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PubMed1994

Metabolism of nitrosamines and aflatoxin B1 by hamster liver CYP2A enzymes.

Using a specific antibody against mouse CYP2A5 and coumarin as inhibitors, and pretreatments known to affect the activities of CYP2A-related enzymes, we studied the contribution of hamster liver CYP2As in the dealkylation of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and hydroxylation of aflatoxin B1 (AFB1). CYP2A5 antibody inhibited AFB1 and NDEA metabolism by 40-60% in untreated hamsters and after treatment with phenobarbital (PB) or 3-methylcholanthrene (MC). After pyrazole (PYR) treatment, there was no inhibition, although PYR increased the metabolism above the controls. NDMA metabolism was inhibited only weakly in all groups. This suggests that CYP2As may contribute significantly to NDEA and AFB1 metabolism and less to NDMA metabolism in untreated hamster liver and after MC or PB treatments, but that PYR treatment may change the expression pattern of CYPs so that the metabolism is mainly catalysed by CYPs not recognized by the antibody. Coumarin inhibited NDEA and NDMA metabolism in all groups of hamsters, including pyrazole-pretreated animals, suggesting that it interacts not only with CYP2As but also with other CYPs that are important in nitrosamine metabolism. On the other hand, coumarin inhibited AFB1 metabolism significantly only in control and PB-treated animals but not at all after PYR or MC treatment. This suggests that enzymes involved in AFB1 metabolism may be different depending on the pretreatment. It is concluded that CYP2As may contribute significantly to nitrosamine and aflatoxin metabolism in hamster liver. However, in view of previous results showing essential differences in their regulation between mouse and hamster, interspecies comparisons may be difficult.

Aflatoxin B1↗
PubMed1979

Gas chromatographic separation of hydroxylated N-nitrosamines.

Derivatives of six hydroxylated N-nitrosamines were prepared by acylation, trifluoroacylation, trimethylsilylation and methylation, and the volatilities and sensitivities of these derivatives on gas chromatographic detection were compared. All six nitrosamines were successfully derivatized by either acylation or trimethylsilylation. The acylated derivatives were easy to prepare; in addition, acylation was more specific than trimethylsilylation for the reaction with hydroxyl groups in the molecule.

Acylation↗
PubMedDate not supplied

Activation of nitrosamines and other carcinogens by mouse-liver S9, mouse hepatocytes and in the host-mediated assay produces different mutagenic responses in Salmonella TA1535.

5 indirect alkylating carcinogens, namely, dimethylnitrosamine (DMNA), methylethylnitrosamine (MENA), diethylnitrosamine (DENA), 1,2-dimethylhydrazine (DMH) and cyclophosphamide (CP), were tested in liquid incubation assays for their mutagenic activity towards Salmonella TA1535 in the presence of mouse-liver homogenate (S9) or freshly isolated, single liver-cell preparations. The capacity of these mouse-liver preparations to activate the compounds to mutagens for TA1535 was compared with the mutagenic effect of low doses of the carcinogens in intrasanguineous host-mediated assays, with the same strain of mice as host. Although the mouse hepatocytes retained their activating capacity longer than S9 preparations did during incubation at 37 degrees C, the latter gave much higher yields of mutants with 10 mM (DMNA, MENA, DMH) and 5 mM (CP) of 4 out of the 5 compounds. DENA was not mutagenic in either assay. These differences between whole cell and disrupted cell preparations were reduced or absent when the concentrations of the test compounds were reduced by a factor of 10. It was concluded that hepatocytes at the maximal concentration of cells have a limited capacity to metabolize the mutagens. On the basis of protein concentration, hepatocytes are more effective (nitrosamines) or equally effective (CP and DMH) in activating the compounds. Compared with the host-mediated assays, both liver fractions have only a marginal potential to activate equal low amounts of the carcinogens. The present results do not indicate that hepatocytes take an 'intermediate' position between existing in vitro and in vivo activation systems, although they do suggest that these mouse hepatocyte preparations activate the nitrosamines DMNA and MENA in a quantitatively or qualitatively different way than do mouse-liver homogenates.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Role of DNA methylation in the activation of proto-oncogenes and the induction of pulmonary neoplasia by nitrosamines.

The relationships between DNA methylation and repair induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the activation of proto-oncogenes and the induction of pulmonary neoplasia by this carcinogen is described. The formation of the O6-methylguanine (O6MG) adduct following metabolic activation of NNK appears to be a major factor in the induction of lung tumors in both rats and mice and in the activation of the K-ras oncogene in lung tumors from A/J mouse. The potent carcinogenicity of NNK in the rat lung correlated strongly with cell specificity for formation and persistence of the O6MG adduct in the Clara cells. This conclusion was supported by studies with nitrosodimethylamine (NDMA), a weak carcinogen in the rodent lung. Treatment with NDMA was not associated with any pulmonary cell specificity for DNA methylation. The high affinity for activation of NNK compared to NDMA was ascribed to a difference in cytochrome P-450 isozymes involved in the activation of these two nitrosamines. In the A/J mouse, the induction of pulmonary tumorigenesis involved direct genotoxic activation of the K-ras proto-oncogene as a result of the base mispairing produced by formation of the O6MG adduct. In contrast, the induction of pulmonary tumors in the rat by NNK does not appear to involve the ras pathway. It is apparent that different molecular mechanisms are involved in the development of pulmonary tumors by NNK in the mouse and rat. The studies described in this paper illustrate the utility of performing dose-response experiments and the quantitation of DNA methylation and repair in not only target tissues but also target cell types. The fundamental knowledge gained from unraveling the mechanism of carcinogenesis by NNK could lead ultimately to the identification of factors important in the development of human lung cancer.

Animals↗
PubMed1991

The genotoxicities of N-nitrosamines in Drosophila melanogaster in vivo: the correlation of mutagenicity in the wing spot test with the DNA damages detected by the DNA-repair test.

The genotoxicities of a series of N-nitrosamines were assayed in the wing spot test and a new short-term test of Drosophila melanogaster. In the spot test, larval flies trans-heterozygous for the somatic cell markers mwh and flr3 were fed the test reagents and the wing hairs in adults were inspected for clones expressing the phenotypes of the markers. In the other test, larval stock consisting of meiotic recombination-deficient (Rec-) double mutant mei-9a and mei-41D5 males and repair-proficient Rec+ females were grown on feed containing the reagents and the DNA damages were detected with the preferential killing of the Rec- larvae as an endpoint. The carcinogenic nitrosamines tested, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodi-n-butylamine (NDBA), N-nitrosomorpholine (NMOR), N-nitro-sopiperidine (NPIP) and N-nitrosopyrrolidine (NPYR), all showed clearly positive activities in both tests. The activities in the wing spot test were ranked in a sequence of NDMA much greater than NMOR greater than NPIP greater than NDEA greater than NPYR greater than NDBA. A similar ranking was obtained in the repair assay. The genotoxicity of N-nitrosodiphenylamine (NDPhA), carcinogenicity studies of which are inconclusive, was marginal in the spot test. The non-carcinogenic N-nitrosoproline (NPRO) and the non-mutagenic N-nitrosothioproline (NTPRO) were negative in the spot test. NDPhA and NPRO were negative in the repair test as well. The DNA-repair test is thus a convenient technique for estimating the mutagenicity of compounds because of its simplicity compared with the wing spot test. These Drosophila tests may be useful in predicting carcinogenic potentials of compounds.

Animals↗
PubMed1980

The pH-dependent response of Salmonella typhimurium TA100 to mutagenic N-nitrosamines.

The mutagenicity of some N-nitrosodialkylamines, i.e. N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodi-n-butylamine, N-nitrosomorpholine and N-nitrosopyrrolidine, was assayed on Salmonella typhimurium TA100 by the pre-incubation method, and the effect of changing the pH of the pre-incubation mixture was examined. Markedly higher mutagenicities were observed when the pre-incubation of bacteria with nitrosamine and S9 mix was done at pH 5.2, compared with mutagenicities observable after the pre-incubations at conventional pH 7. Pre-incubations at pH 6.2 resulted in responses of intermediate strength. With phenobarbital-induced rat S9, the ratios of mutagenic potency found by the pH 5.2 pre-incubation to that found by the pH 7.2 preincubation were 15-30 for N-nitrosodimethylamine, 5-10 for N-nitrosodiethylamine, 10-20 for N-nitrosodi-n-butylamine, 2-3 for N-nitrosomorpholine and 4-6 for N-nitrosopyrrolidine. The mutagenic potency of each nitrosamine varied with the change of S9 source. The S9 sources examined were PCB-induced rat and mouse livers, and uninduced rat and mouse livers. No exceptions were observed for these S9 preparations regarding the higher mutagenicity at pH 5 than at pH 7. It is speculated that the higher mutagenicity observed by the pH 5 pre-incubation was due to the stability of the active intermediate, alpha-hydroxynitrosodialkylamines, in weakly acidic media.

Animals↗
PubMed1984

Effect of organic solvents and unsaturated fatty acids on nitrosamine formation.

Formation of N-nitrosodimethylamine in chloroform or in mixtures of chloroform/citrate buffer or methyl stearate-chloroform (1:9)/citrate buffer was faster than that in citrate buffer alone. The chemically inert non-aqueous solvent may increase the level of the non-ionized active species of the nitrosating agent. The presence of unsaturated fatty acid methyl esters in chloroform suppressed formation of N-nitrosodimethylamine compared to that in chloroform alone but, because of the non-aqueous solvent effect, nitrosamine formation was slightly higher than that in citrate buffer. Fats containing unsaturated fatty acids also inhibited nitrosamine formation in chloroform indicating that the unsaturated fatty acid residues were effective scavengers of the nitrosating agent. Methyl linoleate was converted into peroxide(s) with carbonyl or carbonyl-liberating functions by reaction with nitrous acid, although it is not clear whether the reaction was relevant to the loss of nitrous acid.

Chemical Phenomena↗
PubMed1986

N-nitrosamines in the saliva of tobacco chewers or masheri users.

Saliva was collected from men and women who were habitual chewers of tobacco (with lime or betel quid) and from women who used masheri. The saliva was analysed for tobacco-specific nitrosamines (TSNAs). TSNAs were detected in the saliva of all tobacco users, but within each habit group there were wide variations between donors in salivary nitrosamine levels. TSNA levels in the saliva from men and women chewing betel quid and tobacco were similar, although women used less tobacco for chewing. The saliva of men who chewed tobacco with lime contained higher levels of TSNAs than did that of men who chewed betel quid with tobacco.

Adult↗
PubMed1988

Carcinogenesis in rats by cyclic N-nitrosamines containing sulphur.

The effects of chronic exposure to three sulphur-containing heterocyclic N-nitrosamines were determined after repeated oral administration to female Fischer 344 rats. Nitrosothiazolidine did not significantly affect the survival of the rats or the incidence of tumours at a total dose of 3.5 mmol. Nitrosodithiazine, an analogue of nitrosothiazolidine which contains an extra sulphur atom inserted between the carbons of its CH2-CH2 moiety, produced only three tumours (two of the nasal mucosa) in a group of 20 rats at a total dose of 1.75 mmol/rat. Nitrosothialdine, the all-cis 2,4,6-trimethyl analogue of nitrosodithiazine, was a potent carcinogen that significantly shortened the lifespan and produced oesophageal tumours in 70% of treated rats as well as numerous tumours of the tongue and liver; this outcome was unexpected because alpha-methyl substitution in other heterocyclic nitrosamines usually reduces or eliminates tumorigenicity. The results extend the data base on the carcinogenic activity of molecules containing both divalent sulphur and the nitrosamino function. The lack of significant carcinogenicity of nitrosothiazolidine in this study suggests that its presence in the human food supply presents a relatively minor risk.

Animals↗
PubMed1988

N-nitrosamines in Chinese foods.

A total of 695 different Chinese foods and ten malt samples were analysed, using gas chromatography-thermal energy analysis, for the possible presence of volatile N-nitrosamines. N-Nitrosodimethylamine (NDMA) was found in 146 of 176 beers tested at concentrations ranging from 0.1 to 6 ppb. NDMA was also detected in 201 of 271 meat products tested at concentrations ranging from 0.1 to 7.4 ppb. High levels of NDMA, up to 131.5 ppb, were detected in some seafoods and were further confirmed by gas chromatography-mass spectrometry. Milk products were found to contain less than 0.1-3.6 ppb NPYR, less than 0.1-5.7 ppb NDMA and less than 0.1-0.7 ppb NPIP, while in flavourings the nitrosamine concentrations were less than 0.1-10.3 ppb NPYR, less than 0.1-3.6 ppb NDMA and less than 0.1-0.9 ppb NPIP. Pickled vegetables contained less than 0.1-25.5 ppb NPYR and less than 0.1-15 ppb NDMA.

Alcoholic Beverages↗
PubMed1990

The migration of tobacco-specific nitrosamines into the saliva of chewers of nicotine-containing chewing gum.

In many countries nicotine-containing chewing gum (Nicorette) is used to help to break the habit of smoking. Saliva was collected every 5 min from chewers of nicotine chewing gum and analysed for tobacco-specific nitrosamines. Detectable levels of tobacco-specific nitrosamines were found in all samples collected between 5 and 15 min after chewing had started. The levels of N'-nitrosonornicotine ranged from 0.4 to 19 ng/g of saliva and those for the sum of N'-nitrosoanatabine plus N'-nitrosoanabasine from 1.3 to 46 ng/g. 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone was not detected in the saliva. The nicotine chewing gum was found to contain up to 380 ng tobacco-specific nitrosamines/g of chewing gum.

Adult↗
PubMed1991

Mean daily intake of volatile N-nitrosamines from foods and beverages in West Germany in 1989-1990.

The levels of volatile N-nitrosamines were determined in 38 alcoholic drinks and 215 food samples prepared for human consumption using standard culinary practices. The analyses used gas chromatography-thermal energy analysis. Detectable levels were found in 80 (31.5%) of the individual samples. The average daily intake of volatile N-nitrosamines in West Germany in 1989-1990 was found to be: 0.28 microgram N-nitrosodimethylamine (NDMA)/day, 0.011 microgram N-nitrosopyrrolidine (NPYR)/day and 0.015 microgram N-nitrosopiperidine (NPIP)/day for men, and 0.17 microgram NDMA/day, 0.011 microgram NPYR/day and 0.015 microgram/NPIP/day for women. For men, 31% of the daily NDMA exposure results from the consumption of beer.

Adult↗
PubMed1992

Nitrosamines in rubber bands used for orthodontic purposes.

Fourteen samples from eight brands of elastic-rubber bands used in orthodontics were tested for their nitrosamine content. The presence of N-nitrosodibutylamine and N-nitrosopiperidine was confirmed. The potential for nitrosamine formation from accelerating agents used for vulcanization and from other nitrosatable amines, which may be present in rubber exposed to salivary nitrite, justifies further investigations.

Nitrosamines↗
PubMed1993

Preformed volatile nitrosamines in some Nigerian foodstuffs.

Some common Nigerian foodstuffs were assessed for their content of preformed volatile nitrosamine by chemiluminescence detection following gas chromatographic separation. Nitrosodimethylamine levels of between 0.4 and 4.6 ppb were detected in 75% of the samples analysed. The highest value was found in Brassica oleraceae, while Vernonia amygdalina contained the lowest detectable level. These data suggest that Nigerians may be exposed to chronic but very low levels of carcinogenic nitrosamines in their foods.

Brassica↗
PubMed1978

Studies on the gastrointestinal absorption of N-nitrosamines: effect of dietary constituents.

Studies on the intestinal absorption of N-nitrosodimethylamine (DMN) in the rat have shown that the presence of dietary constituents such as fat markedly reduced the rate of disappearance of this nitrosamine whereas the presence of protein and carbohydrate had little effect on the absorption rate. Fat was also found to reduce the absorption rate of N-nitrosodiethylamine (DEN), N-nitrosopyrrolidine (NPY) and N-nitrosopiperidine (NPIP). Further it was confirmed that the small-intestinal tract of the rat has the ability to degrade DMN. The implications of these findings are discussed in terms of the biological fate of orally ingested nitrosamines.

Animals↗
PubMed1982

Calculations and measurements on the volatility of N-nitrosamines and their aqueous solutions.

The vapour pressures of 30 N-nitrosamines between 0 and 40 degrees C are calculated by means of well-known and experimentally proven formulae. The saturation concentration of the nitrosamines in air is presented as mmHg, ppm and mg/m3. For N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosopyrrolidine (NPYR) the calculated values are compared with actual measurements in the same temperature range and are found to coincide very closely. Furthermore the partial pressures of NDMA, NDEA and NPYR over an aqueous solution were experimentally determined and are tabulated in mmHg and mg/m3, for practical purposes. The calculations have been programmed in BASIC on a scientific computer, however, commercial programmable pocket calculators would also have been sufficient.

Mathematics↗
PubMed1988

Effect of butylated hydroxyanisole added in vitro or administered to rats on N,N-dibutylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine metabolism by post-mitochondrial supernatant of liver homogenates.

The effect of butylated hydroxyanisole (BHA) on P-450-dependent omega-hydroxylation of N,N-dibutylnitrosamine (NDBA) to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and the further oxidation of BBN to N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) by the alcohol/aldehyde dehydrogenase system was investigated using the post-mitochondrial supernatant of liver homogenates (S9) from acutely and chronically BHA pretreated animals or S9 fractions from untreated rats with BHA added. Acute oral BHA (50 and 250 mg.kg-1) did not change NDBA omega-oxidation, which was reduced by 35% only when the compound was administered 0.5% in the diet for 3 weeks. BCPN formation from BBN was unaffected by acute and chronic BHA pretreatment. In order to verify whether BHA or its metabolite(s) had a direct effect on NDBA and BBN oxidation, the compound was added to S9 fractions from untreated rats at various concentrations. Only when BHA concentrations were equimolar or in a 10-fold molar excess to the substrate concentration, we observed 30-50% inhibition of BBN formation and a reduced BCPN formation (60-80% of control values), from BBN. Thus, only at very high BHA concentrations could we confirm the inhibition of P-450-dependent mixed function oxidase and alcohol dehydrogenase activities involved in the metabolism of NDBA and BBN.

Administration, Oral↗
PubMed1984

Carcinogenesis in rats by asymmetric nitrosamines containing an allyl group.

Four asymmetric nitrosamines containing 1 allyl group were administered to rats in drinking water to aid in understanding the failure of nitrosodiallylamine ( NDAA ) to induce tumors in rats. Three of the compounds were given at equimolar doses, the fourth at somewhat lower dose. All four nitrosamines induced tumors of the esophagus and/or nasal cavity. Nitrosoallylethanolamine (NAE) induced a 30% incidence of hepatocellular carcinomas, while nitrosoallyl -2- hydroxypropylamine induced 70% hepatocellular carcinomas and a much lower dose of nitrosoallyl -2- oxopropylamine induced 80% of hepatocellular carcinomas, several of which metastasized. Nitrosoallyl -2,3- dihydroxypropylamine , which increased the mortality from tumors much more than the other compounds, failed to induce tumors in the liver, but induced a high incidence (85%) of tumors of the esophagus. The conclusion is that the allyl group is not metabolically inert, but that its presence in these molecules modifies their metabolism so as to give rise to tumors in a variety of organs. It does not seem that formation of an allylating agent is the common mechanism of carcinogenesis by these compounds.

Allyl Compounds↗