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PubMed1995

Bacteria in the aetio-pathogenesis of gastric cancer: a review.

Severe atrophic gastritis, a precursor lesion of gastric carcinoma, is connected, in two different ways, with intragastric bacterial colonization: (1) in advanced atrophic body gastritis (type A), achlorhydria or severe hypochlorhydria leads to bacterial overgrowth with aerobic and anaerobic flora enabling the conversion of nitrate to nitrite and further to N-nitroso compounds; (2) the newly re-discovered Helicobacter pylori is probably one of the major causes of chronic atrophic antral gastritis (type B). Both types of bacteria may be involved in the pathogenesis of multifocal gastritis (type AB). In the western world, achlorhydric atrophic gastritis is not only found in pernicious anaemia but is latent in about 2 to 6% of the general population. In one study from the Mayo Clinic, about one-third of consecutive gastric carcinomas were present in achlorhydric stomachs, the remainder in acid-secretors. Apart from the N-nitroso compounds, other carcinogenic mechanisms may be active in type A gastritis: elevated serum gastrin; altered cell turnover; immunologic and hereditary traits. The association of H. pylori with gastric carcinoma is mainly based on circumstantial evidence: (i) epidemiological studies indicate a moderately increased risk for gastric cancer in H. pylori-positive subjects compared with H. pylori-negative; (ii) in the presence of H. pylori intragastric levels of the anti-oxidant ascorbic acid are lowered; (iii) H. pylori seems to be linked to mucosal atrophy and intestinal metaplasia; (iv) recent follow-up studies show a significant development of atrophic gastritis in H. pylori-positive patients compared to H. pylori-negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Achlorhydria↗
PubMed1980

Use of nitrates and nitrites as food additives in Nordic countries.

An account is given of the presently permitted use of nitrates and nitrites as food additives in Denmark, Finland, Norway and Sweden. Nitrate permitted to be added to milk for the production of solid, semisolid and mould cheeses at levels of 150-200 mg/l potassium nitrate. Due to the potential formation of especially nonvolatile N-nitroso compounds, attempts are made to reduce their use. Nitrates, but not nitrites, are still permitted in certain semipreserved fish products (herring) in Denmark, Finland and Sweden, but it will probably be phased out within a few years. Nitrates are not permitted in meat products in Norway and Sweden, while the use is being reduced in Denmark and Finland. The use of nitrite (175-200 mg/kg meat product of sodium nitrite) is generally permitted as a preservative in meat products in Sweden, Finland and Denmark, while it is more restricted in Norway. Due the potential risk of formation of carcinogenic N-nitroso compounds in the meat and in the organism of the consumer serious attempts are made to reduce the use of all Nordic countries.

Animals↗
PubMed1994

Antenatal risk factors for malignant brain tumours in New South Wales children.

A population-based case-control study of incident primary malignant brain tumours diagnosed during 1985 to 1989 in children aged 0 to 14 years was carried out in the coastal conurbation of New South Wales comprising Sydney, Wollongong and Newcastle in the period 1988 to 1990. Personal interviews were conducted using a structured questionnaire with mothers of 82 cases and 164 control children individually matched to the cases by sex and age. Among the hypotheses being examined were those related to exposure to parental tobacco smoke, N-nitroso compounds and possible protection from sources of vitamin C. No link was found with tobacco smoking by the mother before or during pregnancy. While exposure during pregnancy of the mother to tobacco smoke of the father appeared to double the risk of childhood brain tumours and a similar risk was found for father (but not mother) smoking before the index pregnancy, there was no "dose-response" and the increased risk was confined to data supplied by the mother (rather than the father himself). The risk of childhood brain tumours rose with reported increasing consumption, during pregnancy, of cured meats, which have high levels of N-nitroso compounds (or their precursors), and fell with rising consumption of vegetables. No association was found between the risk of childhood brain tumours and family history of epilepsy, cancer, or tumours of the nervous system, parental irradiation, previous miscarriage or procedures carried out during pregnancy, maternal consumption of antihistamines, barbiturates or diuretics, or maternal contact with cats or farm-life during pregnancy.

Adolescent↗
PubMed1987

Nitrate-reducing microorganisms in the gastric juice of patients with stomach cancer--experimental data and considerations upon the role of these microorganisms in gastrocarcinogenesis.

During recent years evidence has been accumulated supporting the hypothesis according to which nitroso compounds are involved in the generation of stomach cancer in humans. The present report deals with the occurrence and content of nitrite, nitrate and nitrosamines in the gastric juice of stomach cancer patients with special reference to nitrate-reducing microorganisms. Microorganisms were found to be present in gastric juice in all cases of cancer, mean total count being (5.6 +/- 2.4) log/ml (mean +/- standard deviation) and with limit values 1.4-8.0 log/ml. Nitrate-reducing microorganisms were found in 9 cases from 10. Their mean counts were (5.2 +/- 2.5) log/ml and limit values less than 0.5-8.0 log/ml. The role of nitrate-reducing microorganisms in the formation of nitrite and carcinogenic nitroso compounds is discussed. Some practical measures to control the count of nitrate-reducing microorganisms in stomach are presented.

Adult↗
PubMed2005

Thioproline prevents carcinogenesis in the remnant stomach induced by duodenal reflux.

An excessive duodenal reflux induced by surgery has been widely accepted to cause gastric carcinogenesis in the remnant stomach. As one of causative factors for malignancy, N-nitroso compounds produced by enteric bacteria have been postulated. However, there is no concrete information to prove this hypothesis. This study was undertaken to elucidate the factors underlying the remnant stomach carcinogenesis, by giving thiazolidine-4-carboxylic acid (thioproline; TPRO) to the rats with duodenal reflux as a nitrite scavenger. Operated 39 animals were used, divided into 2 groups; one with a diet containing 0.5% TPRO (n=18), and the other with a diet without TPRO (n=21). Adenocarcinoma developed in 16 rats out of 21 (76.2%) of untreated rats, whereas adenocarcinoma was detected in 1 rat of the TPRO-treated rats (5.6%). TPRO thus prevented the development of gastric cancer in the remnant stomach, thereby suggesting a concern of nitroso compounds to the carcinogenesis.

Adenocarcinoma↗
PubMed1993

[Nitrates and nitrites in gastric juice in chronic gastritis].

Atrophic gastritis is precancerous condition of the intestinal type of gastric carcinoma. This process supposes a genotoxic effect of N-nitroso-compounds which are formed in the stomach by nitrosation of nitrites and organic nitrogen compounds. The authors examined 41 patients with chronic superficial and atrophic gastritis. They examined the pH and concentration of nitrates and nitrites in gastric juice taken in the morning before meal. They discovered that in severe atrophic gastritis the amount of nitrates is significantly increased and the amount of nitrites is decreased, all in comparison with superficial gastritis. An exponential relation of the concentration of nitrites towards the pH of gastric juice was found to be NO2- = epH-6.5, CC = 0.935. A significant elevation of nitrite concentration was observed in cases of pH being higher than 5.5. Nitrate concentration altered in dependence of the value of gastric pH. Oral administration of 300 mg of vitamin C or 250 mg of vitamin E did not significantly affect the amount of gastric nitrites. The work discusses the mutual relation of nitrites, ascorbic acid and alpha-tocopherol towards the formation of N-nitroso-compounds in the stomach inflicted by atrophic gastritis. (Tab. 3, Fig. 2, Ref. 25.)

Adult↗
PubMed1991

Acceleration of N-nitrosation reactions by electrophiles.

Selected mechanisms by which electrophiles can facilitate N-nitrosamine formation are reviewed. Special attention is given to a recently discovered reaction in which nitrogen in its lowest (ammonia) oxidation state is efficiently converted to N-nitroso compounds by oxidation in the presence of secondary amines; an electrophilic transition metal centre (E+) makes this reaction possible by initially N-coordinating the ammonia (E+ + NH3----E-NH3+). Other mechanisms considered include: the conversion of nitrite under nonacidic conditions via nitro complexes to nitrosatively active transition metal nitrosyl intermediates (E+ + NO(2-)----E-NO(2-)----E-NO2+); catalysis of N-nitrosamine formation in nitrite-amine mixtures by electrophilic carbon centres that initiate the reaction by attack on the amine (E+ + R2NH----E-NR2); and coordination of nitrite by carbon electrophiles to form activated O-bound species (E+ + ONO(-)----E-O-NO) capable of performing the required N-nitrosation. The findings suggest that acceleration of N-nitrosamine-forming reactions by electrophiles may be a critical factor to consider in attempting to rationalize, predict and control the distribution of carcinogenic N-nitroso compounds in vivo and in the environment.

Chemical Phenomena↗
PubMed1980

Characterization of cerebellar guanylate cyclase using N-methyl-N'-nitro-N-nitrosoguanidine. Presence of two different types of guanylate cyclase in soluble and particulate fractions.

Some characteristics of guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) in subcellular fractions prepared from rat cerebellum have been analyzed on the basis of responsiveness to N-methyl-N'-nitro-N-nitrosoguanidine and inhibitors related to N-nitroso compounds. The enzyme in 100 000 X g supernatant and crude mitochondrial (P2) fractions were differently activated (11- and 2.5-fold, respectively) by N-methyl-N'-nitro-N-nitrosoguanidine. The soluble fraction obtained by hypo-osmotic treatment and subsequent recentrifugation of the P2 (P2-soluble) contained a significantly higher total guanylate cyclase activity than that of the starting material (P2). The P2-soluble fraction also exhibited a lower responsiveness (1.5-fold) to N-methyl-N'-nitro-N-nitrosoguanidine than that found in the P2. The membrane fraction prepared from the P2 (P2-membrane) had no response to N-methyl-N'-nitro-N-nitrosoguanidine. Hemoglobin and vitamin A derivatives significantly inhibited both N-methyl-N'-nitro-N-nitrosoguanidine-activated 100 000 X g supernatant and basal P2-soluble enzyme activities, without effect on the basal activities in 100 000 X g supernatant and P2-membrane fractions. The present results suggest that two different types of guanylate cyclase may be present in rat cerebellum in terms of the responsiveness of N-nitroso compounds, and P2-soluble guanylate cyclase seems to be activated endogenously through a mechanism similar to the action of N-methyl-N'-nitro-N-nitrosoguanidine.

Animals↗
PubMed1984

Nitrate and nitrite in saliva and urine of inhabitants of areas of low and high incidence of cholangiocarcinoma in Thailand.

Cholangiocarcinoma is one of the main liver diseases in northeast Thailand. Associations with exposure to liver fluke and N-nitrosodimethylamine in formation of the tumour have been demonstrated in animals. This study was carried out to compare possible endogenous formation of N-nitroso compounds in inhabitants of areas with low and high incidences of cholangiocarcinoma by examining the levels of nitrate and nitrite in their saliva and urine. Thirty-two subjects (16 males and 16 females) living in the north-east (high incidence) and 12 volunteers (6 males and 6 females) in Bangkok (low incidence) were allowed to take regular meals, and their saliva and urine were collected before, and 30, 60 and 120 min after each meal. Nitrate and nitrite concentrations in saliva of the group in the high-incidence area were significantly higher than those of the group in Bangkok: salivary nitrate was 2-2.8 times higher and nitrite 2-5.6 times higher in the north-eastern group when compared with levels at each corresponding time interval in the low-incidence group. Nitrate levels in urine were also significantly higher in the north-eastern group at some time intervals, but urinary nitrite levels were similar and very low in both groups throughout the day. This finding may indicate a greater possibility of in-vivo formation of N-nitroso compounds in the north-east area than in Bangkok and might be associated with the occurrence of cholangiocarcinoma in north-east Thailand.

Adenoma, Bile Duct↗
PubMed1981

Alkylation of DNA and tissue specificity in nitrosamine carcinogenesis.

A peculiarity of nitrosamines is the high degree of cell and organ specificity in inducing tumors. There is substantial evidence that the initiation of the carcinogenesis process by carcinogens of this group is linked to the metabolic competence of the target tissue or cell to convert these carcinogens into mutagenic metabolites and to the binding of those metabolites to cellular DNA. Alkylation occurs in the DNA at the N-1, N-3, and N-7 positions of adenine; the N-3, N-7, and O6 of guanine; the N-3, and O2 of cytosine; and the N-3, O4, and O2 of thymine; and the phosphate groups. The initial proportion of each DNA adduct depends upon the alkylating agent used. The various DNA adducts are lost to a variable extent from DNA in vivo by spontaneous release of bases and/or by specific DNA repair processes. Studies conducted in vitro and vivo indicate that alkylation at the oxygen atoms of DNA bases is more critical than alkylation at other positions in the mutagenesis and carcinogenesis induced by N-nitroso compounds. In particular, tissues in which tumors occur more frequently after a pulse dose of nitrosamine are those in which O6-alkylguanine persists longest in DNA, presumably resulting in an increased probability that a miscoding event (mutation) will take place during DNA synthesis. The more rapid removal of O6-methylguanine from the DNA of liver (as compared with extrahepatic tissues) of rats has been associated with the absence of tumor production in this organ by a single dose of dimethylnitrosamine; however, a significant incidence of liver tumors is observed if the same dose is given 24 hr after partial hepatectomy, and tumors are induced by such a dose of dimethylnitrosamine in the liver of hamsters, which has a low capacity to remove O6-methylguanine from its DNA. These data also indicate that the rate of disappearance of 7-methylguanine from the liver or extrahepatic tissues is independent of the dose of dimethylnitrosamine; whereas O6-methylguanine is lost from DNA more rapidly after a low dose of this nitrosamine. It has been shown that in liver the removal of O6-methylguanine but not other DNA adducts, from DNA can be affected by pretreating the animals with N-nitroso compounds. The modulation of DNA repair processes observed after a single dose and after chronic treatment with nitrosamines is discussed in relation to the tissue-specific carcinogenic effect of this group of carcinogens.

Alkylation↗
PubMed1987

Urinary N-nitrosoproline excretion: a further evaluation of the nitrosamine hypothesis of gastric carcinogenesis in precancerous conditions.

Measurement of N-nitroso compounds in gastric juice by different methods has given conflicting results. In order to resolve this controversy, we have assessed endogenous nitrosation by the independent N-nitrosoproline excretion test in subjects who had previously undergone gastric juice analysis by one of these methods. Ten Polya gastrectomy, 10 pernicious anaemia and nine matched control subjects were fed 380 mg of nitrate in beetroot juice and 500 mg proline. N-nitrosoproline (N-Pro) synthesised intragastrically from these precursors, and quantitatively excreted by the kidneys, was measured in 24 hour urine samples (collection checked by creatinine clearance). N-Pro excretion (mean +/- SEM) was reduced (p less than 0.01) in pernicious anaemia (1.1 +/- 0.8 ng/day) compared with matched control (18.0 +/- 7.2 ng/day), and also tended to be lower (NS) in polya gastrectomy (3.2 +/- 2.3 ng/day). Twenty four hour intragastric pH was monitored on a separate occasion in 23 of the 29 subjects; 13 were hypoacidic (pH greater than 4 greater than 50% of 24 hours) and 10 were acidic. N-Pro yields were reduced (p less than 0.01) in the hypoacidic group (0.9 +/- 0.6 ng/day) compared with the acidic group (17.9 +/- 6.6 ng/day), and N-Pro was negatively associated with mean intragastric pH (tau = -0.53, p = 0.001). We conclude that endogenous synthesis of this specific N-nitroso compound is favoured by low rather than high pH. These results are concordant with those previously reported in gastric juice from the same subjects and suggest that nitrosation is chemically rather than bacterially mediated, contrary to the nitrosamine hypothesis of gastric carcinogenesis.

Aged↗
PubMed1996

Mortality in a cohort of Russian fertilizer workers.

OBJECTIVES: The study evaluated the mortality of workers exposed to precursors of N-nitroso compounds in a Russian fertilizer plant. METHODS: Workers employed at least two years between 1945 and 1985 in production departments or other services were included in the cohort, which comprised 2039 men and 2957 women followed from 1965 to 1990. The standardized mortality ratios (SMR) were calculated using cause-specific death rates for the Moscow region as reference. An internal comparison was carried out using Poisson regression modeling. Exposure to arsenic, nitrogen oxides, and sulfur dioxide was estimated from an industrial hygiene survey. RESULTS: The production and other workers had no excess of mortality from all causes or all neoplasms. However the male production workers had excess mortality from all cancers combined (SMR 143) and lung cancer (SMR 186) after a latency period of > or = 20 years. Men with the highest exposure to nitrogen oxides had a twofold increase in mortality from stomach cancer, with a marginally significant increasing trend between stomach cancer and cumulative exposure to nitrogen oxides for both genders. Excess mortality from all cancers and stomach cancer was found for the worker with the highest average exposure to arsenic, and excess lung cancer mortality could be attributed to exposure to arsenic. CONCLUSIONS: The investigation showed a weak association between employment in a fertilizer production plant and increased mortality from cancer. The results somewhat support the hypothesis that occupational exposure to precursors of N-nitroso compounds increases the risk of stomach cancer mortality, as does exposure to arsenic.

Arsenic↗
PubMed1991

Acetylcholine-induced vasodilatation in rabbit hindlimb in vivo is not inhibited by analogues of L-arginine.

Nitric oxide (NO) or related nitroso compounds are an endothelium-derived relaxing factor (EDRF), originating from metabolism of L-arginine, L-Arginine analogues with chemically altered guanidino moity are potent and specific inhibitors of EDRF(NO) release. We evaluated effects of two L-arginine analogues, NG-monomethyl-L-arginine (L-NMMA, 100 microM) and N omega-nitro-L-arginine (L-NARG, 30 microM), on acetylcholine-, substance P-, and nitroglycerin-induced relaxation in the blood-perfused rabbit hindlimb in vivo and femoral arteries in vitro. L-NMMA and L-NARG selectively inhibited the vasodilator response to acetylcholine in rabbit femoral arteries in vitro, whereas endothelium-independent response to nitroprusside increased. L-NMMA (1.6 mg/min ia) in the blood-perfused rabbit hindlimb in vivo increased vascular resistance in the hindlimb by 23 +/- 3% (means +/- SE; n = 10) but did not inhibit the vasodilator responses to acetylcholine or substance P. L-NARG (10 mg/kg iv) increased systemic blood pressure by 26 +/- 3% (n = 7) and vascular hindlimb resistance by 22 +/- 9% (n = 8), and blood flow to hindlimb musculature, measured with microspheres, decreased by 46 +/- 5% (n = 6). Pretreatment with L-NARG, however, did not impair vasodilator responses to acetylcholine and substance P. These findings are consistent with the view that basal tone in resistance vessels in the rabbit hindlimb may be mediated by nitroso compounds, whereas agonist-stimulated vasodilation may be mediated by other mechanisms that do not involve the NO-synthesizing enzyme.

Acetylcholine↗
PubMed2003

Conditions for acid catalysed luminal nitrosation are maximal at the gastric cardia.

BACKGROUND: Saliva has a high nitrite concentration, derived from the enterosalivary recirculation of dietary nitrate, and is the main source of nitrite entering the acidic stomach. Acidification of nitrite in the presence of secondary amines or amides generates potentially carcinogenic N-nitroso compounds. The reaction is inhibited by ascorbic acid and catalysed by thiocyanate. AIM: To determine whether there is intragastric regional variation in the chemical conditions promoting luminal nitrosation following nitrate ingestion. METHODS: Using microdialysis probes, we measured concentrations of nitrite, ascorbic acid, total vitamin C, and thiocyanate simultaneously in saliva, the distal oesophagus, cardia, and the proximal and distal stomach of 17 healthy volunteers before and following intragastric nitrate (2 mmol) administration. RESULTS: The median pH in the distal oesophagus, cardia, and proximal and distal stomach were 7, 2.6, 1.9, and 1.7, respectively, before, and were similar following nitrate administration. Mean nitrite concentration in the distal oesophagus was similar to that of saliva, being 29.1 micro M and 36.7 micro M, respectively, before nitrate and increasing to 181.6 micro M and 203.3 micro M after nitrate ingestion. Within the stomach, mean (SEM) nitrite concentration following nitrate was higher in the cardia (45.5 (12.7) micro M) than in the mid (7.8 (3.1)) (p<0.01) or distal (0.8 (0.6)) (p<0.1) stomach, and ascorbic acid concentration was lower at the cardia (13.0 (6.1)) than in the mid (51 (19.2)) (p<0.02) or distal (86 (29)) (p<0.01) stomach. Consequently, the median ascorbic acid to nitrite ratio was lowest at the cardia (0.3) (p<0.01) versus the mid (7.8) or distal (40) stomach. Thiocyanate concentration was similar throughout the stomach. CONCLUSIONS: The conditions favouring luminal generation of N-nitroso compounds from dietary nitrate are maximal at the most proximal cardia region of the acidic stomach and may contribute to the high incidence of mutagenesis at this site.

Adolescent↗
PubMed2006

Risk of non-Hodgkin lymphoma and nitrate and nitrite from drinking water and diet.

INTRODUCTION: Nitrate and nitrite are precursors in the in vivo formation of N-nitroso compounds, potent animal carcinogens. METHODS: We conducted a population-based case-control study of non-Hodgkin lymphoma (NHL) in 1998 to 2000 in Iowa, Detroit, Seattle, and Los Angeles. Because nitrate levels were elevated in many drinking water supplies in Iowa, but not in the other study centers, we evaluated water nitrate levels and risk of NHL in Iowa only. Monitoring data for public supplies were linked to water source histories from 1960 onward. Nitrate was measured at interview homes with private wells. We limited most analyses to those with nitrate estimates for > 70% of their person-years since 1960 (181 cases, 142 controls). For those in the diet arm of the study (458 cases, 383 controls from 4 centers) and for Iowa participants in both the diet and drinking water analyses, we estimated dietary nitrate and nitrite intake using a 117-item food-frequency questionnaire that included foods high in nitrate and nitrite. Odds ratios and 95% confidence intervals were calculated using logistic regression, adjusting for the study matching factors, education, and caloric intake (diet analyses only). RESULTS: We found no overall association with the highest quartile of average drinking water nitrate (> 2.90 mg/L nitrate-N: odds ratios = 1.2; 95% confidence interval = 0.6-2.2) or with years > or = 5 mg/L (10+ years: 1.4; 0.7-2.9). We observed no evidence of an interaction between drinking water nitrate exposure and either vitamin C or red meat intake, an inhibitor and precursor, respectively, of N-nitroso compound formation. Among those in the diet arm, dietary nitrate was inversely associated with risk of NHL (highest quartile: 0.54; 0.34-0.86). Dietary nitrite intake was associated with increasing risk (highest quartile: 3.1; 1.7-5.5) largely due to intakes of bread and cereal sources of nitrite. CONCLUSION: Average drinking water nitrate levels below 3 mg/L were not associated with NHL risk. Our study had limited power to evaluate higher levels that deserve further study.

Aged↗
PubMed1987

Nitrosation products from the plant Ephedra altissima and their potential endogenous formation.

The plant species Ephedra is commonly used in both folk medicine and for the preparation of health teas. Nitrosation of a tea made from Ephedra altissima yielded N-nitrosoephedrine (NEP), N-nitrosopseudoephedrine (NPEP), N-nitrosoproline (NPRO), N-nitrosomethylbenzylamine (NMBA), trace quantities of 2 unidentified non-volatile nitrosamines and the new nitroso compound 2-(N-nitroso-N-methylamino)propiophenone (NMAP). Incubation of a tea extract at 37 degrees C and pH 2.0 under conditions simulating the normal fasting stomach with a constant nitrite concentration (25 microM) for 1 h produced NEP, NPEP, NMAP and NPRO. The synthesis and preliminary results for the mutagenic effect of NMAP on the reversion of Salmonella typhimurium strains TA100 and TA1535 in the Ames test are reported.

Dimethylnitrosamine↗
PubMed1997

Carcinogenicity of methylurea or morpholine in combination with sodium nitrite in rat multi-organ carcinogenesis bioassay.

For carcinogenic risk assessment of combinations of N-nitroso precursors in man, the effects of feeding methylurea (MU) or morpholine (Mor) plus sodium nitrite (NaNO2) were investigated using a multi-organ carcinogenesis model. In experiment 1, to initiate multiple organs, groups of 10 or 20 male F344 rats were treated with 6 carcinogens targeting different organs. Starting a week after completion of this initiation phase, animals were given 0.1% MU or 0.5% Mor in their food and/or 0.15% NaNO2 in their drinking water for 23 weeks. The induction of tumors and/or preneoplastic lesions in the forestomach and esophagus was significantly increased in the group receiving MU plus NaNO2. The numbers and areas of liver glutathione S-transferase placental form (GST-P)-positive foci were significantly elevated with MU or Mor plus NaNO2. Experiment 2 was conducted to assess formation of N-nitroso compounds in the stomach, and to detect DNA adduct generation in target organs by immunohistochemical staining. Groups of 5 or 14 animals were starved overnight, then given 0.4% MU or 2.0% Mor in the diet, or basal diet alone for 1 h. Then NaNO2 or distilled water was given intragastrically. The mean gastric N-methyl-N-nitrosourea yield in the MU plus NaNO2 group was 7700 micrograms at 2 h after combined administration. The mean N-nitrosomorpholine yield in the group given Mor plus NaNO2 was 6720 micrograms. Immunohistochemically, N7-methyldeoxyguanosine-positive nuclei were evident in the forestomach epithelium at 8 h after the combination treatment with MU plus NaNO2.

Administration, Oral↗