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PubMed1985

The role of oral nitrate in the nitrosation of [14C]proline by conventional microflora and germ-free rats.

The urinary excretion of N-nitroso-L-[U-14C]proline by conventional microflora and germ free rats was used to assess the role of the gut bacteria and oral nitrate in the endogenous formation of N-nitroso compounds. The formation of nitrosoproline was qualitatively similar in conventional and germfree rats (equivalent to nitrosation of approximately 0.01-0.05% of the initial dose of [U-14C]proline) suggesting no involvement of the intestinal flora in this reaction. Furthermore, nitrosamino acid production was similar following the administration of nitrate and [U-14C]proline or [U-14C]proline alone, demonstrating no involvement of exogenous nitrate under the conditions of the experiment. Dietary contamination with nitrate/nitrite was negligible. The results are consistent with the suggestion that nitrate/nitrite reserves in the body are important in the formation of nitrosoproline in vivo.

Administration, Oral↗
PubMed1986

N-nitrosamines and Nigerian habitual drinks, and cancer.

Commercially available samples of Nigerian lager beers and bottled palm wine, and of root cuttings of medicinal plants, assayed for volatile N-nitroso compounds and nitrosatable entities, respectively, by chromatographic, chemiluminescence, colorimetric, derivatisation and nitrosation methods, contained nitrosodimethylamine (0.2-2.3 micrograms/kg; mean, 0.9 micrograms/kg) only in the drinks, and dimethylamine (DMA) and piperidine (1 mg/kg as DMA) in the roots.

Beer↗
PubMed1986

Synthesis of nitrosomethylisoamylamine from isoamylamine and sodium nitrite by fungi.

Nitrosomethylisoamylamine (NMIA), a carcinogenic N-nitroso compound was synthesized from isoamylamine (IAA) in a glucose-ammonium nitrate medium after several days' incubation with fungi and subsequent nitrosation with sodium nitrate. The nitrosamine was not produced by control reactions which lacked either IAA or fungi. The yield of NMIA varied with the length of incubation after inoculation with the fungi, and with the concentrations of IAA and NaNO2, the duration of nitrosation, the pH of the medium and the species of the fungi. The optimum conditions for the formation of the nitrosamine are reported.

Amines↗
PubMed1987

Mechanism of N-acetylcysteine (NAC) and other thiols as both positive and negative modifiers of MNNG-induced mutagenicity in V79 Chinese hamster cells.

Carcinogenic xenobiotics can be detoxified by nucleophilic thiols, which interact directly or through enzyme catalyzed reactions with electrophilic metabolites/compounds or metabolically produced oxidants. Formation of such conjugates is assumed to be a dominating competitive pathway reducing the mutagenic and carcinogenic effects of several known carcinogens. In the case of the potent carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) the situation is different since this carcinogen is transformed to reactive intermediates by nucleophilic agents such as thiols. As a consequence of this, the modulating effect of thiols has to be discussed in relation to the reaction kinetics of this nitroso compound. In this report we present data on the mutagenicity of MNNG which was enhanced by intracellular excess of glutathione, achieved by pre-treatment with N-acetylcysteine, cysteine and glutathione. Depletion of GSH by treatment with diethylmaleate or buthioninesulfoximine resulted in a decreased mutagenic effect of MNNG. A decreased effect of MNNG was also obtained by extracellular excess of thiols. The modification of MNNG-mutagenicity was compared to the effect of thiols on the mutagenicity of N-methyl-N'-nitrosourea (MNU) in V79 Chinese hamster cells. No effect of the thiols could be detected on the mutagenicity of MNU, indicating that the intermediates of MNU and MNNG react, in agreement with the reaction kinetics, in favour of water and thiols become less important. The results indicate that the activation of MNNG to mutagenic intermediates is occurring within the cells. This activation is mediated by reaction of MNNG with thiols (and amines) and subsequent release of short-lived alkylating intermediates. The mutagenic effect of MNNG can be reduced or enhanced respectively by decreasing or increasing the intracellular thiol levels. As demonstrated with MNU, intracellular thiol concentrations (in milli/molar range), which is high enough to bring about the activation of MNNG, are not sufficiently high to protect DNA from damage by the alkylating intermediate. Extracellular levels of thiols 'protect' the cells simply by increasing the decomposition of MNNG in the treatment solution.

Acetylcysteine↗
PubMed1988

Dose-time relationship of the development of preneoplastic liver lesions induced in rats with low doses of N-nitrosodiethanolamine.

The carcinogenic efficiency of very low doses of N-nitrosodiethanolamine (NDELA), an N-nitroso compound of environmental significance, was assessed by administering it to male Sprague-Dawley rats at five different dose levels: 0.2, 0.63, 1.5, 6 and 25 mg/kg b.w./day in the drinking water. Quantitation of the numbers and size of liver foci positive for glucose-6-phosphate dehydrogenase (G6PDH) by morphometric methods revealed a good correlation between the dose and duration of carcinogen treatment and the extent of G6PDH-positive foci development. Thus the area density increased proportional to time and dose. The dose-time relation for the induction of 1% G6PDH-positive liver tissues assessed as a double logarithmic plot gives a straight line with the same characteristics as that which results when the induction of liver tumors is evaluated.

Animals↗
PubMed1988

Comparative study on the carcinogenicity of N-nitrosodiethylamine, N-nitrosodimethylamine, N-nitrosomorpholine, N-nitrosopyrrolidine and N-nitrosodi-n-propylamine to the lung of Syrian golden hamsters following intermittent instillations to the trachea.

N-Nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitrosomorpholine (NMOR), N-nitrosopyrrolidine (NPYR) and N-nitrosodi-n-propylamine (NDPA) were instilled into the lungs of male Syrian golden hamsters by intratracheal instillations once a week for 15 weeks. The total doses given were 1.5 mg of each drug. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During the total lifespan, tumor incidence rates in the respiratory organs were 100% in the NDEA group, 6% in the NDMA group, 43% in the NMOR group, 0% in the NPYR group, 72% in the NDPA group and 4% in the control group. The incidence rates in the liver were 19% in the NDMA group and 4% in the NPYR group. No liver tumors developed in the other groups. The carcinogenic potencies of these N-nitroso compounds to the respiratory organs was provisionally estimated to be in the following order: NDEA greater than NDPA greater than NMOR greater than NDMA = NPYR, at the 1.5 mg dosage level. However, the difference in the rates of tumor incidence between the NDMA or NPYR group and the control group was not significant.

Adenoma↗
PubMed2003

Novel mechanism of nitrosative stress from dietary nitrate with relevance to gastro-oesophageal junction cancers.

High luminal concentrations of nitric oxide are generated at the human gastro-oesophaegal junction and within Barrett's oesophagus due to the reduction of salivary nitrite to nitric oxide by acidic gastric juice. Salivary nitrite is derived from the entero-salivary recirculation of dietary nitrate. Our aim was to determine whether nitric oxide generated within the lumen will exert nitrosative stress on the adjacent epithelium. A benchtop model was constructed reproducing the nitrite chemistry occurring within the lumen of the upper gastrointestinal tract where saliva encounters acidic gastric juice. It incorporated an epithelial compartment maintained at pH 7.4 and separated from the lumen by a hydrophobic barrier with the properties of the epithelial lipid cell membrane. The secondary amine morpholine was used to measure N-nitroso compound formation in both the lumen and epithelial compartment. Adding 100 micro M nitrite to the acidic (pH 1.5) luminal compartment depleted of ascorbic acid generated 6.2 +/- 2.0 micro M (mean +/- SE) N-nitrosomorpholine in that compartment and 2.2 +/- 0.1 micro M nitrosomorpholine in the epithelial compartment at 30 min. When 100 micro M nitrite was added to the acidic luminal compartment containing physiological concentrations of ascorbic acid, all the nitrite was immediately converted to nitric oxide and no N-nitrosomorpholine was formed within that compartment. However, the nitric oxide rapidly diffused from the luminal compartment into the epithelial compartment and there generated very high concentrations of N-nitrosomorpholine (137 +/- 5.6 micro M at 30 min). The addition of ascorbic acid or glutathione to the epithelial compartment could only reduce nitric oxide-induced nitrosation within that compartment by 40%. The nitrate-derived nitric oxide generated within the lumen where saliva encounters gastric acid is likely to exert substantial nitrosative stress on the adjacent epithelium. This may contribute to the high prevalence of mutagenesis at this anatomical site.

Ascorbic Acid↗
PubMed2004

Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical.

Red meat consumption is associated with endogenous metabolic generation of mutagenic N-nitroso compounds (NOC) and may be implicated in causation of colorectal cancer. Assessment of a biologically relevant dose of NOCs is hampered by imperfect understanding of NOC interactions with other dietary components. This study tests the hypothesis that NOC effects upon mutational biomarkers in mouse colon may be modulated by a non-genotoxic diet-related compound. N-methyl-N-nitrosourea (MNU) and undegraded lambda carrageenan (lambdaCgN) were selected as test chemicals, representing a NOC and a non-genotoxic agent, respectively. Study end-points included (i) DNA adduct formation and (ii) metallothionein (MT) crypt restricted immunopositivity indices (MTCRII) which are considered representative of crypt stem cell mutations. Frequency and size of MT immunopositive foci as well as total number of MT immunopositive crypts were assessed. Biologically effective doses of MNU and lambdaCgN were determined in model validation studies and the agents were then tested alone and in combination. Continuous lambdaCgN treatment for 10 weeks induced significantly greater colonic mucosal injury than a drinking water control. In combined treatment regimens, lambdaCgN treatment did not significantly affect MNU-induced DNA adduct formation. However, combinations of lambdaCgN with MNU significantly increased MTCRII in excess of those induced by MNU alone. Recurrent or continuous lambdaCgN regimens had greater interactive effects with MNU upon MTCRII than short-term lambdaCgN treatment. This study has shown that exposure to a non-genotoxic diet-related compound (lambdaCgN) modulates the effective NOC dosimetry for induction of MT crypt restricted immunopositivity.

Alkylating Agents↗
PubMed2005

DNA repair polymorphisms and cancer risk in non-smokers in a cohort study.

Environmental carcinogens contained in air pollution, such as polycyclic aromatic hydrocarbons, aromatic amines or N-nitroso compounds, predominantly form DNA adducts but can also generate interstrand cross-links and reactive oxygen species. If unrepaired, such lesions increase the risk of somatic mutations and cancer. Our study investigated the relationships between 22 polymorphisms (and their haplotypes) in 16 DNA repair genes belonging to different repair pathways in 1094 controls and 567 cancer cases (bladder cancer, 131; lung cancer, 134; oral-pharyngeal cancer, 41; laryngeal cancer, 47; leukaemia, 179; death from emphysema and chronic obstructive pulmonary disease, 84). The design was a case-control study nested within a prospective investigation. Among the many comparisons, few polymorphisms were associated with the diseases at the univariate analysis: XRCC1-399 Gln/Gln variant homozygotes [odds ratios (OR) = 2.20, 95% confidence intervals (CI) = 1.16-4.17] and XRCC3-241 Met/Met homozygotes (OR = 0.51, 95% CI = 0.27-0.96) and leukaemia. The recessive model in the stepwise multivariate analysis revealed a possible protective effect of XRCC1-399Gln/Gln in lung cancer (OR = 0.22, 95% CI = 0.05-0.98), and confirmed an opposite effect (OR = 2.47, 95% CI = 1.02-6.02) in the leukaemia group. Our results also suggest that the XPD/ERCC1-GAT haplotype may modulate leukaemia (OR = 1.28, 95% CI = 1.02-1.61), bladder cancer (OR = 1.38, 95% CI = 1.06-1.79) and possibly other cancer risks. Further investigations of the combined effects of polymorphisms within these DNA repair genes, smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process.

Adult↗
PubMed1989

Nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate (NO3-) in drinking water in Denmark is of concern due to the possibility of an associated increase in long-term exposure to endogeneously formed N-nitroso compounds. Using a duplicate portion technique in combination with a qualitative description of diet and other background variables, the total nitrate intake in a Danish rural population and the contribution of drinking water to the total nitrate exposure is estimated. People drinking nitrate-free water have an intake of 37 mg NO3- per day. At 47 mg NO3- per litre, the exposure is increased to 89 mg, about 60% of which originates from the water. At 84 mg NO3- per litre, the daily exposure is 123 mg, 70% of which originates from the drinking water. These crude comparisons between three groups of people are supplemented with quantitative modelling of nitrate exposure at individual level. Apart from drinking water, consumption of vegetables is a major source of nitrate in this population. Using nitrate in overnight urine samples to quantify exposure is less accurate than the duplicate dietary portion technique and tends, in the present study, to underestimate the contribution of water-derived nitrate to total nitrate intake.

Adult↗
PubMed1994

Nitrate in drinking water. A case-control study on primary brain tumours with an embedded drinking water survey in Germany.

BACKGROUND: Nitrate is known to be a precursor in the endogenous formation of N-nitroso compounds which are thought to be associated with the development of brain tumours. METHODS: We conducted a population-based case-control study on the aetiology of primary brain tumours in adults in which the nitrate concentration in drinking water was investigated as a quantitative variable. For this purpose, an additional drinking water survey was performed. RESULTS: Analysis of 173 incident cases and 418 controls did not show any relationship between exposure to nitrate in drinking water and risk of developing primary brain tumours. We found mean nitrate concentrations of 15.98 mg/l (SD 15.61) in the drinking water history of the cases and of 16.16 mg/l (SD 15.72) for controls. In addition, we compared the quantitative history of nitrate contamination of the study participants to a semi-quantitative assessment by a stick method. Although we found good agreement between these methods we would recommend the use of detailed water surveys for retrospective studies on contaminants in drinking water. CONCLUSION: The results suggest the absence of an association between nitrate levels in drinking water and the risk of brain tumours. However in order to draw definite conclusions quantitative prospective studies are needed.

Adult↗
PubMed1997

Comparing dietary recall data for mothers and children obtained on two occasions in a case-control study of environmental factors and childhood brain tumours.

BACKGROUND: Food frequency questionnaires (FFQ) have been widely used in epidemiological studies of dietary factors, despite persistent questions about the quality of the data they generate. To address concerns about the influence of disease status on dietary recall, we examined the temporal consistency of dietary recall data obtained in a case-control study of environmental factors and childhood brain tumours. METHODS: On two occasions separated by approximately 4.5 years, the mothers of children with brain tumours and healthy matched controls were asked about their diets during pregnancy and their children's diets prior to diagnosis. Forty-five case and 60 control mothers completed both FFQ for themselves and/or their children. Daily dietary intakes of substances related to dietary N-nitroso compounds were estimated from the responses to each of the questionnaires and compared. The dietary intakes of the cases were also compared to their matched controls. RESULTS: The changes in estimated dietary intakes from the first to the second questionnaire administration were similar in both groups of mothers, indicating negligible case-control differences in healthy individuals recalling their own diets. Control mothers reported for their children a higher intake of the index foods on the second questionnaire than on the first while estimated intakes for the case children were lower the second time compared to the first. Significant case-control differences among the children were seen for the majority of dietary components examined. CONCLUSIONS: The results suggest that the magnitude and direction of errors in dietary recall data can vary by disease status, and further suggest that reliance on retrospective reports of children's diets may be inappropriate in a case-control study.

Adolescent↗
PubMed2002

Hunting for electrophiles that harm human DNA: Frits Sobels Award Lecture.

This lecture is dedicated to Frits Sobels and his farsighted vision on research directions in genetic toxicology. Some accomplishments by the author's research group in the area of cancer etiology research and pre-clinical drug safety evaluation are presented. Praziquantel, an antischistosomal drug, was found to be devoid of any genetic effects which determined the drug companies to proceed with further safety evaluation and marketing. This highly efficient life-saving drug is now in use world wide. Biomonitoring methods have been developed to quantitate carcinogens, their metabolites or DNA adducts in humans exposed environmentally and endogenously to genotoxic agents. The methods were applied in ecological and case-control studies aimed at establishing causal relationships between exposure and disease. Results from both field studies in Iran and laboratory investigations supported the hypothesis that opium use, in particular ingestion of its pyrolysates, may be a risk factor for esophageal cancer in this region, probably acting together with nutritional deficiencies and thermal injury. By applying the nitrosoproline (NPRO) test in ecological studies on esophageal cancer causation in China some support was obtained for the involvement of N-nitroso compounds. In inhabitants of high risk areas endogenous nitrosamine synthesis could be markedly reduced by ingestion of vitamin C. Ultrasensitive detection methods for etheno-DNA adducts, which are formed by lipid peroxidation products resulting from increased oxidative stress, have been developed. Known cancer risk factors such as metal storage, chronic inflammatory processes and a high omega-6 PUFA fat diet increased the background level of these miscoding DNA adducts many times. They were found to increase progressively in premalignant lesions of cancer-prone tissues of humans and rodents, probably contributing to the genetic instability that drives cells to malignancy. Etheno-DNA adducts are thus promising markers to verify the efficiency of chemopreventive measures in humans.

Animals↗
PubMed2000

Resistant starches.

Initially, it was hoped that resistant starches (ie, starches that enter the colon) would have clear advantages in the reduction of colon cancer risk and possibly the treatment of ulcerative colitis. Recent studies have confirmed the ability of resistant starch to increase fecal bulk, to increase the molar ratio of butyrate in relation to other short-chain fatty acids, and to dilute fecal bile acids. However, reduction in fecal ammonia, phenols, and N-nitroso compounds have not been achieved. At this point the picture from the standpoint of colon cancer risk reduction is not clear. Nevertheless, there is a fraction of what has been termed resistant starch (RS1), which enters the colon and acts as slowly digested, or lente, carbohydrate. Foods in this class are low glycemic index and have been shown to reduce the risk of chronic disease. They have been associated with systemic physiologic effects such as reduced postprandial insulin levels and higher high-density lipoprotein cholesterol levels. Consumption of low glycemic index foods has been shown to be related to a reduced risk of type 2 diabetes. Type 2 diabetes has in turn been related to a higher risk of colon cancer, especially colon cancer deaths. If carbohydrate has a protective role in colon cancer prevention, it may lie in the systemic effects of low glycemic index foods. The colonic advantages of different carbohydrates, therefore, remain to be documented. However, there is reason for optimism about the possible health advantages of so-called resistant starches that are slowly digested in the small intestine.

Journal Article↗
PubMed2001

Municipal drinking water nitrate level and cancer risk in older women: the Iowa Women's Health Study.

Nitrate contamination of drinking water may increase cancer risk, because nitrate is endogenously reduced to nitrite and subsequent nitrosation reactions give rise to N-nitroso compounds; these compounds are highly carcinogenic and can act systemically. We analyzed cancer incidence in a cohort of 21,977 Iowa women who were 55-69 years of age at baseline in 1986 and had used the same water supply more than 10 years (87% > 20 years); 16,541 of these women were on a municipal supply, and the remainder used a private well. We assessed nitrate exposure from 1955 through 1988 using public databases for municipal water supplies in Iowa (quartile cutpoints: 0.36, 1.01, and 2.46 mg per liter nitrate-nitrogen). As no individual water consumption data were available, we assigned each woman an average level of exposure calculated on a community basis; no nitrate data were available for women using private wells. Cancer incidence (N = 3,150 cases) from 1986 through 1998 was determined by linkage to the Iowa Cancer Registry. For all cancers, there was no association with increasing nitrate in drinking water, nor were there clear and consistent associations for non-Hodgkin lymphoma; leukemia; melanoma; or cancers of the colon, breast, lung, pancreas, or kidney. There were positive associations for bladder cancer [relative risks (RRs) across nitrate quartiles = 1, 1.69, 1.10, and 2.83] and ovarian cancer (RR = 1, 1.52, 1.81, and 1.84), and inverse associations for uterine cancer (RR = 1, 0.86, 0.86, and 0.55) and rectal cancer (RR = 1, 0.72, 0.95, and 0.47) after adjustment for a variety of cancer risk/protective factors, agents that affect nitrosation (smoking, vitamin C, and vitamin E intake), dietary nitrate, and water source. Similar results were obtained when analyses were restricted to nitrate level in drinking water from 1955 through 1964. The positive association for bladder cancer is consistent with some previous data; the associations for ovarian, uterine, and rectal cancer were unexpected.

Age Factors↗
PubMed1991

Direct involvement of human gastric mucosa in the activation of alimentary pro-carcinogens.

Exposure to N-nitroso-compounds and aromatic amines, xenobiotics which require an activation in order to exert their genotoxic potential, is causally associated with gastric cancer. We evaluated the capacity of microsome-containing fractions from human gastric mucosa to activate two model carcinogenic compounds. A 9,000 x g supernatant (S9) was obtained from gastric mucosal specimens and, for comparison, from human liver and aroclor-induced and non induced rat liver. The capacity of the S9 to activate N-nitrosopyrrolidine (NPY) and 2-aminofluorene (2AF) to mutagenic metabolites was tested in the Ames/Salmonella reversion assay, while dimethylnitrosamine (DMN) and aminopyrine (AP) demethylation activities were spectrophotometrically evaluated by using an enzymatic assay of the amount of formaldehyde released following the enzymatic demethylation of the corresponding substrates. Results indicate that human gastric S9 fractions may activate 2AF to a genotoxic derivative and are characterized by DMN and AP demethylase activities higher (p < 0.05) than those of human liver, when expressed in mg/protein (p < 0.05). Although the parameters evaluated can only be considered as a partial measure of the general activating capacity toward dietary and environmental procarcinogens, these results suggest that human gastric mucosa may be directly involved in the metabolic activation of these compounds to mutagenic/carcinogenic species.

Aminopyrine N-Demethylase↗