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PubMed2003

Haem, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat.

Many N-nitroso compounds (NOC) are carcinogens. In this controlled study of 21 healthy male volunteers, levels of NOC on a high (420 grams) red meat diet were significantly greater (P = 0.001) than on a low (60 grams) meat diet but not significantly greater when an equivalent amount of vegetable protein was fed. An 8-mg supplement of haem iron also increased fecal NOC (P = 0.006) compared with the low meat diet, but 35-mg ferrous iron had no effect. Endogenous N-nitrosation, arising from ingestion of haem but not inorganic iron or protein, may account for the increased risk associated with red meat consumption in colorectal cancer.

Adult↗
PubMed1989

Epidemiological studies of perinatal carcinogenesis.

Epidemiological evidence for prenatal carcinogenesis includes associations between cancer in young people and intrauterine exposure to X-rays, drugs and hormones and prezygotic events such as specific chromosomal aberrations associated with specific cancers. Recent findings suggest that the hormonal environment during early gestation can result not only in the development of clear-cell adenocarcinoma of the vagina but also in the development of germ cell tumours of the testes and ovary. Hormone-related risk factors for testicular germ cell neoplasms include maternal use of exogenous oestrogens during early gestation and, possibly, maternal nausea, maternal obesity and race as well. Ovarian germ cell tumours also appear to be related to maternal use of hormones and obesity. Several epidemiological studies of cancer in young people have been directed towards suggested associations with parental occupational exposures, parental cigarette smoking and household exposures to electric and magnetic fields (EMF). The findings of the many studies of parental occupational exposures are inconsistent and are often nonspecific with respect to the type of childhood cancer and the job exposure implicated. Parental cigarette smoking has been associated in some studies with an increased risk for cancer among children and young adults, and in other studies with an increased risk among mature adults, but the findings are not consistent across studies. Three studies of all types of childhood cancer found risk to be related to household exposures to EMF; in all three, the risk for central nervous system tumours was increased, and in two of the three leukaemia risk as well. A fourth study showed no association between childhood leukaemia and EMF. A hypothesis is proposed which suggests that prenatal and early childhood exposure to N-nitroso compounds (NOC) may be related to the development of primary tumours of the brain in children. Experimentalists have shown that various NOC are potent nervous system carcinogens, particularly when animals are exposed transplacentally. This experimental model and findings from a Los Angeles case-control study (209 pairs) of brain tumours in young people led to the proposed epidemiological hypothesis. Although this and other epidemiological studies of NOC have major limitations, findings from epidemiological studies of congenital defects and of other childhood cancers lend the hypothesis some support. A large international collaborative case-control study of childhood brain tumours was begun recently. This study has a major advantage over most case-control studies in adults because the exposure period of greatest interest (gestation) is clearly defined.

Animals↗
PubMed1997

[Colorectal cancer: controversial role of meat consumption].

Diet is supposed to influence the colorectal cancer etiology, but the precise causative factors are yet unknown. International ecological studies show a strong correlation between meat consumption and the colorectal cancer incidence. Most case-control studies (22 of 29) show an increased risk to develop a colorectal cancer for those eating higher amounts of meat. In contrast, only 2 out of the 5 best prospective cohort studies have shown this positive association for red meat. Two studies out of 4 show an association with processed meat. Consumption of white meat or of fish is not associated with a high risk, and might even reduce the occurrence of colorectal cancer. Several plausible hypotheses concerning the link between meat and colon carcinogenesis have been suggested. They involve saturated fat, protein, iron, heterocyclic amines produced by cooking, and N-nitroso compounds. High fat diets may promote cancer because they have a high caloric content, or because they lead to increased levels of bile acids in the colonic lumen. Six experimental studies are published on the effect of meat, or meat fractions, on the colon tumor incidence in rodents initiated with chemical carcinogens. Data from these studies do not support the belief that red meat (beef) has a specific effect on intestinal carcinogenesis. Instead, diets containing beef meat (cooked or raw) decrease carcinogenesis when compared to control diets containing similar amounts of fat and protein of vegetal origin. However, high fat or high protein diets often increase carcinogenesis when compared to low fat or low protein diets. Thus, one cannot state, nor exclude, that meat promotes colorectal cancer.

Amines↗
PubMed1988

Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention.

Although the proof that N-nitroso compounds (NOC), a versatile class of carcinogens in animals, are also carcinogenic in man is lacking, humans are exposed through ingestion or inhalation to preformed NOC in the environment and through the endogenous nitrosation of amino precursors in the body. Activated macrophages can synthesize nitrate, nitrite and nitrosating agents that can form NOC. A number of bacterial strains isolated from human infections can produce NOC enzymatically from precursors at neutral pH. As a consequence endogenous nitrosation may occur at various sites of the body such as the oral cavity, stomach, urinary bladder, lungs, and at other sites of infection or inflammation. Since the demonstration by Mirvish et al. (1972) showing that ascorbate can reduce tumor formation in animals following feeding of nitrite plus amine, numerous substances to which humans are exposed have been identified and shown to inhibit formation of NOC in vitro, in animal models and in humans. Such inhibitors of nitrosation include vitamins C and E, phenolic compounds, and complex mixtures such as fruit and vegetable juices or other plant extracts. Nitrosation inhibitors normally destroy the nitrosating agents and thus act as competitors for the amino compound that serves as substrate for the nitrosating species. Independently, epidemiological studies have already established that fresh fruits and vegetables that are sources of vitamin C, other vitamins and polyphenols have a protective effect against cancers at various sites and in particular gastric cancer. Although the evidence that endogenously formed NOC are involved in human cancers is far from conclusive, it is suggestive and justifies preventive measures for reducing exposure to NOC. This article briefly reviews (i) the chemistry of NOC formation and inhibition, (ii) the studies in experimental animals which showed that inhibition of endogenous NOC synthesis leads to a reduction of toxic, mutagenic and carcinogenic effects, (iii) recent studies in humans where the degree of inhibition of endogenous NOC synthesis was directly quantified and lastly (iv) the contribution of nitrosation inhibitors to human cancer prevention.

Animals↗
PubMed1989

Nitrosation by stimulated macrophages. Inhibitors, enhancers and substrates.

Macrophages and their immortalized cell lines can be activated to form nitrite and nitrate via oxidation of arginine and this is accompanied by the formation of N-nitroso compounds. The mechanism of nitrosamine formation has been investigated through the use of compounds which are known either to inhibit or enhance acid-catalyzed nitrosation. The range of nitrogen acceptors has been expanded to include ureas as well as amines of varying pKa and structure. The results are consistent with a mechanism in which NO is oxidized to N2O3 and N2O4, which are capable of nitrosating amines, but not ureas or amides, at neutral pH. This is in agreement with a recent observation that macrophage cell-free extracts can oxidize arginine to NO. The effect of ascorbic acid on intact activated macrophages is complex since nitrite formation is enhanced over a very wide range of ascorbate concentrations (5-500 microM) while nitrosation is inhibited at ascorbate concentrations greater than 50 microM.

Arginine↗
PubMed1993

The site of antiviral action of 3-nitrosobenzamide on the infectivity process of human immunodeficiency virus in human lymphocytes.

The C-nitroso compound 3-nitrosobenzamide, which has been shown to remove zinc from the retroviral-type zinc finger of p7NC nucleocapsid proteins, inhibits acute infection of human immunodeficiency virus type 1 in cultured human lymphocytes. The attachment of the virus to lymphocytes and the activities of critical viral enzymes, such as reverse transcriptase, protease, and integrase, are not affected by 3-nitrosobenzamide. However, the process of reverse transcription to form proviral DNA is effectively abolished by the drug, identifying the mode of action of 3-nitrosobenzamide as interrupting the role of p7NC in accurate proviral DNA synthesis during the infectious phase of the virus life cycle.

Antiviral Agents↗
PubMed1977

Covalent binding and endogenous incorporation as illustrated by nitroso carcinogens.

Serious problems of interpretation may arise when metabolic studies are carried out with radioactively labeled drugs and other foreign chemicals. Detection of free or bound radioactivity in tissues or body fluids may indicate the presence of the unchanged chemical or of various products of its decomposition. Some radioactivity may, however, represent incorporation of certain metabolites of foreign chemicals into body constituents by normal biosynthetic pathways. The interpretation of the results of such metabolic experiments from the standpoint of safety evaluation will be profoundly different if the radioactivity represents covalent binding to a cellular macromolecule than if it results from normal endogenous incorporation. These two distinct types of binding of radioactivity to body constituents are well illustrated by experimental studies with some carcinogenic nitroso compounds, such as dimethylnitrosamine and N-methylnitrosourea. Dimethylnitrosamine requires metabolic activation by microsomal enzymes and yields formaldehyde and a chemically reactive methylating intermediate, probably a methyl carbonium ion. The latter reacts with nucleophilic sites in nucleic acids and proteins, and also with water to yield methanol. N-Methylnitrosourea does not require metabolic activation but yields the same methylating intermediate spontaneously under physiologic conditions. Both formaldehyde and methanol are metabolized largely to CO2, but they also enter the one-carbon metabolic pool and became biosynthetically incorporated into nucleic acids, proteins, and other cell components. Alkylation of cellular constituents is associated with various biological effects, including cytotoxicity, carcinogensis, and mutagenesis, and the same effects are produced by the activated forms of a variety of other chemical carcinogens. It is clearly of paramount importance to distinguish between these two types of incorporation of radioactivity.

Animals↗
PubMed1985

Volatile nitrites. Use and adverse effects related to the current epidemic of the acquired immune deficiency syndrome.

Early reports of the acquired immune deficiency syndrome (AIDS) in homosexual men suggested that the cause might be related to homosexual life-style practices, including use of recreational drugs. Inhalation of volatile nitrites is a possible contributing factor in AIDS because their pharmacologic properties lead to toxicity. Metabolism of N-nitroso compounds produces mutagens, teratogens, and potent carcinogens in 39 different animal species, and volatile nitrites have deleterious effects on human lymphocytes in vitro and in vivo. In relation to the current AIDS epidemic, the timing of production and sales of volatile nitrites for recreational use is the only new life-style factor that might answer the question "why AIDS now?" Prevalence of nitrite use among male homosexuals is very high, and almost every reported case of Kaposi's sarcoma during the past three years includes a history of prior nitrite use. The age of the group of patients in whom Kaposi's sarcoma and AIDS are developing is consistent with a cohort initially exposed seven to 10 years ago. Cessation of nitrite use could reduce the epidemic.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Gastric juice ascorbic acid: effects of disease and implications for gastric carcinogenesis.

N-nitroso compounds (NOC) are strongly implicated in the causation of cancer of the stomach and it has been suggested that ascorbic acid might reduce the risk of gastric cancer by preventing their formation within gastric juice. However, until recently there have been no measurements of gastric juice ascorbic acid concentrations. We have measured both gastric juice ascorbic and total vitamin C (ascorbic acid and dehydroascorbic acid). Our findings suggest that ascorbic acid is secreted into the gastric lumen so that gastric juice concentrations are often greater than those in plasma. Gastric pathology affects this secretion, leading to values in gastric juice that are lower than plasma levels. Stimulation of gastric secretion does not raise vitamin C concentrations in individuals whose values are initially low. The role of ascorbic acid in preventing formation of NOC and protecting against gastric cancer is discussed in the light of these findings.

Ascorbic Acid↗
PubMed1981

Promoting effect of Roussin's red identified in pickled vegetables from Linxian China.

Roussin's red (dimethylthiotetranitrosodiiron) has been identified as a non-alkylating N-nitroso compound present in pickled vegetables from Linxian, a high risk area for oesophageal cancer in China. In vitro experiments showed that Roussin's red had no significant mutagenic and transforming activities at the doses used, but it did enhance transformation in C3H/10TI/2 cells initiated with 3-methylcholanthrene (0.1 microgram/mI) and it decreased the number of sebaceous glands and increased the epidermal thickness in short term skin tests. In this respect Roussin's red resembled 12-O-tetradecanoyl-phorbol-13-acetate and the results indicate that it may be a new naturally-occurring tumour promoter. The in vitro promoting effect of extracts of pickled vegetables that has been previously reported can be explained, at least in part, by the presence of Roussin's red. The possible role of Roussin's red in the aetiology of oesophageal cancer is discussed.

Animals↗
PubMed1989

[An experimental study on bladder carcinogenesis in dogs by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and its urinary metabolites].

N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was administered to beagle dogs to examine the urinary metabolites. After extraction and purification of the urine sample, the urinary metabolites were identified by gas-chromatography mass-spectrometry and measured using a gas chromatograph equipped with a thermal energy analyzer (GC-TEA). Five N-nitroso-compounds (N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), N-butyl-N-(2-hydroxy-3-carboxypropyl)-nitrosamine (BHCPN), N-butyl-N-(carboxymethyl)-nitrosamine (BCMN), N-butyl-N-(2-oxopropyl) nitrosamine (BOPN) and BBN-glucuronide) were detected and identified by comparison with mass spectra of synthetic specimens. In the quantitative analysis by GC-TEA, BCMN greater than BHCPN greater than BCPN were larger part than BOPN and BBN-glucuronide. In early experimental period (0-25 wks) administered BBN (600 mg/day) to two dogs, small tumor was recognized in the urinary bladder of one dog earlier than the other. The former dog excreted larger amounts of BCPN in the urine than the latter. In late experimental period (100 wks approximately) administered BBN (400 mg/day) to five dogs, the dog that was found initial tumor earliest (103 wk) excreted the largest amounts of BCPN in the urine. Therefore, the excretion of BCPN had correlated with the carcinogenesis.

Animals↗
PubMed1991

[The age-related dynamics of the activity of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase in different organs of rats].

Concentrations of O6-alkylguanine-DNA alkyltransferase (AT) which repairs a procarcinogenic DNA adduct O6-alkylguanine formed following exposure to carcinogenic N-nitroso compounds were measured in the liver, kidney and peripheral blood leukocytes of male L10 rats aged 1, 4, 14, 22 and 36 months. In the liver, peak AT level was observed at the age of 14 and 22 months. No age-related differences were established for kidney and leukocytes. The highest concentration of AT was registered in the kidney while the lowest--in leukocytes. The study revealed stoichiometric transfer of O6-methylguanine methyl group to cysteine residue of AT. No positive correlation was established between individual tissue AT levels in different animals. The highest level of total protein and the lowest concentration of DNA were observed in the liver and kidney of 14-22 month-old rats. The data obtained provide an explanation for relative resistance of 1-2 year-old rats to hepatotropic nitrosamine and suggest that the level of AT in a given tissue is not predictive of its activity in other tissues.

Aging↗
PubMed2005

Workgroup report: Drinking-water nitrate and health--recent findings and research needs.

Human alteration of the nitrogen cycle has resulted in steadily accumulating nitrate in our water resources. The U.S. maximum contaminant level and World Health Organization guidelines for nitrate in drinking water were promulgated to protect infants from developing methemoglobinemia, an acute condition. Some scientists have recently suggested that the regulatory limit for nitrate is overly conservative; however, they have not thoroughly considered chronic health outcomes. In August 2004, a symposium on drinking-water nitrate and health was held at the International Society for Environmental Epidemiology meeting to evaluate nitrate exposures and associated health effects in relation to the current regulatory limit. The contribution of drinking-water nitrate toward endogenous formation of N-nitroso compounds was evaluated with a focus toward identifying subpopulations with increased rates of nitrosation. Adverse health effects may be the result of a complex interaction of the amount of nitrate ingested, the concomitant ingestion of nitrosation cofactors and precursors, and specific medical conditions that increase nitrosation. Workshop participants concluded that more experimental studies are needed and that a particularly fruitful approach may be to conduct epidemiologic studies among susceptible subgroups with increased endogenous nitrosation. The few epidemiologic studies that have evaluated intake of nitrosation precursors and/or nitrosation inhibitors have observed elevated risks for colon cancer and neural tube defects associated with drinking-water nitrate concentrations below the regulatory limit. The role of drinking-water nitrate exposure as a risk factor for specific cancers, reproductive outcomes, and other chronic health effects must be studied more thoroughly before changes to the regulatory level for nitrate in drinking water can be considered.

Drinking↗
PubMed2003

Maternal prenatal exposure to nitrosatable drugs and childhood brain tumours.

BACKGROUND: A compelling hypothesis was proposed that childhood brain tumours are associated with maternal exposure to N-nitroso compounds during the prenatal period. Many common drugs, such as antihistamines, aspirin, and antibiotics, are nitrosatable and depending upon the product, potentially carcinogenic. We hypothesized that maternal ingestion of certain subgroups of nitrosatable drug products during pregnancy increases the risk of brain tumour development in offspring. METHODS: Data were collected as part of a population-based case-control study of childhood brain tumours and mothers' self-reported exposure to therapeutic drugs and dietary nitrites. Cases were enrolled from three US West Coast SEER tumour registries: Seattle-Puget sound, Los Angeles County, and the San Francisco-Oakland Bay Area. Tumours were grouped into three major histological tumour subtypes: astroglial, primitive neural ectodermal tumours, and all remaining glial tumours ('other glial'). Therapeutic drugs reported by mothers were translated into active chemical compounds and classified as secondary amines, tertiary amines, amides, or none of the three. Risk estimates were computed according to classes of nitrosatability, potential carcinogenicity, teratogenicity, and predicted end product. RESULTS: We found no significant association between maternal use of nitrosatable drugs, either overall or within any of the nitrosatable drug classifications, and subsequent development of brain tumours in children. Nitrite consumption from cured meats was not an effect modifier. However, exposure to nitrosoephedrine during pregnancy was associated with significantly increased risk of 'other glial' tumours (OR = 3.1; 95% CI: 1.1-9.2). CONCLUSIONS: These findings do not support an association between maternal use of nitrosatable drugs during pregnancy and brain tumour risk in offspring. While exposure to the nitrosation end product nitrosoephedrine was associated with increased risk for other glial tumours, the finding was not specific to any one type of tumour.

Adolescent↗
PubMed1998

DNA adducts in humans after exposure to methylating agents.

Human exposure to methylating agents appears to be widespread, as indicated by the frequent occurrence of methylated DNA adducts in human DNA. The high incidence of methylated DNA adducts even in humans thought not to have suffered extensive exposure to environmental methylating agents implies that chemicals of endogenous origin, probably N-nitroso compounds such as the strongly carcinogenic N-nitrosodimethylamine (NDMA), may be primarily responsible for their formation and raises the question of the carcinogenic risks associated with such exposure. In addition to accumulation of DNA damage, other factors (such as induced cell proliferation) appear to be important in determining the probability of induction of mutation or cancer by NDMA, implying that high to low dose risk extrapolations should not be based on the assumption of dose- or even adduct-linearity. Comparative studies of the accumulation and repair of methylated adducts in humans and animals treated with methylating cytostatic drugs do not reveal significant species differences. Based on this and the dosimetry of adduct accumulation in rats chronically exposed to very low doses of NDMA, it is suggested that the exposure needed to account for the levels of adducts found in human DNA may be of the order of hundreds of micrograms NDMA (or equivalent) per day, a level of exposure which may well represent a significant carcinogenic hazard for man.

Animals↗
PubMed1992

Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex.

Nitric oxide (NO) is an important messenger both systemically and in the CNS. In digital Ca2+ imaging and patch-clamp experiments, clinically available nitroso compounds that generate NO are shown to inhibit responses mediated by the NMDA subtype of the glutamate receptor on rat cortical neurons in vitro. A mechanism of action for this effect was investigated by using the specific NO-generating agent S-nitrosocysteine. We propose that free sulfhydryl groups on the NMDA receptor-channel complex react to form one or more S-nitrosothiols in the presence of NO. If vicinal thiol groups react in this manner, they can form a disulfide bond(s), which is thought to constitute the redox modulatory site of the receptor, resulting in a relatively persistent blockade of NMDA responses. These reactions with NO can afford protection from NMDA receptor-mediated neurotoxicity. Our results demonstrate a new pathway for NO regulation of physiological function that is not via cGMP, but instead involves reactions with membrane-bound thiol groups on the NMDA receptor-channel complex.

Alkylating Agents↗
PubMed1989

Endogenous nitrosation in relation to nitrate exposure from drinking water and diet in a Danish rural population.

Increasing levels of nitrate in drinking water is of concern due to the possibility of an associated increase in long-term exposure to endogenously formed carcinogenic N-nitroso compounds. Excretion of N-nitrosoproline in 12-h overnight urine after intake of 500-mg L-proline was used to quantify the rate of endogenous nitrosation in 285 individuals in an area in northern Denmark with large variation in nitrate concentration of the drinking water. Nitrate intake was measured in a 24-h duplicate diet sample. The crude association between nitrate concentration in drinking water and rate of endogenous nitrosation in individuals is only weakly positive and not quite statistically significant (P = 0.08). The risk of having detectable nitrosation increases significantly with total nitrate intake and tobacco smoking. In nonsmokers, nitrosation is determined by nitrate intake. Smokers have increased nitrosation which does not depend on nitrate intake. Effect modification through dietary factors was evaluated and indicated a protective effect of tea consumption, while the effect of eating vegetables was not clear-cut. The experimental design (12-h urine sample; proline dose taken in the evening) is likely to underestimate the effect of nitrate in drinking water relatively to nitrate in the diet.

Denmark↗
PubMed1991

Nitrite-trapping capacity of thioproline in the human body.

Human nitrosating capacity has been monitored using proline; however, N-nitrosothiazolidine 4-carboxylic acid (NTCA; N-nitrosothioproline), one of the predominant N-nitroso compounds in human urine, is also nonmutagenic and, presumably, noncarcinogenic. Thioproline is nitrosated about 1000 times faster than proline in vitro, and NTCA is excreted into the urine without being metabolized. We have therefore proposed thioproline as an effective nitrite-trapping agent in the human body. Recently, we found thioproline in various cooked foods, including cod and dried shiitake mushrooms. In the study reported here, we evaluate the nitrite trapping capacity of thioproline in a male nonsmoking volunteer ingesting NO3- and eating a controlled diet. The highest level of NTCA excreted, 5.89 mumol, was measured after the subject ingested 6 mmol NO3- followed by 0.45 mmol (60 mg) thioproline. We estimated the effective amount of nitrite, defined as the actual amount of nitrite participating in nitrosation in the stomach, to be 0.3% of the NO3- ingested. Thus, the effective amount of NO2- for 6 mmol NO3- ingested was calculated to be 18 mumol, and 33% of this nitrite was trapped by ingestion of 0.45 mmol thioproline. We conclude that thioproline is a most sensitive probe for evaluating human nitrosating capacity and an effective nitrite-trapping agent.

Ascorbic Acid↗