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PubMed1989

The utilization of whole-body autoradiography and allied tracer techniques in distribution and biotransformation studies of N-nitrosamines.

The tissue-disposition of various N-nitrosamines has been examined by whole-body autoradiography and allied tracer techniques in a series of studies at our department. Tracing of N-nitrosamine-metabolizing tissues was a major purpose of the studies. The data obtained provide evidence that the in vivo localization of N-nitrosamine metabolites in various tissues is almost invariably due to local metabolism in the same tissues and that the tumourigenesis by N-nitrosamines is to a considerable extent correlated with this metabolism. The epithelial linings of the upper digestive tract and respiratory pathways were usually very active in N-nitrosamine metabolism, and these tissues also were prevalent sites for N-nitrosamine-carcinogenesis. The presence of cytochrome P-450-activity has been shown in these structures and may normally play a role in defending the body against unrestrained uptake of xenobiotics. However, noxious effects may instead be induced for chemicals bioactivated by cytochrome P-450-dependent reactions, such as N-nitrosamines.

Animals↗
PubMed1984

Carcinogenicity and metabolic activation of tobacco-specific nitrosamines: current status and future prospects.

Over the past decade, research on the carcinogenicity and metabolism of tobacco-specific nitrosamines has provided a basis for understanding their possible roles in human cancer. 4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone appears to be the most important tobacco-specific nitrosamine, because of its strong carcinogenicity. A large population of smokers and snuff dippers is exposed to significant quantities of this and the other tobacco-specific nitrosamines on a daily basis. Further research should now focus on the relationship between human exposure to tobacco-specific nitrosamines and the risk of developing tobacco-related cancers. Several important areas can be identified: we need to develop sensitive assays that can be used routinely to quantify the levels of tobacco-specific nitrosamines or their metabolites in human blood, and the levels of their DNA adducts in human tissues; we need to establish, through comparative metabolic and DNA-binding studies, the relationships between the organospecificity of tobacco-specific nitrosamines in experimental animals and that in humans; we may also be enabled to identify naturally-occurring substances that can inhibit carcinogenesis by tobacco-specific nitrosamines. These research approaches will hopefully lead to a reduction in the incidence of tobacco-related cancers.

Animals↗
PubMed1978

A comparison of ascorbic acid excretion with other indicators of nitrosamine hepatotoxicity.

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.

Animals↗
PubMed1980

Investigations on formation and occurrence of volatile nitrosamines in Danish cheese.

The formation and occurrence of volatile nitrosamines in Danish cheese has been studied. The investigations showed that nitrosamines are evenly distributed within a given cheese and between cheeses from the same lot. No influence of production factors, such as nitrate addition, composition and type of cheese, storage or packaging conditions, could be demonstrated. Seventy-six percent of 156 samples of commercially produced Danish cheeses contained no nitrosamines ((detection limit 0.1 micrograms/kg). Trace amounts (0.1-0.3 micrograms/kg) of nitrosamines were found in 22% of the samples and 2% contained 0.6-0.7 micrograms/kg. Forty-two percent of 19 cheeses imported to Denmark contained no nitrosamines. Trace amounts of nitrosamines were found in 37% of the samples and 21% contained 0.4-3.6 micrograms/kg. Cheese samples from retail shops had slightly higher contents of nitrosamines than samples taken at dairy plants.

Animals↗
PubMed1980

Monitoring exposure of personnel to volatile nitrosamines in the laboratory environment.

A convenient sampling method was developed for collection of volatile nitrosamines from large-volume air samples. Stainless steel tubes containing 0.3 g Tenax GC were employed to collect nitrosamines from 5-30 1 air samples. Nitrosamines were eluted from the sample tubes with diethylether to minimize formation of artifacts which were observed when thermal desorption was employed. Eluates were analysed directly by GC-TEA and nitrosamine identities were confirmed using high-resolution GC-MS with selected ion-monitoring. The detection limit was approximately 0.8 micrograms/m3 (0.3 ppb) for NDMA in 2 ml of diethylether extract. The laboratory operations studied included chemical synthesis, trace analysis, animal treatment, microbial mutagenesis tests and in vitro biochemical procedures. In most cases, nitrosamines were not detected in laboratory air, but levels of 200-800 micrograms/m3 (42 to 180 ppb) of N-nitrosomethyl-tert-butylamine were measured during animal treatment, 0.8-8.6 micrograms/m3 (0.3 to 2.8 ppb) of NDMA during mutagenesis assays, 12-22 micrograms/m3 (4-7 ppb) of NDMA during in vitro metabolism studies and 11 micrograms/m3 (3.6 ppb) of NDMA in a walk-in refrigerator. Appropriate corrective measures reduced all nitrosamine levels to below the detection limit. Hamsters and rats treated with NDAA (80 mg/kg, s.c.) excreted 4.4 and 12.9%, respectively, of the nitrosamine in expired air in 24 hr. This route of excretion may be metabolically significant and should be considered in the safe design of animal treatment and holding facilities.

Air Pollutants↗
PubMed1981

Absence of volatile nitrosamines in human feces.

Using a method for nitrosamine analysis that gives high recovery values and that is free from artifactual synthesis of nitrosamines, we have shown that human feces do not contain volatile nitrosamines (detection limit, 0.1 to 0.5 microgram/kg). We also showed that nitrosation reactions are not catalyzed by fecal organisms. Following a 2-day anaerobic incubation of feces with either a secondary amine (dimethylamine, dipropylamine, or morpholine) or nitrite, no nitrosamine was formed. When the amine and nitrite were added together, nitrosamine was formed, but at a level of 2 to 20% of that formed in autoclaved feces under the same conditions. Nitrosamines were stable following anaerobic incubation with feces for up to 4 days. These results suggest that fecal organisms inhibit the chemical formation of nitrosamines instead of catalyzing it. When morphine and nitrate were added together, nitrosomorpholine was formed. Morpholine nitrosates so rapidly that it intercepts nitrite formed by the action of nitrate reductase before the nitrite can be further reduced. However, very high concentrations of morphine and nitrate, which are far from the conditions in normal feces, were required to form measurable nitrosomorpholine. We may conclude that N-nitroso compounds are unlikely to be formed in any significant amounts in the human colon.

Feces↗
PubMed1993

High variability of nitrosamine metabolism among individuals: role of cytochromes P450 2A6 and 2E1 in the dealkylation of N-nitrosodimethylamine and N-nitrosodiethylamine in mice and humans.

We undertook this study to answer several questions regarding nitrosamine metabolism. Kinetics of nitrosamine metabolism showed the involvement of at least two enzymes in the dealkylation of N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) in mouse liver microsomes. Coumarin inhibited both reactions competitively. On the other hand, microsomal coumarin 7-hydroxylase was inhibited by NDMA (Ki 2.7 mM) and NDEA (Ki 0.013 mM). The big difference in the Ki values suggests a higher affinity of NDEA than NDMA to Cyp2a-5 (mouse cytochrome P450coh). A specific antibody against Cyp2a-5 inhibited more of the microsomal NDEA (up to 90%) than NDMA (up to 40%) dealkylation. The converse was true with anti-Cyp2e-1 antibody. These results suggest that the primary substrate for Cyp2a-5 is NDEA and for Cyp2e-1, NDMA. Western blot analysis of human liver microsomes showed a great interindividual variation in the amounts of CYP2A6 (human cytochrome P450coh) and CYP2E1. Also, coumarin 7-hydroxylation and nitrosamine dealkylation varied greatly among individuals. A high correlation (r = 0.93, P < 0.001) was found between NDEA and coumarin metabolism. Both activities were associated with CYP2A6. On the other hand, little or no correlation was found between microsomal CYP2A6 and CYP2E1 or between CYP2E1 and NDEA dealkylation. Immunoinhibition of human microsomal NDEA metabolism by CYP2a-5 antibody varied greatly among individuals (10-90%), suggesting, as in the case of mice, that NDEA is metabolized primarily by CYP2A6, at least in some individuals. Taken together the data suggest that (1) the metabolic activation of nitrosamines in humans varies greatly among individuals; (2) different nitrosamines may partially be metabolized by different cytochrome P450 isozymes; and (3) because of similarities between nitrosamine metabolism in mice and humans, inbred strains of mice would be relevant experimental models for studying nitrosamine activation.

Animals↗
PubMed1993

Clearance of N-nitrosodimethylamine and N-nitrosodiethylamine by the perfused rat liver. Relationship to the Km and Vmax for nitrosamine metabolism.

The first-pass clearance of dietary N-nitrosodimethylamine (NDMA) by the liver is the most important factor in the pharmacokinetics of this carcinogen in the rat, but is less important in the pharmacokinetics of N-nitrosodiethylamine (NDEA). The reason for the difference in clearance of these two nitrosamines is not known. These experiments were carried out to see whether the general characteristics of the clearance of these two carcinogens in vivo could be reproduced in the perfused liver, and whether the clearance could be correlated with the Michaelis-Menten parameters Km and Vmax for their metabolism. If this could be done one would be able to predict the possible extent of first-pass clearance of nitrosamines in man from measurement of Km and Vmax for nitrosamine metabolism by the human liver. The Km (22 microM) and Vmax (10.2 and 13.4 nmol/g liver/min) for the metabolism of NDMA by slices from two human livers, the inhibition of that metabolism by ethanol (Ki 0.5 microM), and the rate of N-7 methylation of DNA when slices are incubated with NDMA, were measured. These results are similar to those reported previously with rat liver. The Km (27 microM) for the metabolism of NDEA by rat liver slices and the inhibition of that metabolism by ethanol (Ki 1 microM) were estimated from the rate of ethylation of the DNA of the slices. The clearance of both these nitrosamines by the perfused rat liver was measured, and the results appeared to parallel those in vivo with a striking difference between the clearance of NDMA and NDEA. The maximal rate of clearance of NDMA was 11.2 nmol/g liver/min and of NDEA 8.9 nmol/g liver/min, similar to the Vmax for metabolism of NDMA by liver slices and to the estimated maximal rate of liver metabolism of both nitrosamines in the living rat. However, although the Km for metabolism of these two nitrosamines by liver slices is similar (about 25 microM), the logarithmic mean sinusoidal concentration [see Bass and Keiding, Biochem Pharmacol 37: 1425-1431, 1988] giving half maximal clearance during perfusion (the equivalent to Km) was 2.3 microM for NDMA and 10.6 microM for NDEA. The almost 5-fold difference between these two values is the basis for the difference between the clearance of the two nitrosamines.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Volatile nitrosamine levels and genotoxicity of food samples from high-risk areas for nasopharyngeal carcinoma before and after nitrosation.

Traditional life-style, especially food habits, infection by Epstein-Barr virus (EBV) and genetic factors, have been associated with an increased risk of nasopharyngeal carcinoma (NPC). N-Nitroso compounds and other carcinogens either present in food or formed endogenously, as well as food constituents that activate EBV, have been suspected as etiological factors in NPC pathogenesis. For their characterization preserved food items, frequently consumed in NPC endemic areas in Tunisia, South China and Greenland, were sampled and screened for the presence of mutagens and volatile nitrosamines before and after nitrosation. Aqueous extracts as well as 2 organic extracts of the samples were assayed for genotoxicity in 2 Salmonella typhimurium strains and the SOS chromotest. The same extracts had previously been analyzed for volatile nitrosamines and for EBV-activating substances in Raji cells. In our study, 13 out of 16 food samples showed a weak, directly-acting genotoxicity in the SOS chromotest in at least one of the extracts, but only one sample from Greenland was found to be weakly mutagenic in Salmonella TA 98. Chemical nitrosation for 9 out of 15 samples of aqueous food extracts increased the genotoxic effect in the SOS chromotest. Levels of volatile nitrosamines were also elevated for 12 out of 15 samples; highest levels of N-nitrosodimethylamine were found in hard salted and dried fish from China (1,200 micrograms/kg) and highest N-nitrosopyrrolidine levels in a Tunisian spice (3,840 micrograms/kg). In non-nitrosated aqueous food extracts, the level of volatile nitrosamines and genotoxic activities were not correlated with the EBV-inducing activity of the same samples. After chemical nitrosation, EBV-inducing activity was decreased or showed no change and was not correlated with increases in either the genotoxicity or the nitrosamine levels. Our results suggest that EBV-activating compounds belong to a different class of substances. However, there was an association between the changes in genotoxicity and nitrosamine levels due to nitrosation.

Carcinoma↗
PubMed1986

Relevance of N-nitrosamines to esophageal cancer in China.

Studies on the relevance of the N-nitrosamines to esophageal cancer in China are reviewed. Esophageal cancer is a complex and multifactorial problem. Although a causal association between nitrosamines exposure and esophageal cancer in China has not yet been rigorously established, exposure of Lin-Xian subjects to nitrosamines either directly or as a result of their in vivo formation has been detected in our study. Several N-nitrosamines (NDMA, NDEA, NMBzA, NPyr, NPip, and NSAR) in gastric juice collected from Lin-Xian inhabitants have been detected. A correlation was found between the lesions of esophageal epithelium and the amount of nitrosamines present. In addition, the amounts of N-nitrosamino acids (N-nitrosoproline, N-nitrosothiazolidine 4-carboxylic acid, NSAR, and nitrates) excreted in 24-hr urine of subjects in Lin-Xian were significantly higher than those in Fan-Xian, indicating a higher exposure to N-nitroso compound and their precursors of the inhabitants in the high-risk area. The effect of nitrosamines on human esophagus has been investigated at the cellular levels. The amounts of O6-MedG in DNA of esophageal or stomach mucosa of patients from Lin-Xian were higher than that from Europe (Lyon and Essen). The presence of O6-MedG in the human fetal esophagus cultured with NMBzA was also detected. These findings indicate that the elevated levels of O6-MedG in esophageal DNA could be the result of a recent exposure to N-nitroso compounds or a genetically determined reduced cellular capacity for repair of O6-MedG from DNA. The hyperplasia was induced in the esophagus of human fetus that cultured with NMBzA for 2 weeks to 2 months. The intervention studies of esophageal cancer in Lin-Xian have been pursued. Intake of moderate doses of ascorbic acids by Lin-Xian subjects effectively reduced the urinary levels of N-nitrosamino acids to those found in un-dosed subjects in the low-risk area. If N-nitroso compounds are formed in vivo and are among the causative factors of esophageal cancer in Lin-Xian, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds. Thus, the plan of chemoprevention is carried out in Lin-Xian.

Ascorbic Acid↗
PubMed1979

Binding of nitrosamines to cytochrome P-450 of liver microsomes.

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.

Animals↗
PubMed1996

Analysis of N-nitrosamines by high-performance liquid chromatography with post-column photohydrolysis and colorimetric detection.

N-Nitrosamines eluted from reversed-phase HPLC were quantitatively photohydrolysed in a UV photoreactor in aqueous solution to give the nitrite ion which could be determined colorimetrically with the Griess reagent. The chromatographic behavior of N-nitroso compounds (including 19 volatile dialkyl and 7 non-volatile N-nitrosamines) was studied on three octadecylsilane columns. The capacity factor varies linearly with the number of carbons atom of the n-dialkyl chains. N-nitrosamines bearing di-n-alkyl chains with the same number of carbon atoms could be separated with a highly polar mobile phase. The yield of photohydrolysis depends upon pH and time of exposure under UV light. The response was shown to be linear in the 0-200 ng range with a limit of detection of 8 pmoles injected for N-dialkyl nitrosamines. This limit was 20 pmoles for N-nitrosamines bearing two phenyl groups. Although N-nitrosamines could be detected at 230 nm without post-column reaction, such a reaction enhances the specificity of detection in biological matrices such as gastric juice or alcoholic beverages.

Beer↗
PubMed1990

Metabolic activation and biological effects of nitrosamines in the mammalian lung.

Nitrosamines and their precursors are among the most common contaminants of our environment, and many of them are highly carcinogenic. Nitrosamines are believed to require metabolic activation in the host organism, and many of them demonstrate a pronounced organ and cell type specificity. This review summarizes recent in vivo and in vitro experiments which focus on the mechanisms of nitrosamine-induced lung carcinogenesis. Currently available in vivo and in vitro data suggest that nitrosamines may be metabolized by cytochrome P-450, prostaglandin endoperoxide synthetase, or monoamine oxidases. The presence of one or the other of these enzyme systems may be partially responsible for the cell type-specific effects of this class of chemicals. Moreover, evidence in vitro suggests selective uptake of nitrosamines by cell type-specific receptors, a phenomenon which offers a more logical explanation than previously published theories for the selectivity of biological effects exerted by nitrosamines.

Animals↗
PubMed1979

Mutagenicity of nitrosamines formed from nitrosation of spermidine.

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.

Dose-Response Relationship, Drug↗
PubMed1983

Volatile N-nitrosamines in snuff and chewing tobacco on the Swedish market.

Snuff and chewing tobacco on the Swedish market in 1981-82 were analysed for volatile N-nitrosamines using gas chromatography-thermal energy analysis. Detectable levels of N-nitrosodimethylamine and N-nitrosopyrrolidine were found in nearly all of the 36 samples analysed. N-nitrosopiperidine and N-nitrosomorpholine were also found in some samples. The total concentration of volatile N-nitrosamines found in any sample was between 0.5 and 145.9 micrograms/kg wet weight. Storage of snuff in unopened boxes for 20 wk at -20, +2 or +23 degrees C resulted in small but statistically insignificant changes in the volatile N-nitrosamine content. Storage for 20 wk at +2 degrees C in boxes that had been opened and resealed led to a larger but statistically insignificant increase in the mean level of total volatile N-nitrosamines. The levels of volatile N-nitrosamines found in Swedish snuff in 1981 and 1982 were significantly (P less than 0.05) lower than those found in 1979. It is estimated that in Sweden today the use of snuff can increase the normal intake of the N-nitrosamines studied here by about 10 to 100%.

Humans↗
PubMed1983

An examination of human blood for the presence of volatile nitrosamines.

Human blood was examined for the presence of volatile nitrosamines. Nitrosamines were detected by chemiluminescence and mass spectrometry after separation from blood by distillation and solvent extraction. N-nitrosodimethylamine was detected in all but one of 51 blood samples taken from 23 different people, at concentrations from the detection limit (0.1 microgram/litre) to 1.4 microgram/litre with a mean concentration of 0.5 microgram/litre. N-Nitrosodiethylamine was detected in 11 samples, the detection limit being 0.1 microgram/litre. No other volatile nitrosamines were detected. After a test meal of bacon, spinach, bread and beer, the concentration of N-nitrosodimethylamine increased. There was no appreciable difference between the nitrosamine concentrations in the blood of laboratory workers and in the blood of other people. Salivary nitrite concentrations measured semi-quantitatively concurrently with blood sampling varied considerably but showed no apparent correlation with blood nitrosamine levels. Measurements in rabbits given a continuous infusion of N-nitrosodimethylamine gave a clearance rate approximately equal to the blood flow through the liver and a volume of distribution of 1.2 litre/kg body weight. By applying these results to man, the body burden after the meal was calculated as 40-50 microgram. This is substantially higher than the estimated weekly intake of volatile nitrosamines from food.

Adult↗
PubMed1987

N-nitrosamines and nitrosatable amines, potential precursors of N-nitramines, in children's pacifiers and baby-bottle nipples.

Sixteen types of children's pacifiers and baby-bottle nipples, bought in shops in Israel but produced both there and elsewhere in the world, were analyzed for their contents of N-nitrosamines, which have been shown to be potent carcinogens in animals, and of nitrosatable amines. Two methods were used: one, originating in the United States, involved dichloromethane extraction of total volatile N-nitrosamines from the nipples and pacifiers, and the other, from the Federal Republic of Germany, consisted of analysis of N-nitrosamines and their amine precursors that migrated into artificial saliva. N-Nitrosodibutylamine (NDBA). N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA). N-nitrosopiperidine (NPIP), and N-nitrosopyrrolidine (NPYR) were detected by the first method, at individual levels as high as 369 ppb. Using the second method, NDBA, NDEA, NDMA, and N-nitrosomorpholine (NMOR) were detected at concentrations up to 41 ppb, in addition to the three nitrosatable amines dibutylamine, diethylamine, and dimethylamine. Upon nitrosation in the artificial saliva, these amines produced not only the related N-nitrosamines but also relatively high levels of the corresponding N-nitramines (N-nitrodibutylamine, N-nitrodiethylamine, and N-nitrodimethylamine), probably formed by oxidation of the N-nitrosamines by peroxides used for vulcanization of elastomers. Thus, if N-nitramines are not measured in addition to N-nitrosamines after nitrosation, the second method may underestimate the quantities of nitrosatable amines present in artificial saliva extracts. Whether N-nitramines, some of which have been shown to be both mutagenic and carcinogenic, also occur in the saliva of babies exposed to these products remains to be confirmed. Of the samples tested, 50% failed to meet both the U.S. and the FRG regulations. A larger percentage, 60%, would not conform to the new standard suggested in the United States, and more than 80% failed to comply with the even stricter Dutch standard.

Amines↗
PubMed1991

Tumor induction in a rat model for ureterosigmoidostomy without evidence of nitrosamine formation.

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.

Adenocarcinoma↗