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PubMed2000

Diet and colorectal cancer prevention.

The majority of cancers are sporadic and epidemiological estimates suggest that up to 80% of colorectal cancer is attributable to diet. Epidemiologically, cross-sectional comparisons, case-control studies and trends in food intake show high rates of colorectal cancer in populations consuming diets high in meat and fat, and low in starch, NSP (non-starch polysaccharides, fibre) and vegetables. In general, prospective studies tend to support these findings although estimates of relative risk are not high. Existing prospective studies have however used crude indices of diet subject to substantial measurement error, and interactions with genetic polymorphisms in, for example, phase-I and -II enzymes have been studied only rarely. The association between meat consumption and colorectal cancer is usually attributed to the formation of heterocyclic amines in meat when it is cooked. In addition, in humans high-meat diets increase the level of nitrosatable material entering the colon so that faecal N-nitroso compounds (NOCs) increase in a dose-responsive manner following endogenous synthesis in the colon. Some of the mutations and guanine adducts accumulated during colorectal cancer progression are characteristic of alkylative damage, which would be compatible with NOC exposure. To date, NSP, resistant starch and vegetables have not reduced faecal NOC levels.

Colon↗
PubMed2001

Alterations in intragastric nitrite and vitamin C levels during acid inhibitory therapy.

Most nitrite entering the healthy acid-secreting stomach is derived from dietary nitrate. The latter is absorbed from the small intestine, 25% then being secreted by the salivary glands into the mouth. Buccal organisms subsequently convert 20% of this nitrate to nitrite. When this nitrite is swallowed, the ascorbic acid in the acidic gastric juice reduces it to nitric oxide, which is absorbed by the mucosa. In the process, the ascorbic acid is oxidized to dehydroascorbic acid. When the intragastric pH is elevated by powerful anti-secretory agents, this gastric chemistry is profoundly modified. At a neutral pH, the swallowed nitrite does not react with ascorbic acid but accumulates in the stomach. The level of nitrite in the gastric juice during treatment with anti-secretory medication is particularly high after a nitrate-containing meal. Powerful anti-secretory medication also lowers the intragastric concentration of ascorbic acid and total vitamin C, probably because of the relative instability of the vitamin at a higher pH. These changes in the intragastric concentrations of nitrite and ascorbic acid are most marked in Helicobacter pylori -infected subjects on proton pump inhibitor therapy. It is recognized that an elevated nitrite-to-ascorbic acid ratio predisposes to the formation of potentially carcinogenic N -nitroso compounds. It is, however, unclear at present whether such compounds are formed within the human stomach.

Anti-Ulcer Agents↗
PubMed2000

Omeprazole, Helicobacter pylori status, and alterations in the intragastric milieu facilitating bacterial N-nitrosation.

BACKGROUND & AIMS: Omeprazole produces greater acid inhibition in Helicobacter pylori-positive than -negative subjects. We investigated whether this is accompanied by more profound changes in the intragastric milieu that facilitates bacterial synthesis of N-nitroso compounds. METHODS: Gastric juice pH; nitrite, ascorbic acid, and total vitamin C concentrations; and colonization by other bacteria were examined before and during omeprazole treatment in subjects with and without H. pylori infection. Studies were performed in the fasting state and after consumption of 2 mmol nitrate (equivalent to a salad meal). RESULTS: Before omeprazole, H. pylori-positive and -negative subjects were similar for all parameters. During omeprazole, H. pylori-positive subjects had a higher intragastric pH (7.8 vs. 3.0; P < 0.00001) and greater colonization with non-H. pylori species (5 x 10(7) vs. 5 x 10(5) CFU/mL; P < 0.05). These bacteria included nitrosating species. During omeprazole treatment, H. pylori-positive subjects had higher intragastric nitrite levels after the nitrate meal (median area under the concentration/time curve, 12,450 vs. 4708 micromol/L. min; P = 0.04). Omeprazole lowered intragastric vitamin C levels in H. pylori-positive but not -negative subjects (1.8 vs. 3.4 microg/mL, respectively; P = 0.02). CONCLUSIONS: In H. pylori-positive subjects, omeprazole produces disturbances in intragastric nitrite, vitamin C, and bacterial colonization that facilitate bacterial N-nitrosation. This may place them at increased risk of mutagenesis and carcinogenesis.

Adult↗
PubMed1993

O6-methylguanine-DNA methyltransferase protects against nitrosamine-induced hepatocarcinogenesis.

We previously generated transgenic C3H/HeN mice by introducing the Escherichia coli O6-methylguanine-DNA methyltransferase (MGMT, DNA-O6-methylguanine:protein-L-cysteine S-methyltransferase, EC2.1.1.63) gene, ada, attached to the Chinese hamster metallothionein I gene promoter. One transgenic mouse line expressing both ada-specific mRNA and Ada protein could be propagated over many generations in a homozygous state with respect to the integrated DNA. Liver extracts from transgenic homozygous mice have consistently demonstrated about 3 times the control activity of normal mice. Furthermore, in the transgenic homozygotes treated with ZnSO4, activity is increased to 6-8 times the normal level in mice and is equivalent to that for man. To examine whether these increased levels of MGMT activity can actually decrease the susceptibility of animals to N-nitroso compounds, we studied liver carcinogenesis in our transgenic mice expressing high amounts of MGMT. Groups of transgenic and nontransgenic mice, each comprising about 200 suckling animals (14 +/- 1 days old), were divided each into eight subgroups, providing paired groups of transgenic and nontransgenic mice. They received an i.p. injection of ZnSO4 to induce MGMT, and 10 hr thereafter were given an i.p. injection of either dimethylnitrosamine or diethylnitrosamine. Liver tumor development was quantitatively assessed at 7-11 months. Here, we report statistically significant reduction of tumor formation in transgenic mice of four of the six paired groups that received treatment. The remaining two demonstrated results in line with dose dependence. Therefore, our data indicate that MGMT can indeed protect animals from low-dose exposure to environmental alkylating carcinogens.

Animals↗
PubMed1990

The effect of dietary nitrate on nitrate and nitrite excretion in man.

Dietary nitrate and nitrite may affect colonic pathophysiology. These anions influence fermentation, and nitrite has been shown to augment sodium absorption by the colon and participate in the formation of N-nitroso compounds. There is, however, no general agreement as to how much dietary nitrate and nitrite reaches the colon. To help resolve this question, balance studies were performed on six healthy ileostomy subjects who were given diets that varied in nitrate content from 0.83 to 5.20 mmol/d. Nitrate and nitrite excretion in ileal effluent and urine were measured by anion-exchange chromatography with conductivity detection. There was no significant nitrite in the diets, urine or ileal effluent. Dietary nitrate was largely excreted in urine (1.31-4.25 mmol/d). The urinary excretion findings indicated net synthesis of nitrate at low dietary intakes and net catabolism of nitrate at high intakes. Nitrate losses in ileal effluent were very low (0.03-0.05 mmol/d, 0.03-0.06 mmol/kg) and unrelated to intake for all the diets. It is concluded that dietary nitrate and nitrite do not enter the colon from the small intestine in amounts that would affect fermentation and mucosal metabolism in man. The possibility of significant amounts of nitrate reaching the colon via blood in normal subjects has not been excluded.

Aged↗
PubMed1991

Endogenous nitrosation of L-proline by dietary-derived nitrate.

Two studies were conducted to assess the availability of normal dietary sources of nitrate for endogenous nitrosation of an amino acid substrate, L-proline, and to investigate the potential for dietary ascorbic acid to inhibit such nitrosation. In the first study, 16 subjects consumed a salad meal (containing about 172 mg nitrate) with and without a loading dose of proline. A significant increase (10.8 compared with 2.7 micrograms/24 hrs, p less than 0.0001) in mean urinary N-nitrosoproline (NPRO) excretion following meal plus substrate ingestion was indicative of intragastric proline nitrosation by meal-derived nitrate. In the second study (19 different subjects), the mean urinary NPRO level was significantly decreased (15.8 micrograms compared with 28.4, p = 0.022) by inclusion of ascorbic acid sources in the meal. This demonstrated inhibition of proline nitrosation by dietary sources of the vitamin. Large interindividual variation in nitrosating ability was apparent that was associated with variation in meal nitrate to salivary nitrite conversion. Although meals containing fresh vegetables, as tested here, could provide sufficient nitrate to result in endogenous formation of N-nitroso compounds, there will be considerable inter- and intraindividual variation in the extent of this process.

Administration, Oral↗
PubMed1999

Detection of lignin biopolymer- and vitamin E-stimulated reduction of DNA strand breaks in H2O2- and MNNG-treated mammalian cells by the comet assay.

In this study the possible protective effects of water-soluble sulfur-free lignin biopolymer and vitamin E (alpha-tocopherol) on DNA in human VH10 cells and hamster V79 cells exposed to H2O2 and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated. The level of DNA damage (DNA strand breaks) was measured using single-cell gel electrophoresis, i.e., comet assay. Lignin biopolymer and vitamin E exhibited a protective effect against the overall DNA damage induced after H2O2 treatment. If H2O2-treated human cells were incubated for 90 minutes to ligate frank breaks of DNA, two lesion-specific enzymes, endonuclease III and formamidopyrimidine DNA glycosylase (FPG), significantly increased the level of DNA strand breaks originating from oxidized pyrimidines and purines. Preincubation of cells with lignin or vitamin E reduced mainly the level of oxidized pyrimidines. Reduction of oxidized purines was less evident. In addition, lignin biopolymer exhibited a protective effect against MNNG-induced DNA damage, whereas vitamin E exhibited a protective effect only against H2O2-induced DNA damage. These findings suggest that the antioxidant nature of lignin biopolymer enables a reduction of the level of frank breaks and of oxidized DNA bases in H2O2-treated cells, and its adsorptive capacity enables binding of nitroso compounds and reduction of alkylation in MNNG-treated cells.

Animals↗
PubMedDate not supplied

A rapid method for the determination of nitrate and nitrite by chemiluminescence.

Nitrite and nitrate + nitrite can be determined by selective chemical reduction to nitric oxide which is measured using a chemiluminescence analyser. The reducing agents are sodium iodide in acetic acid for nitrite and ferrous ammonium sulphate-ammonium molybdate for nitrate + nitrite. The concentrations of the reducing agents have been optimized to obtain the maximum yield of nitric oxide and the minimum coefficient of variation. Under these conditions, it is possible to inject repeated samples into the refluxing reducing agents and to obtain rapid evolutions of nitric oxide from which the determinations can be made. Nitric oxide has also been produced using the nitrite reagents from organic nitrites, a S-nitrosothiol, a pseudonitrole and N-nitrosamines. Similarly, an organic nitrate and some C-nitroso compounds respond to the method for nitrate but only to the extent of a yield of nitric oxide of about 10% of the theoretical. Very low or zero responses were evident from aliphatic and aromatic C-nitro compounds but not omega-N-nitroarginine which gave a large yield of nitric oxide using the reagents for nitrate. In general, however, concentrations of nitrate will be in considerable excess of those of related compounds which would interfere with the determinations. Nitrate can be determined either by difference in its mixtures with nitrite or by prior removal of the nitrite using ascorbic acid provided oxygen and nitric oxide are removed by degassing with nitrogen.

Indicators and Reagents↗
PubMedDate not supplied

Influence of nitrate, ascorbic acid, and nitrate reductase microorganisms on N-nitrosamine formation during Korean-style soysauce fermentation.

Traditional Korean soysauce samples were collected from households in Chinju, Gyeongnam, Korea and analysed for volatile N-nitrosamines. Five of 24 samples contained NDMA (range = 1.6-10.4 micrograms/l) which was the only volatile N-nitroso compound found. Soysauce made from well water contained NDMA more often (4 of 6 samples) than soysauce made from tap water (1 of 18). This suggests that the water source is a determinate in the NDMA content of soysauce, probably due to a higher nitrate content of well water. The source of salt used did not clearly influence NDMA content. Soysauce was prepared in the laboratory using traditional methods but with 0 to 400 mg/l nitrate and in some cases made 6.5 to 65 mM in ascorbic acid and fermented for 120 days. The NDMA content of the samples was positively correlated with increasing nitrate concentration. Nitrate at 400 mg/l resulted in an NDMA content of 203 micrograms/l. Ascorbic acid substantially inhibited NDMA formation. All samples contained large numbers of nitrate reductase-containing organisms (greater than 1 x 10(7) CFU/ml).

Ascorbic Acid↗
PubMed1996

Dietary intakes of nitrate, nitrite and NDMA in the Finnish Mobile Clinic Health Examination Survey.

Concern about potential health hazards of nitrate, nitrite and N-nitroso compounds necessitates calculations of exposures to these compounds and their distribution in normal populations. This study describes dietary intake of nitrate (NO3-), nitrite (NO2-) and N-nitrosodimethylamine (NDMA) among 5304 adult men and 4750 women, who participated in the Finnish Mobile Clinic Health Examination Survey in 1967-72. Food consumption data for each individual over the preceding year were collected by a dietary history interview. Intakes of nitrate, nitrite and NDMA from vegetables, fruits, cheese, meat and fish products were calculated using available values mainly derived from Finland and other countries in northern Europe. Nitrate and nitrite from drinking water were not included in the study. Mean daily dietary intake of nitrate was 77 mg, of nitrite 5.3 mg, and of NDMA 0.05 microgram respectively. Intake of NDMA from beer, estimated in a part of the study population, was 0.07 microgram per day. More than 90% of dietary nitrate was derived from vegetables, including potatoes. Nitrite was mainly provided by cured meat products. Cured meat products and smoked and salted fish were important food sources of NDMA. The total daily intake of nitrate was similar in men and women, whereas intakes of nitrite and NDMA were higher in men than in women. The diet of farmers was characterized by lower amounts of nitrate, nitrite and NDMA, whereas white collar workers and those employed in industry had higher intakes. Current smokers were exposed to higher dietary intakes of nitrate, nitrite and NDMA than non-smokers. Intakes of dietary nitrate, nitrite and NDMA estimated on an individual level are suggested to be useful in evaluating the health effects of these compounds in epidemiological studies.

Adolescent↗
PubMed1998

Application of liquid chromatography-atmospheric pressure chemical ionization mass spectrometry and tandem mass spectrometry to the determination of volatile nitrosamines in dry sausages.

A high-performance liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric method was developed for the determination of volatile nitrosamines in dry sausages. Tandem mass spectrometry was applied for the detection of N-nitrosopyrrolidine, N-nitrosodiethylamine and N-nitrosopiperidine. N-nitrosomethylamine was detected by using the selected ion monitoring mode. The occurrence of the four different nitrosamines was monitored in 27 dry sausage samples and a correlation was observed between N-nitrosopyrrolidine and biogenic amines. Nitroso compounds are thus not only formed in heated conditions but formation can also occur during ripening of dry sausages by reaction between residual nitrite and amines formed during the fermentation process.

Animals↗
PubMed1986

An IARC Manual series aimed at assisting cancer epidemiology and prevention. "Environmental carcinogens: selected methods of analysis".

Since 1975, the IARC has been preparing a series of volumes entitled "Environmental Carcinogens: Selected Methods of Analysis" (IARC Manual series) of which the purposes are to assist analysts, epidemiologists and regulatory authorities in planning or performing exposure measurements that are truly comparable between different studies. The Manual series provides expert information within each volume on multi-media sampling, methods of analyses and some background of epidemiology, metabolism, use/occurrence for a group of known or suspect carcinogens. So far, eleven volumes have been published or are in preparation on the following subjects: N-nitrosamines, vinyl chloride, PAH, aromatic amines, mycotoxins, N-nitroso compounds, volatile halogenated hydrocarbons, metals, passive smoking, benzene and alkylated benzenes, dioxins, PCDFs and PCBs. The presentation will discuss needs and priorities for use of analytical chemistry in estimating exposures of apparently greatest relevance to cancer causation, i.e. the approach to developing this series. Indications from epidemiology, evaluations of carcinogenic risk to humans, and recent developments in total exposure assessment are that new methods and matrices need more emphasis, e.g. as with biochemical dosimetry, exhaled breath, and in indoor air.

Carcinogens, Environmental↗
PubMed2001

The mechanisms for nitration and nitrotyrosine formation in vitro and in vivo: impact of diet.

The detection of 3-nitro-L-tyrosine residues associated with many disease states, including gastric cancer, has implicated a role for peroxynitrite in vivo, and thus endogenously produced nitric oxide and superoxide. Additionally, dietary nitrate has been suggested to be involved in the pathogenesis of gastric cancer through a mechanism involving reduction to nitrite and subsequent formation of potentially mutagenic nitroso-compounds. Studies have now demonstrated that a multitude of reactive nitrogen species other than peroxynitrite are capable of producing nitrotyrosine. Thus, we have reviewed the evidence that dietary nitrate, amongst other reactive nitrogen species, may contribute to the body burden of nitrotyrosine.

Animals↗
PubMedDate not supplied

Toxins and carcinogens in the environment: an observation in the tropics.

The incidence of primary liver cancer in the countries of tropical Africa is the highest in the world. There is a growing belief that the relatively high prevalence of hepatocellular carcinoma in Nigeria may have a multiple chemical factor etiology in such forms as food contaminants, herbal teas, and environmental chemicals. Major chemical toxins and carcinogens that have been identified so far in the tropical environment include sapotoxin, cycasin, mushroom toxin, capsaicin, oxalic acid, prussic acid, fluorooleic acid, N-nitroso compounds, aflatoxin, palmotoxin, pyrrolizidine alkaloids, quinine, DDT, and cyclamate.

Carcinogens, Environmental↗
PubMed1986

Oxidative destruction of hydrazines produces N-nitrosamines and other mutagenic species.

As part of the joint International Agency for Research on Cancer-National Cancer Institute program for the evaluation and development of methods for the degradation of chemical carcinogens, four oxidative techniques for the degradation of hydrazines were investigated. The oxidizing agents used were as follows: sodium hypochlorite, calcium hypochlorite, potassium iodate, and potassium permanganate in sulfuric acid. In each case, at least 99% of the hydrazine initially present was destroyed; however, the potential usefulness of these methods was compromised by the formation (in some reaction mixtures) of carcinogenic N-nitroso compounds and/or unknown mutagenic species. Oxidative degradation of hydrazines is recommended only for the decontamination of glassware and for the treatment of spills, for which reductive degradation methods are not suitable.

Animals↗
PubMed1987

Gas chromatographic/mass spectrometric analysis of extracts of workplace air samples for nitrosamines.

Three capillary gas chromatography/mass spectrometry (GC/MS) procedures were developed to confirm the presence of N-nitrosamines in workplace air sample extracts, which were previously analyzed by gas chromatography with a thermal energy analyzer. In the first procedure, high resolution ion monitoring of NO+ was used to confirm the presence of eight N-nitrosamines and to screen the samples for other N-nitroso compounds. In the second procedure, high resolution monitoring of parent ions was used for confirmation of specific N-nitrosamines; and in the third procedure, full-scan GC/MS was used for identification of compounds above the level of 2 ng per injection. Detection limits of the three procedures and retention time precision of both selected ion monitoring techniques are given. Typical examples in the use of these techniques for confirmation of N-nitrosamines in sample extracts also are described.

Air Pollutants, Occupational↗
PubMed2003

Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age.

Type 1 diabetes is an immune-mediated disease characterized by a preclinical prodrome during which beta cell autoimmunity proceeds at a variable rate. Large geographic differences and a conspicuous increase in incidence, especially among young children since the 1950s, and the relatively low concordance in identical twins are factors that favor a critical role of environmental factors in the etiology of this disease. Only approximately 5% or fewer subjects with HLA-conferred genetic susceptibility to type 1 diabetes actually develop the clinical disease. Breastfeeding, nicotinamide, zinc, and vitamins C, D, and E have been reported as possibly protecting against type 1 diabetes, whereas N-nitroso compounds, cow milk, increased linear growth, and obesity may increase the risk. Thus far, only the significance of infant feeding, cow milk, and vitamin D have been studied in both case-control and cohort settings. The major shortcoming of most studies done so far is that only single dietary exposures have been assessed at single time points. Putative nutritional and other confounding factors have received little attention as have the limitations of the dietary methods used. There is little firm evidence of the significance of nutritional factors in the etiology of type 1 diabetes. The availability of good markers of preclinical type 1 diabetes and of genetic risk have decreased the sample sizes needed and made longitudinal cohort studies of the assessment of children's diets feasible.

Animals↗