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Carcinogenic effect of 14 N-nitrosamines related to N-butyl-N-(4-hydroxybutyl(nitrosamine (BBN) and N,N-dibutylnitrosamine (DBN) was studied in ACI/N male rats by administration in the drinking water. BBN homologs having methyl, ethyl, or pentyl group selectively induced urinary bladder tumors, but a homolog with tert-butyl group did not have any carcinogenic effect. N-Ethyl-N-(3-carboxypropyl)nitrosamine, the principal urinary metabolite of the ethyl homolog of BBN, did also induce bladder tumors selectively, thus providing an additional evidence that N-alkyl-N-(3-carboxypropyl)nitrosamines are responsible for the selective induction of bladder tumors by BBN homologs. N-Butyl-N-(carboxymethyl)nitrosamine and BBN analogs having 3-hydroxypropyl chain together with ethyl or butyl group were found to be noncarcinogenic. N-Propyl-N-butylnitrosamine and DBN induced hepatomas, but simultaneous development of esophageal tumors were observed only with the former. N-Butyl-N-(3-hydroxybutyl)nitrosamine, one of the principal metabolities of DNB, did not induce any tumors, but its further transformation product, N-butyl-N-(3-oxobutyl)nitrosamine as well as N-butyl-N-(2-oxobutyl)nitrosamine, another metabolic intermediate of DBN, induced hepatomas. Possible correlation of structure and metabolism with organotropic carcinogenesis by N-N-dialkylnitrosamines is discussed, with special reference to selective induction of urinary bladder tumors.
A hundred samples of total diets, 19 samples of cheese (mainly Dutch), a total of 30 samples of muscle, fat liver, kidney, blood and fried meat from experimental veal calves (fed daily with 0.6 or 300 mg of potassium nitrate per kg b.w.) and 14 samples of urine of patients medicated with massive amounts of ammonium nitrate (up to an equivalent of 180 mg potassium nitrate per kg b.w.) have been analysed with GC-TEA for their content of the following N-nitrosamines: NDMA, NDEA, NDPA, NDBA, NPIP, NPYR and NMOR. NDMA was frequently found, but always in the sub micrograms per kg range, except for two diets (1.2 and 1.7 microgram/kg). Other N-nitrosamines were sporadically found in the same concentration range, except for one diet (NPYR, 1.9 microgram/kg). No correlation was found between NDMA content and the composition of diets or the nitrate load of patients or veal calves. Mean daily intake of NDMA, potassium nitrate and sodium nitrite from total diets was calculated to be 0.5 microgram, 215 mg and 7.7 mg respectively. N-nitrosamine recoveries from the various samples were determined mostly at the 1 microgram/kg level. Contents of potassium nitrate and sodium nitrite are reported for 124 samples of various vegetables, 94 samples of canned baby food and 48 samples of human saliva, collected at various times after the intake of meals. Some kinds of vegetables showed high to very high nitrate contents, for example, purslane, red beets, spinach and lettuce. Only traces of nitrite were found in the vegetables. Salivary nitrite content was shown to be highly dependent on the dietary intake of nitrate and increased up to 60 times its initial value after the consumption of vegetable-rich meals.
The effects of the bladder carcinogens butyl(4-hydroxybutyl)nitrosamine (BBN) and butyl(3-carboxypropyl)-nitrosamine (BCPN) on proliferating transitional rat epithelium in organ culture were studied. At low to intermediate concentration ranges (0.5--2.9 mM), both compounds appeared to stimulate hyperplasia in some regions of epithelia. The major effect of both carcinogens, however, was to suppress hyperplasia in other regions of epithelia and, at higher concentrations (5--6 mM), to cause necrosis. For comparable concentrations, BBN was more effective in suppressing proliferation and causing necrosis than was BCPN.
The homologons alkyl-acetoxymethyl-nitrosamines were tested for carcinogenicity in SD rats. All compounds were found to be carcinogenic and induced within the same time carcinomas of the forestomach. The total doses necessary for induction of tumors are related to the length of the alkyl chain and hence to the watersolubility. These results are discussed.
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In parallel with a larger experiment on 4080 rats fed 16 different concentrations of N-nitrosodiethylamine (NDEA) or N-nitrosodimethylamine (NDMA) from 6 weeks of age, a variety of smaller experiments on a total of 1040 rodents were undertaken and are the subject of the present report. Three separate subjects were addressed. Studies of 16 different concentrations of N-nitrosopyrrolidine and N-nitrosopiperidine given from age 6 weeks onwards to small groups of rats yielded dose-response relationships for the effects of N-nitrosopyrrolidine on liver tumors and for those of N-nitrosopiperidine on tumors of the liver and upper gastrointestinal tract that resembled those seen for NDMA and NDEA, respectively, except that N-nitrosopyrrolidine and N-nitrosopiperidine were less potent [the respective dose rates needed to halve the proportion of tumorless survivors after 2 years of treatment being approximately 0.4 (males) and 0.6 (females) mg/kg adult body weight/day for each agent]. Alternatively, it was estimated that the risks to rats from lifelong exposure to 1 microgram/kg adult body weight/day of each agent might be about 0.1%, and that the risks to rats from lower doses would be proportionately less. Studies of 16 different concentrations of NDEA on small groups of female mice and female hamsters yielded the types of dose response that would be expected for upper gastrointestinal tumors, liver cell tumors, and Kupffer cell tumors in mice (no other types of liver tumor being produced, in contrast with previous reports) and for tracheal and liver cell tumors in hamsters (no clear effect on upper gastrointestinal tumors being apparent in hamsters). The dose rates needed to halve the proportion of tumorless survivors after 2 years of treatment were approximately 0.3 mg/kg adult body weight/day, i.e., 5 times that for the same agent in rats. In part, however, this may be because treatment started at an older age in these species. Studies were undertaken of the effects on esophageal and liver tumorigenesis of starting the treatment of rats with NDEA at 3 or at 20 weeks of age instead of at 6 weeks of age (as in the main experiment). Earlier treatment resulted in slightly greater dosage rates, if dosage was measured in mg/kg/day, and hence in a correspondingly more rapid yield of esophageal tumors, but the effect was not large. By contrast, an earlier start to treatment resulted, after a fixed duration of treatment, in animals having a 3-fold higher incidence rate of liver tumors, while a later start resulted in a 2-fold decrease.(ABSTRACT TRUNCATED AT 400 WORDS)
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The influence of various dietary constituents--phenethylisothiocyanate (PEITC), oleic acid (OA), triolein (TO), and vitamin A (ROL)--on the genotoxic activity of nitrosamines (NDMA, NDELA, NPYR) was investigated. For this purpose differential DNA repair assays with Escherichia coli K-12 strains were performed in vitro and in vivo with mice. Under in vitro conditions (liquid holding), all compounds reduced nitrosamine induced DNA-damage in the indicator bacteria in the dose range 1-10 micrograms/ml, the ranking order of efficiency being PEITC greater than OA greater than ROL greater than or equal to TO. In animal-mediated assays, acute oral treatment with PEITC (17-150 mg/kg), 2 h before nitrosamine administration, resulted in a marked decrease of nitrosamine genotoxicity in liver, kidneys, lungs and in the blood. Also in other organs (spleen, testes) an increase in differential survival (which serves as a measure for repairable DNA damage) occurred. With ROL only a comparatively moderate antigenotoxic effect was obtained at a high dose level (250 mg/kg) under identical experimental conditions. OA (2000 mg/kg) and TO (16,000 mg/kg) were completely inactive. Upon repeated treatment (consecutive oral administration of the putative antigenotoxins over 4 days, a final treatment 24 h before nitrosamine administration) PEITC (150 mg/kg/day), ROL (80 mg/kg/day) and OA (2000 mg/kg/day) had no influence on the genotoxic effects of the nitrosamines. Repeated treatment with TO (4000-16,000 mg/kg/day) resulted in a moderate dose-dependent reduction of NDMA-induced DNA-damage in the indicator bacteria, whereas in combination with NPYR only a marginal effect was observed. Biochemical experiments indicated that the antigenotoxic effects of PEITC seen under in vivo conditions were due to inhibition of alpha-hydroxylation of the nitrosamines, whereas ROL and TO appeared not to interfere strongly with this metabolic activation step. Our results indicate that in vitro assays do only partly reflect the antigenotoxic properties of the different food constituents in vivo and that animal-mediated DNA repair assays with E. coli strains are an appropriate approach to study the effects of modifiers of nitrosamine genotoxicity in the living animal.
The formation of carcinogenic N-nitrosamines in neutral and alkaline aqueous solutions (pH 6-14) at 25 degrees C is reported using dissolved N2O3 and N2O4 gases. These reactions are very much faster than those with acidified nitrite: typically, 2 X 10(-3) M amine gives ca. 10-50% N-nitrosamine in a few seconds with 5-20 fold excess of nitrogen oxide. The N-nitrosamine yield in 0.1 M sodium hydroxide is independent of amine basicity from pKA 11.2-0.99, but decreases with decreasing pH of the reaction solution for the more basic amines. Significantly, N-nitrosamine yields are not lowered with diluted nitrogen oxides (1000 ppm) and moderately basic amines (eg. N-methylpiperazine) react readily at physiological pH. The mechanism by which these reactions occur is discussed, with particular reference to the existence of two reactive tautomeric forms of N2O3 and N2O4. The formation of carcinogenic N-nitrosamines from NO in ethanol at 25 degrees C is also reported. These reactions are slow in the absence of air (oxygen), I2 or metal salts. Oxygen accelerates nitrosation by converting NO via NO2 to either N2O3 or N2O4, but both I2 and metal salts are effective under anaerobic conditions, where reaction rates are virtually independent of amine basicity but depend on the nature of the added reagent. The most effective substance is I2, which gives quantitative yields of N-nitrosamine in a few minutes at 25 degrees C by forming the reactive nitrosyl iodide (NOI) reagent. Acceleration in ethanol at 25 degrees C is also observed with AgI, CuI, CuII, ZnII, FeIII and CoII salts, among others, with substantial amounts of N-nitrosamine being produced in ca. 30-300 min. Metal iodides intervene by way of the NOI reagent, as for I2, but other salts require a mechanism involving reaction between a metal-amine complex and NO, itself. The results show that carcinogenic N-nitrosamines may form under a much wider range of experimental conditions than suspected hitherto. Their relevance to human exposure is discussed, with particular reference to urban pollution and the effect of dietary antioxidants.
Volatile nitrosamines from the smoke of different cigarettes were enriched by manifold clean-up procedures. Amines obtained after acid catalyzed denitrosation were transformed to fluorescent derivates of 7-chloro-4-nitrobenzofuranzane (NBD-Cl). These NBD-amines separated on polyamid sheets were fluorimetrically determined with a chromatogram-spectrophotometer. Recovery rates of 60--80% were found for the different nitrosamines in cigarette smoke condensate. The following nitrosamines were quantitatively determined: N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopiperidine, N-nitrosopyrrolidine, N-nitrosoethylmethylamine, N-nitroso-ethyln-propylamine and N-nitroso-methyl-n-propylamine, N-nitroso-ethyl-n-propylamine and N-nitroso-methyl-n-propylamine. The last mentioned nitrosamine was proved for the first time in cigarette smoke. At the same time correlations between the nitrosamine content of the corresponding tobacco or condensate and the content of nitrate, total nitrogen, nicotine, volatile bases and ammonia were investigated. The nitrate content as well as the content of volatile bases showed an influence on the nitrosamine yield. The content of the different nitrosamines varied cosiderably depending on tobacco origin, so that a NNO-determination is recommended as index.
A total of 391 gastric juice samples was collected from Ji Yuan and An Shi counties, high and medium risk areas of esophageal carcinoma in Henan province. NDMA, NDEA, NMBzA, NPip and unknown compounds were assayed in the fasting gastric juice. Among these nitrosamines, NMBzA, NPyr and NPip were specific in inducing esophageal cancer in animals. The amount of nitrosamines in the gastric juice collected from Ji Yuan county was higher than that from An Shi county. The exposure level of nitrosamines of subjects from these two localities were significantly different (P < 0.001). There was a positive relationship between the nitrosamines exposure level and esophageal cancer mortality rate. The amount of gastric N-nitrosamines from An Shi subjects as treated with vitamin C was reduced. It is evident that vitamin C can inhibit N-nitrosamine formation in the stomach, thereby, reducing the N-nitrosamines exposure level.
Nitrosamines are toxic chemical compounds found low in quantity, but widespread in the environment. This work investigated the kinetics of chemical reaction of activated nitrosamines with various organic substrates. The mechanism by which nitrosamines react demonstrates possible pathways in which the toxicity is expressed. Once activated nitrosamines are very reactive. Chemical compounds which can act as nucleophilic substrates may be alkylated by the activated nitrosamines. A broad category of chemical compounds are shown to be suitable substrates for nitrosamine induced alkylation. This large category of substrates suggests a substantial potential for toxic activity in vivo. By investigating the reaction kinetics of activated nitrosamines a greater understanding of their toxic effects may be possible.
All of the 4 noncarcinogenic nitrosamines (NA) and 4 of 7 carcinogenic nitrosamines examined increased the urinary ascorbic acid output after oral administration to rats. Of the remaining carcinogenic nitrosamines, dimethyl-NA decreased, and diethyl-NA and methyl-n-pentyl-NA only marginally affected ascorbic acid output. All of the carcinogenic nitrosamines, except dipentyl-NA, increased pentobarbital-induced sleeping time (PST), serum glutamic oxalacetic transaminase (SGOT) and produced loss of glycogen and necrosis in the centrologular area of the liver after 1 or 3 oral doses. In contrast, noncarcinogenic nitrosamines and dipentyl-NA shortened PST and had no effect on liver histology (light microscopy) and SGOT. Generally, changes in ascorbic acid output correlated neither with carcinogenicity nor acute hepatotoxicity of known nitrosamines, hence the ascorbic output could not be used to predict the carcinogenicity of unknown or untested nitrosamines.
The interactions of 5 carcinogenic and 1 non-carcinogenic nitrosamines with hepatic microsomal cytochrome (cyt.) P-450 were investigated, using both optical difference and electron paramagnetic resonance (EPR) spectroscopic methods. Liver microsomes from phenobarbital (PB)-pretreated mice and 3-methylcholanthrene (3-MC)-pretreated rats were used, in order to have an increased specific content of cyt. P-450 and cyt. P-448 respectively. The optical and EPR spectral data obtained in the oxidised state suggest that nitrosamines are able to bind both as substrates and as ligands to the hemoprotein cyt. P-450, depending on the concentration of nitrosamine, its chemical identity and the cytochrome species present. After reduction with dithionite or NADPH in the optical difference spectrum a Soret band developed between 444 and 453 nm to an extent, which is dependent on the particular nitrosamine present. This initial nitrosamine-induced spectrum might represent a ferrous nitric oxide (NO)-cyt. P-450 complex. It appears unstable and is converted kinetically into a spectrum lacking a Soret band, but with a predominant absorbance minimum at about 425 nm. A visible band is located at 585 nm. In the EPR spectrum a sharp 3-line signal around g = 2.01 appears concomitantly. Both spectral parameters are typical of a NO-cyt. P-420 complex. These results, in conjunction with metabolic studies, indicate that nitrosamines are denitrosated by a reductive process in which cyt. P-450 appears to be involved. The resulting NO-cyt. P-450 complex denatures to a NO-cyt. P-420 complex when the dioxygen level is not sufficiently high to complete successfully.
5 nitrosamines formed from the nitrosation of spermidine were investigated for mutagenicity using various strains of Salmonella typhimurium in the presence and absence of S9 mix. Using the plate incorporation method, 3-butenyl-(2-propenyl)-N-nitrosamine, 3-hydroxybutyl (2-hydroxypropyl)-N-nitrosamine, 4-hyroxybutyl-(2-hydroxypropyl)-N-nitrosamine, 4 hydroxybutyl-(3-hydroxypropyl)-N-nitrosamine, and in the liquid test 3-hydroxybutyl-(3-hydroxypropyl)-N-nitrosamine were mutagenic in the absence of S9 mix.
Twenty rats were randomized into a vesicosigmoidostomy and an unoperated control group. In both groups the 24 hour excretion of secondary amines, nitrate, nitrite and nitrosamines was measured before and after gavage of proline and nitrate, piperazine and nitrate, N-nitrosoproline, mono-N-nitrosopiperazine. The urinary nitrosamine concentrations were not significantly different between both groups neither before nor after application of the several substances. Thirty rats were randomized into two vesicosigmoidostomy groups with and without antibiotic coverage and an unoperated control group. After ligation of distal rectum and mesosigmoid the rectosigmoids were removed. No significant concentrations of volatile nitrosamines could be measured in the rectosigmoid contents of the three groups. One hundred and twenty rats randomized into three groups following vesicosigmoidostomy received the potential nitrosamine antidotes sodium-2-mercaptoethane sulfonate or sodiumpentosan-polysulfate or acted as controls. 12/118 (10.2%) developed adenomas and 25/118 (21.2%) adenocarcinomas at the vesico-colonic anastomosis with no significant differences between the three groups concerning tumor incidence or mortality. The results show that colon carcinomas occur in a rat model for ureterosigmoidostomy without evidence for thus induced nitrosamine formation. This and the missing effect of nitrosamine antidotes suggest that other factors than nitrosation must be responsible for colon carcinogenesis following urinary diversion via intestine.
An acetyltransferase-overexpressing strain of Salmonella typhimurium (NM2009) has been used to investigate roles of human liver microsomal cytochrome P450 (P450) enzymes in the activation of carcinogenic nitrosamine derivatives, including N-nitrosodialkylamines and tobacco-smoke-related nitrosamines, to genotoxic products. Studies employing correlation of activities with several P450-dependent monooxygenase reactions in different human liver samples, inhibition of microsomal activities by antibodies raised against human P450 enzymes and by specific P450 inhibitors, and reconstitution of activities with purified P450 enzymes suggest that the tobacco-smoke-related nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and N-nitrosonornicotine (NNN) as well as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are oxidized to genotoxic products by different P450 enzymes, particularly P450 2E1 and 2A6. The activation of NDMA and NNN by liver microsomes was suggested to be catalyzed more actively by P450 2E1 than by other P450 enzymes because the activities were well correlated with NDMA N-demethylation and aniline p-hydroxylation in different human samples, and purified P450 2E1 had the highest activities in reconstituted monooxygenase systems. The relatively high contribution of P450 2A6 to the activation of NDEA and NNK was supported by the correlation seen with coumarin 7-hydroxylation in human liver microsomes, and antibodies raised against P450 2A6 inhibited both activities by approximately 50%. P450 3A4, 2D6 and 2C enzymes appear not to be extensively involved in the activation of these nitrosamines as judged by several criteria examined. Thus, this work indicates that several P450 enzymes, particularly P450 2E1 and 2A6, catalyze metabolic activation of nitrosamine derivatives including N-nitrosodialkylamines and tobacco-smoke-related nitrosamines in human liver microsomes.