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PubMedDate not supplied

The riddle of hepatic neoplasia in brown bullheads from relatively unpolluted waters in New York State.

Since 1985, pathologists at Cornell University have investigated the causes of lesions in freshwater fish throughout New York waters in order to clarify possible impairment of fish health by environmental contaminants. Fishermen and biologists alerted us to several relatively protected reservoirs and ponds in which we have found no evidence of elevated levels of anthropogenic environmental contaminants but in which up to 100% of brown bullheads exhibited skin neoplasia. Complete necropsies and histologic study revealed that over 30% of mature brown bullheads from some of these sites had benign or malignant hepatocellular or biliary liver neoplasia. Up to 50% of brown bullheads had benign or malignant liver neoplasia in other relatively unpolluted waters with no evidence of skin neoplasia in bullheads. Multiple samplings of brown bullheads from several of these sites have revealed puzzling variability in the prevalence of skin, liver, and other neoplasia in these fish populations. The cause of these striking epizootics of neoplasia in brown bullheads in unpolluted waters in New York State remains unclear. We hypothesize that natural carcinogens such as N-nitroso compounds formed in aquatic sediments or radon from geologic formations may contribute to epizootic fish neoplasia in New York waters.

Animals↗
PubMedDate not supplied

Tobacco, alcohol, diet and risk of prostate cancer.

A hospital-based case-control study of the association between tobacco smoking, alcohol drinking and several relevant dietary items and prostate cancer was carried out in the National Cancer Institute of Uruguay between January 1988 and December 1994. The sample included 156 patients with histologically proven prostatic cancer and 302 controls with a variety of neoplastic and non-neoplastic diseases. The results showed increased risks of prostate cancer associated with beer drinking, meat, milk and fruit consumption, after adjusting for major confounders. The possible role of N-nitroso compounds from beer in prostatic carcinogenesis is discussed.

Adult↗
PubMed1995

The preclinical toxicological evaluation of sumatriptan.

1 Sumatriptan is a potent and selective 5-HT1 receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicological programme employing high doses of sumatriptan was carried out in a range of animal species. The studies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential of sumatriptan. 2 The administration of relatively high single and repeated doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intravenous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachycardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathological changes related to treatment with high concentrations of sumatriptan consisted of local reactions at the site of subcutaneous administration. 3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds. 4 Sumatriptan was neither genotoxic nor oncogenic. 5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and postnatal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats. 6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.

Administration, Oral↗
PubMed2001

Study of N-nitrosomorpholine-induced DNA strand breaks in Caco-2 cells by the classical and modified comet assay: influence of vitamins E and C.

We have studied the genotoxic effects of the well-known heterocyclic liver carcinogen N-nitrosomorpholine (NMOR), an N-nitroso compound, which was prepared in our laboratory by nitrosation of the secondary amine morpholine with NaNO2. NMOR induced DNA strand breaks in human colon carcinoma Caco-2 cells. The concentration-dependent DNA-damaging effects of NMOR were proved by the comet assay. We further characterized DNA strand breaks induced by NMOR as follows: 1) We pretreated cells with vitamins E and C, which are able to eliminate oxidative DNA damage. 2) We varied the pH of the comet assay (12.1 and 13). In general, alkali-labile sites are stable until pH is raised to 12.5. 3) We used the site-specific repair enzymes exonuclease III and formamidopyrimidine-DNA glycosylase in the modified comet assay. Results showed that NMOR-induced DNA strand breaks have their origin exclusively in alkali-labile sites. Nevertheless, vitamins E and C decreased the level of DNA strand breaks. These results showed that antioxidants may have biological activities other than free radical scavenging that relate to their cancer-prevention properties. Our conceptions about reduction of NMOR-induced DNA lesions in Caco-2 cells by vitamins E and C are presented in this work.

Anticarcinogenic Agents↗
PubMed2002

Effect of vegetables, tea, and soy on endogenous N-nitrosation, fecal ammonia, and fecal water genotoxicity during a high red meat diet in humans.

Red meat increases colonic N-nitrosation, and this may explain the positive epidemiological relationship between red meat intake and colorectal cancer risk. Vegetables, tea, and soy have been shown to block N-nitroso compound (NOC) formation and are associated with protection against colorectal cancer. To determine whether these supplements affect fecal NOC excretion during consumption of a high red meat (420 g/day) diet, 11 male volunteers were studied over a randomized series of 15-day dietary periods. Seven of these subjects completed a further dietary period to test the effects of soy (100 g/day). Soy significantly suppressed fecal apparent total NOC (ATNC) concentration (P = 0.02), but supplements of vegetables (400 g/day as 134 g broccoli, 134 g brussels sprouts, and 134 g petits pois) and tea extract (3 g/day) did not affect mean levels of fecal ATNC, nitrogen and ammonia excretion, and fecal water genotoxicity. However, fecal weight was increased (P < 0.001) and associated with reduced transit time (r = 0.594, P < 0.0001), so that contact between ATNC, nitrite, and ammonia and the large bowel mucosa would have been reduced. Longer transit times were associated with elevated fecal ATNC concentrations (r = 0.42, P = 0.002). Fecal nitrite was significantly suppressed during the tea supplement compared with the meat-only (P = 0.0028) and meat + vegetables diets (P = 0.005 for microgram NO2/g).

Adult↗
PubMed1993

Reduction of nitro and azo compounds by NADPH-cytochrome P-450 reductase-cytochrome c heme peptide system.

Octa heme peptide, an enzymic digestion product of Candida Krusei cytochrome c, was found to catalyze nitro and azo reduction in the presence of NADPH and NADPH-cytochrome P-450 reductase under anerobic conditions. The reduction was dependent on the concentrations of heme peptide and reductase, and inhibited by carbon monoxide and oxygen. Comparison of the activities of the reductase-heme peptide system with liver microsomes revealed that heme peptide was as effective as cytochrome P-450 in nitro reduction, although less effective in azo reduction. Thus, cytochrome c heme peptide may serve as an artificial substitute for cytochrome P-450 at least in the reductive metabolism of xenobiotics.

Amino Acid Sequence↗
PubMed2000

NO-Mediated aromatic nitration during decomposition of phenolic S-nitrosothiols in non-aqueous aerobic medium.

Five novel S-nitrosothiol compounds (6-10) derived from L-cysteine were generated in solution and their decomposition rate was followed by UV spectroscopy. In acetonitrile, compounds 9 and 10 were the most stable of this series with a half-life of 24 h. The final organic decomposition products of the five S-nitrosothiols were also analysed. Derivatives 8, 9, and 10, possessing a phenolic hydroxyl group, afforded an unexpected decomposition pathway, with nitration of aromatic ring occurring in non-aqueous media. A mechanism involving a phenoxy radical seems to be implicated.

Aerobiosis↗
PubMed1990

Conceptus uptake of the 106RuNO-nitro complex in relation to gestational stages.

106RuNO-nitro complex was administered intravenously to pregnant rats to study uptake of the radioruthenium complex by the conceptus in relation to gestational stages. Each conceptus was sampled periodically with respect to its placenta, fetal membrane, fetal fluid and fetus. Perceptible radioactivity in the fetus was detected only in the later stage of gestation and its relative concentration, defined as the ratio radioactivity per unit weight in the body tissue at sacrifice to that in the whole-body at dosing, was very low compared with other tissues. The average number of fetuses in one litter was 13 and the transfer rate of nitro complex into the fetuses 24 hr after injection to rats on the 20th day of gestation was about 1% of initial maternal dose. The relative concentration in the placenta and fetal membrane was much higher than in the fetus and decreased with time after injection. These results indicate that the placenta and fetal membrane play significant roles as barriers to the transfer of 106RuNO-nitro complex into the fetus.

Animals↗
PubMed1998

Volatile N-nitrosamine formation after intake of nitrate at the ADI level in combination with an amine-rich diet.

Formation of nitrite from ingested nitrate can result in several adverse health effects and implies a genotoxic risk as a consequence of endogenous formation of carcinogenic N-nitroso compounds. We studied the formation of volatile N-nitrosamines after intake of nitrate at the acceptable daily intake (ADI) level in combination with a fish meal rich in amines as nitrosatable precursors. Twenty-five volunteers consumed this meal during 7 consecutive days; a diet low in nitrate was consumed during 1 week before and 1 week after the test week. Nitrate intake at the ADI level resulted in a significant rise in mean salivary nitrate and nitrite concentrations. Mean urinary nitrate excretion increased from 76 mg/24 hr in the first control week to 194 and 165 mg/24 hr in the test week, followed by a decline to 77 mg/24 hr in the second control week. The urine samples were analyzed for volatile N-nitrosamines, and both N-nitrosodimethylamine (NDMA) and N-nitrosopiperidine (NPIP) were detected in the samples. Mean urinary NDMA excretion significantly increased from 287 ng/24 hr in the control week to 871 and 640 ng/24 hr in the test week and declined to 383 ng/24 hr in the second control week. Excretion of NPIP was not directly related to the nitrate intake and composition of the diet. Nitrate excretion and NDMA excretion were significantly correlated, as well as salivary nitrate and nitrite concentration and NDMA excretion. We conclude that nitrate intake at the ADI level in combination with a fish meal containing nitrosatable precursors increases NDMA excretion in urine and thus demonstrates increased formation of carcinogenic N-nitrosamines.

Adolescent↗
PubMed1985

Quantitation and visualization of alkyl deoxynucleosides in the DNA of mammalian cells by monoclonal antibodies.

Conventional radiochromatographic procedures for the quantitation of carcinogen/mutagen-induced structural DNA modifications have a number of limitations. Thus, these techniques for the most part require application of radioactively labeled carcinogens and the use of relatively large amounts of DNA for analysis at low levels of DNA modification. Radiochromatographic methods also preclude analyses at the level of single cells and DNA molecules. Recently developed immunoanalytical methods have improved this situation considerably. Monoclonal antibodies (Mab) characterized by a high substrate specificity and affinity, in combination with radio- and enzyme-immunoassays, or with "immuno-slot-blot" techniques, now permit the detection of femtomole to subfemtomole amounts of, e.g., alkyldeoxynucleosides in small samples of DNA isolated from tissues or cultured cells previously exposed to nonradioactive N-nitroso compounds. Furthermore, selected Mab can be used to quantitate by direct immunofluorescence (with the aid of computer-based image analysis of electronically intensified fluorescence signals), specific alkyldeoxynucleosides in the nuclear DNA of single cells. With this method, the detection limit for the alkylation product O6-ethyldeoxyguanosine (O6-EtdGuo) is presently of the order of 10(2) -10(3) O6-EtdGuo residues per diploid mammalian genome. Individual cells can thus be monitored for the presence of specific carcinogen-DNA adducts, and with respect to their capacity for enzymatic removal of such modified structures from DNA (as exemplified here by the kinetics of the enzymatic elimination of O6-EtdGuo from the DNA of malignant neurogenic rat cell lines). In combination with transmission electron microscopy, Mab also permit direct visualization (via Mab binding sites) of specific carcinogen-modified structures in individual DNA molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylating Agents↗
PubMed1989

Markers of exposure to carcinogens.

Methods have been developed for the detection of exposure to carcinogens and other DNA damaging agents in experimental animals and man through the detection of carcinogens or their metabolic derivatives in body fluids, or through adducts bound covalently to DNA or hemoglobin. The successful use of urinary markers of genotoxic exposures has been reported with respect to nitrosoproline as an indicator of exposure to N-nitroso compounds. The same approach has been used to detect AFB1 and AFB1-N7-Gua as markers of exposure to aflatoxin B1; of 3-methyladenine produced as a result of exposure to methylating agents; and thymine glycol as an indicator of exposure to agents causing oxidative damage to DNA. Detection of adducts formed between genotoxic agents and hemoglobin has been reported in studies of populations occupationally exposed to ethylene oxide, in which 3-hydroxyhistidine and 3-hydroxyvaline have been measured, and in smokers, whose hemoglobin has been found to contain levels of 4-aminobiphenyl and 3-hydroxyvaline that were correlated with the frequency of cigarette smoking. Detection of DNA adducts of genotoxic agents in the cells and tissues of exposed individuals has also been accomplished through the use of several types of analytical methods. Immunoassays and physicochemical methods have been applied to detect adducts formed through the major intermediate in the activation of benzo(a)pyrene, the 7,8-diol-9,10-epoxide (BPDE). This adduct has been found in the DNA of peripheral leukocytes of workers in foundries, aluminum manufacturing plants, roofers, and coke oven plants, and also in cigarette smokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Nitrate intake does not influence bladder cancer risk: the Netherlands cohort study.

OBJECTIVES: N-nitroso compounds, endogenously formed from nitrate-derived nitrite, are suspected to be important bladder carcinogens. However, the association between nitrate exposure from food or drinking water and bladder cancer has not been substantially investigated in epidemiologic studies. METHODS: We evaluated the associations between nitrate exposure and bladder cancer in the Netherlands Cohort Study, conducted among 120,852 men and women, 55-69 years of age at entry. Information on nitrate from diet was collected via a food frequency questionnaire in 1986 and a database on nitrate content of foods. Individual nitrate exposures from beverages prepared with tap water were calculated by linking the postal code of individual residence at baseline to water company data. After 9.3 years of follow-up and after excluding subjects with incomplete or inconsistent dietary data, 889 cases and 4,441 subcohort members were available for multivariate analyses. We calculated incidence rate ratios (RR) and corresponding 95% confidence intervals (CIs) using Cox regression analyses. We also evaluated possible effect modification of dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever). RESULTS: The multivariate RRs for nitrate exposure from food, drinking water, and estimated total nitrate exposure were 1.06 (95% CI, 0.81-1.31), 1.06 (95% CI, 0.82-1.37), and 1.09 (95% CI, 0.84-1.42), respectively, comparing the highest to the lowest quintiles of intake. Dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever) had no significant impact on these results. CONCLUSION: Although the association between nitrate exposure and bladder cancer risk is biologically plausible, our results in this study do not support an association between nitrate exposure and bladder cancer risk.

Aged↗
PubMed1991

Nitrate contamination of drinking water: evaluation of genotoxic risk in human populations.

Nitrate contamination of drinking water implies a genotoxic risk to man due to the endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite. Thus far, epidemiological studies have presented conflicting results on the relation of drinking water nitrate levels with gastric cancer incidence. This uncertainty becomes of relevance in view of the steadily increasing nitrate levels in regular drinking water supplies. In an attempt to apply genetic biomarker analysis to improve the basis for risk assessment with respect to drinking water nitrate contamination, this study evaluates peripheral lymphocyte chromosomal damage in human populations exposed to low, medium, and high drinking water nitrate levels, the latter being present in private water wells. It is shown that nitrate contamination of drinking water causes dose-dependent increases in nitrate body load as monitored by 24-hr urinary nitrate excretion in female volunteers, but this appears not to be associated with peripheral lymphocyte sister chromatid exchange frequencies.

Body Burden↗
PubMed1995

Bacterial infection as a cause of cancer.

Bacterial infections traditionally have not been considered major causes of cancer. Recently, however, bacteria have been linked to cancer by two mechanisms: induction of chronic inflammation and production of carcinogenic bacterial metabolites. The most specific example of the inflammatory mechanism of carcinogenesis is Helicobacter pylori infection. H. pylori has been epidemiologically linked to adenocarcinoma of the distal stomach by its propensity to cause lifelong inflammation. This inflammation is in turn thought to cause cancer by inducing cell proliferation and production of mutagenic free radicals and N-nitroso compounds. H. pylori is the first bacterium to be termed a definite cause of cancer in humans by the International Agency for Research on Cancer. Mutagenic bacterial metabolites are also suspected to increase risk for cancer. This model is best exemplified in colon cancer. Bile salt metabolites increase colonic cell proliferation. Exogenous compounds such as rutin may be metabolized into mutagens by resident colonic flora. Moreover, Bacteroides species can produce fecapentaenes, potent in vitro mutagens, in relatively high concentrations. In vivo data on human carcinogenesis by bacterial metabolites, however, are inconsistent. Local bacterial infections may also predispose to nonnodal lymphomas, although the mechanisms for this are unknown. Gastric lymphomas and immunoproliferative small intestinal disease have been most strongly linked to underlying bacterial infection. Because bacterial infections can be cured with antibiotics, identification of bacterial causes of malignancy could have important implications for cancer prevention.

Bacterial Infections↗
PubMed1996

Nitrate contamination of drinking water: relationship with HPRT variant frequency in lymphocyte DNA and urinary excretion of N-nitrosamines.

We studied peripheral lymphocyte HPRT variant frequency and endogenous nitrosation in human populations exposed to various nitrate levels in their drinking water. Four test populations of women volunteers were compared. Low and medium tap water nitrate exposure groups (14 and 21 subjects) were using public water supplies with nitrate levels of 0.02 and 17.5 mg/l, respectively. Medium and high well water nitrate exposure groups (6 and 9 subjects) were using private water wells with mean nitrate levels of 25 and 135 mg/l, respectively. Higher nitrate intake by drinking water consumption resulted in a dose-dependent increase in 24-hr urinary nitrate excretion and in increased salivary nitrate and nitrite levels. The mean log variant frequency of peripheral lymphocytes was significantly higher in the medium well water exposure group than in the low and medium tap water exposure groups. An inverse correlation between peripheral lymphocyte labeling index and nitrate concentration of drinking water was observed. Analysis of N-nitrosamine in the urine of 22 subjects by gas chromatography-mass spectrometry revealed the presence of N-nitrosopyrrolidine in 18 subjects. Analysis of the mutagenicity of well water samples showed that a small number of the well water samples were mutagenic in the Ames Salmonella typhimurium test after concentration over XAD-2 resin. In conclusion, consumption of drinking water, especially well water, with high nitrate levels can imply a genotoxic risk for humans as indicated by increased HPRT variant frequencies and by endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite.

Female↗
PubMed2003

A noncarcinogenic small dose of n-methylnitrosourea enhances colon tumorigenesis in F344 rats.

Very small amount of carcinogens such as nitroso compounds and heterocyclic amines has been found in human feces. This study was designed to investigate in F344 rats whether an intrarectal noncarcinogenic small dose of n-methylnitrosourea (0.2 mg, 3 times weekly) affects colon carcinogenesis initiated with an intrarectal large dose (2 mg, 3 times weekly) of this carcinogen. The colon tumor yield at week 50 in 12 rats receiving the large dose for 2 weeks and then the small dose for the next 30 weeks significantly increased as compared to 23 rats receiving only the large dose for 2 weeks: 100% vs. 70% in tumor incidence and 4.3 vs. 1.2 in mean number of tumors per rat. No tumors were found in 12 rats receiving only the small dose for 30 weeks. The results indicate that a very small amount of carcinogens could participate in a tumor-enhancing effect on the high-risk colon induced with a large dose of carcinogens, even though their less amounts insufficient to complete carcinogenesis process. Further study is needed to elucidate if administration of such a small dose could induce epigenetic alterations or further genetic changes in the initiated colonic cells.

Administration, Rectal↗
PubMed1982

Nitrite and nitrosamines in gastric juice: risk factors for gastric cancer?

Nitrite and nitrosamine concentrations have been measured in 108 patients undergoing gastroscopy as a part of routine gastrointestinal investigations. The nitrite and nitrosamine values of 20 patients with duodenal and 11 patients with benign gastric ulcer were within the range of the values of 26 normal subjects. The nitrite and nitrosamine concentrations in 32 patients with inflammatory changes of the gastric mucosa were slightly higher than normal values and correlated with the progressive degrees of the severity. In 19 patients with atrophic gastritis the concentrations of nitrite and nitrosamines were significantly elevated in comparison with those of all other groups. Our data suggest a relationship between the constant exposure of an already damaged gastric mucosa to N-nitroso compounds and the known high incidence of gastric cancer in atrophic gastritis.

Atrophy↗
PubMed1985

Bacterial overgrowth as a consequence of reduced gastric acidity.

Reduction in acid secretion in atrophic gastritis allows bacterial colonization of the stomach, most extremely in achlorhydric patients with pernicious anaemia, in whom overgrowth may cause nitrate reduction and formation of potentially carcinogenic N-nitroso compounds. Subsequent bacterial contamination of the upper small intestine can induce mucosal damage and malabsorption. The situation is similar after gastrectomy. In achlorhydria and after gastrectomy, the risk of gastric cancer is increased. There is controversy as to the risks of long-term treatment with H2-receptor antagonists. Increase in nitrate-reducing bacteria, nitrite and N-nitrosamine have been observed in patients by some investigators but not in volunteers and patients by others. Bacterial concentrations after cimetidine are inversely related to pretreatment acid secretory capacity. Demonstration of increased mutagenicity of gastric juice after H2-receptor antagonists gives grounds for caution. Drastic acid reduction may in future be reserved for short-term and intermittent treatment and mild or moderate reduction for long-term treatment of peptic ulcer and ulcer prevention.

Achlorhydria↗