading U.S. moist snuff brands were bought in July 1994 from retailers in six areas and transferred immediately to the analytical laboratory. After extraction, N-nitrosamino acids and TSNAs were determined on a gas chromatograph interfaced with a thermal energy analyzer (GC-TEA) and integrator. Each 5-g sample of ground, freeze-dried tobacco was extracted twice, and each extract was analyzed twice by GC-TEA. All P values reported are two sided. RESULTS: Copenhagen, Skoal fine cut, and Kodiak as a group had statistically significant higher levels of nicotine (P = .0017), NNN (P < .0001), NNK (P = .0119), and total TSNAs (P < .0001) than the Hawken and Skoal Bandits group. Concentrations (means +/- SD) of nicotine, NNN, NNK, and total TSNAs comparing the two major brand categories are as follows: nicotine--11.6 +/- 1.01 mg/g versus 6.96 +/- 3.62 mg/g (P = .0017), NNN--7.74 +/- 1.70 micrograms/g versus 4.17 +/- 1.35 micrograms/g (P < .0001), NNK--1.23 +/- 0.68 micrograms/g versus 0.61 +/- 0.41 micrograms/g (P = .0119), and total TSNAs--14.3 +/- 3.82 micrograms/g versus 6.3 +/- 2.56 micrograms/g (P < .0001). CONCLUSIONS: The three leading U.S. snuff brands (Copenhagen, Skoal fine cut, and Kodiak; making up 92% of the U.S. market) showed not only high levels of pH, nicotine, and unprotonated (free) nicotine, but also high concentrations of the strongly carcinogenic TSNAs in comparison with the fourth and fifth best selling moist snuff brands, Hawken and Skoal Bandits (3% of the U.S. market).

Carcinogens↗
PubMed2002

Effect of ethanol treatment on metabolic activation and detoxification of esophagus carcinogenic N-nitrosamines in rat liver.

In order to elucidate the mechanism underlying enhancement by ethanol of N-nitrosodiethylamine (DEN)- and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats, hepatic levels of cytochrome P-450 (CYP) enzymes, mutagenic activation of several N-nitrosamines and three kinds of UDP-glucuronyltransferase (UDPGT) activities were assayed in F344 rats. Immunoblot analyses of microsomal CYP proteins revealed induction of CYP2E1 (approximately 2-fold), but not CYP2B1/2, 1A1/2 or 3A2, by treatment with 10% ethanol in the drinking water for 2 weeks. In contrast, s.c. treatment with 0.5 mg/kg NMBA three times per week for 2 weeks produced no significant alterations in the levels of these CYP species. Ethanol treatment also elevated the mutagenic activities of N-nitrosodimethylamine (DMN), DEN and N-nitrosopyrrolidine (NPYR) in strain TA100 up to 2.1-, 1.6- and 2.3-fold above each control, respectively. However, this was not the cases for four N-nitrosamines, including NMBA, in strain TA100 and two heterocyclic amines and aflatoxin B(1) in strain TA98. In addition, ethanol did not affect UDPGT activities towards 4-nitrophenol, bilirubin and testosterone. Hepatic CYP species responsible for mutagenic activation of selected N-nitrosodialkylamines were confirmed by use of specific CYP inducers and inhibitors with the liver from F344 and Wistar rats, indicating that DMN, DEN and NMBA are selectively activated by CYP2E1, predominantly by CYP2E1 with a slight contribution by CYP2B2 and selectively by CYP2B1/2, respectively. These results demonstrate that ethanol exerts an enhancing effect on mutagenic activation by CYP2E1 of DMN, DEN and NPYR, but does not affect that of NMBA and the other carcinogens by CYP2B1/2, 1A1/2 and 3A2 and UDPGT1A1, 1A6 and 2B1 activities. Consequently, this suggests that enhancement by ethanol of DEN-induced esophageal carcinogenesis in F344 rats can be attributed to an increase in hepatic activation during the initiation phase, but that of NMBA-induced tumorigenesis is not attributable to metabolic activation and inactivation via glucuronidation in liver.

Animals↗
PubMed1989

Antimutagenic effects of betel leaf extract against the mutagenicity of two tobacco-specific N-nitrosamines.

Epidemiological studies have implicated chewing tobacco alone to be more hazardous than chewing tobacco with betel quid. Experimental studies have shown that betel leaf is antimutagenic against standard mutagens like benzo[a]pyrene and dimethylbenz[a]anthracene. Since the tobacco-specific N-nitrosamines (TSNA) are the only carcinogens present in unburnt forms of tobacco, including chewing tobacco, we tested the effect of an extract of betel leaf against the mutagenicity of the two important TSNA, viz., N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, using the Ames Salmonella/microsome assay with TA100 +S9 and the in vivo micronucleus test. In both the test systems it was observed that betel leaf extract suppressed the mutagenic effects of both the nitrosamines to a significant extent.

Animals↗
PubMedDate not supplied

Smoke yields of tobacco-specific nitrosamines in relation to FTC tar level and cigarette manufacturer: analysis of the Massachusetts Benchmark Study.

OBJECTIVES: This research assessed the relationship between the deliveries of carcinogenic tobacco-specific nitrosamines (TSNAs) and the Federal Trade Commission (FTC) "tar" ratings of US commercial cigarettes. METHODS: Analysis of covariance (ANCOVA) was used to assess the explanatory power of FTC tar, the particular manufacturer, and other cigarette characteristics to predict the yields of four TSNAs (N'-nitrosonornicotine [NNN], 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone [NNK], N'-nitrosoanatabine [NAT], and N'-nitrosoanabasine [NAB]) in 26 US commercial brands tested in the 1999 Massachusetts Benchmark Study. RESULTS: When FTC tar alone was used to predict TSNA yield, the squared correlation coefficient (R(2)) was only 38% for NNN, 76% for NNK, 46% for NAT, and 49% for NAB. Inclusion of manufacturer-specific variables significantly (p < 0.001) increased the estimated R(2) for three of the four species of nitrosamine to: 78% for NNN, 88% for NNK, and 81% for NAT. Inclusion of other cigarette characteristics (filter type, paper permeability, tobacco weight, tip dilution) did not reduce the significance of the manufacturer-specific effects. Federal Trade Commission nicotine and carbon monoxide (CO) yields were no better at predicting TSNA levels. CONCLUSIONS: FTC ratings for tar, nicotine, and carbon monoxide do not tell the entire story about the comparative yields of toxic agents in marketed cigarette brands. The significant manufacturer-specific effects suggest that proprietary blending and processing of tobacco matter as well. Public, brand-by-brand disclosure of the yields of TSNA and possibly other smoke constituents appears to be warranted.

Analysis of Variance↗
PubMedDate not supplied

Implications of the carcinogenic hazard of low doses of three hepatocarcinogenic N-nitrosamines.

The data of a large-scale experiment on single and combination effects of very low doses of the hepatocarcinogenic N-nitrosamines N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), and N-nitrosodiethanolamine (NDElA) were modeled by new statistical methods to derive implications of the carcinogenic hazard of dose ranges so low as to result in long-term toxic effects only slightly different from the background. According to this model a linear relationship was found to exist between daily exposure to low N-nitrosamine levels and time to death with liver tumor. Extrapolation of these data to zero exposure suggested the occurrence of one to ten percent of spontaneous liver tumors in animals surviving more than 1000 days. At this advanced age a further reduction of carcinogen-induced liver tumor incidence does not contribute to a longer overall survival due to competitive, probably independent, causes of death. A quasi-threshold in terms of a "no-observed-effect level" can thus be derived from the data. The observed combination effect indicates a mere additivity in liver tumor occurrence, even at very low doses which alone cause no significant carcinogenic effect during the animal's lifetime. Within the combination of NDEA, NPYR and NDElA, N-nitrosodiethylamine was found to be the most carcinogenic agent: it contributes by at least 17 orders of magnitude more to the relative risk of dying with liver tumor than the other two compounds, if the daily dose is increased by one unit (0.1 mg/kg). Likewise, NDEA shows the steepest slope when assessing the relationship between daily carcinogen doses and time to liver tumor occurrence; relative to NDElA--the least potent carcinogen on a weight basis--and NPYR a 40-fold and 9-fold quicker appearance of liver tumors has to be expected, if the daily doses are increased by an equivalent amount.

Animals↗
PubMed2000

Dose- and sex-related carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine in Wistar rats.

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control -- untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators) -- treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, drinking water), N, N'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0. 2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.

Animals↗
PubMed1981

The role of N-nitrosamine in carcinogenesis at the ureterocolic anastomosis.

Seven cases of colonic tumours occurring at the ureterocolic anastomosis (UCA) in patients diverted for benign disease are presented and comparisons made with existing literature. There appears to be a definite increase in the incidence of colonic malignancy in patients with this diversion. A theory of carcinogenesis involving bacterial activation of endogenously formed N-nitrosamine is suggested. Preliminary results of rectal urine analysis support this theory in that high concentrations of N-nitrosamine have been found mutagens demonstrated.

Adenocarcinoma↗
PubMed1993

Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis by compounds derived from cruciferous vegetables and green tea.

We have shown that PEITC and I3C, both of cruciferous origin, inhibited lung tumor formation induced by the tobacco-specific nitrosamine NNK. The inhibition by PEITC is due largely to its inhibitory effect on the enzymes of NNK metabolism, whereas; the inhibition by I3C may be attributed to its ability to induce hepatic enzyme activity of NNK metabolism, which resulted in decreased availability of NNK to the lung. On a molar basis, PEITC is considerably more effective than I3C. PEITC was released upon consumption of watercress. The N-acetylcysteine conjugate of PEITC is a promising urinary marker for quantitating uptake of this dietary anticarcinogen in humans. These studies also showed that green tea polyphenol EGCG inhibited the NNK-induced lung tumorigenesis, probably due to its antioxidant property. These studies provide for the first time evidence for the involvement of free radicals in nitrosamine tumorigenesis. The mechanism by which free radicals are generated by NNK treatment is not yet known. The reduced levels of oxidative lesions in lung as a result of EGCG treatment may be related to its ability to reduce reactive oxygen species and/or to chelate iron ion resulting in a decreased production of hydroxyl radicals. Overall, these studies have identified ingredients in cruciferous vegetables and green tea that are inhibitory against lung tumorigenesis induced by NNK in rodents.

Adenoma↗