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Etiological research on gastric cancer and its precursor lesions in Shandong, China.

Research over the past several years in an area of Shandong, China, with one of the world's highest rates of gastric cancer, has yielded clues to the environmental determinants of this tumour. Interviews with 564 gastric cancer patients and 1131 population-based controls revealed increased risks associated with consumption of sour pancakes, a fermented staple unique to the area, in samples of which volatile N-nitrosamines have been detected. Lower risks were found among people who had a higher intake of fresh vegetables, including garlic and other Allium vegetables which contain constituents that can inhibit carcinogenesis by N-nitrosamines and other substances in experimental animals. A pilot study involving assays of urine and gastric juice from 60 individuals in a screening programme showed higher levels of N-nitrosoproline and of cis- and trans-N-nitroso-2-methylthiazolidine 4-carboxylic acid among persons with gastric dysplasia than in either normal controls or those with chronic atrophic gastritis. We are trying to characterize the transition and progression of precursor lesions to gastric cancer and to evaluate the role of dietary variables, nutrients, N-nitroso compounds and other factors in particular stages of the carcinogenic process.

China↗

Agriculturally-related carcinogenic risk.

Although all people are exposed throughout life to pesticides (during manufacture and use, in the environment, via the food chain), with the exception of vinyl chloride and the arsenic compounds, no human carcinogen pesticide is known. In experimental animals and short-term tests, however, many pesticides have proved to be carcinogenic or genotoxic. In order to elucidate possible modes of action related to genotoxicity (short-term tests) and carcinogenicity, data on 83 pesticides were analysed. A definitive promoter effect was demonstrated for five compounds, and a suspected promoter effect could be attributed to 16 compounds. Almost all were organohalogens. Ethylenthiourea and aminotriazole are also carcinogens, which induce tumours through hormonal imbalance. Ethylenthiourea is the degradation product and metabolite of certain ethylene-bisdithiocarbamate pesticides. Chlorphenol and chlorophenoxyacetic acid-type pesticides contain 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD) as a contaminant. TCDD has definite promoter action. Seventeen tumorigenic pesticides could be regarded as genotoxic, and similar activity could be suspected in three other carcinogenic pesticides. Many pesticides contain N-nitroso impurities in various amounts. Nitrosation of the original pesticide or its derivative, such as dialkylamines, alkyl-arylamines, methyleneimines, gives rise to the formation of N-nitroso compounds. Amides containing secondary amines, such as ethylcarbamate and alkylurea, could be nitrosated in vivo and in vitro. Most nitrosated pesticides are strong genotoxic carcinogens.

Agricultural Workers' Diseases↗

New NO-donors with antithrombotic and vasodilating activities, Part 20. Azodioxides activated by electron acceptors in geminal or vicinal position.

Twenty-two nitroso compounds with cyano, acyloxy, or carbonyl groups in geminal position were prepared, eight of them for the first time. In the solid state these compounds dimerize to colorless azodioxides. Exceptions are the 4-nitrobenzoyloxynitroso compounds 7b, f, and g which form bright blue crystals. In vitro (Born test, collagen) considerable antiplatelet activity was observed in each class of compounds. Azodioxides with cyano groups in geminal position (3a, b) were most active (IC50 approximately 10 microM) suggesting the importance of strong electron withdrawing groups in geminal position to the azodioxide partial structure. When administered orally to rats (60 mg/kg) all compounds inhibited the thrombus formation in mesenteric arterioles and venules. The acetyloxy derivatives 5d and 5e were most active (18-21% inhibition in arterioles and 11-15% inhibition in venules). In aqueous media at 37 degrees C the cyanonitroso compound 3b and the benzoyloxynitroso compound 7a decomposed to nitric oxide and its reduced form nitrosohydrogen. This suggests that the above pharmacological effects are mediated by a NO dependent mechanism.

Animals↗

Microflora of the nasopharynx in Caucasian and Maghrebian subjects with and without nasopharyngeal carcinoma.

The possible role of bacteria in the etiology of nasopharyngeal carcinoma (NPC) was studied by bacteriological and biochemical analyses of nasopharyngeal swabs collected in the cavum and in the fossa of Rosenmüller of NPC patients and healthy controls in France and Algeria. Counts of total bacteria and of total nitrate-reducing bacteria, mainly enterobacteria, were higher in the Maghrebians than in the Caucasians. The composition of the bacterial flora was different: in Maghrebians, enterobacteria were present in five of 17 control subjects and eight of 15 NPC patients, while the prevalence was only one out of 15 control subjects in Caucasians. Twelve of 32 bacterial species isolated from Caucasians and Maghrebians with normal or tumorous nasopharyngeal microflora were able to catalyse nitrosation of morpholine in vitro. This result suggests that colonization of the nasopharynx by microflora that contain nitrate-reducing microorganisms which can form N-nitroso compounds might represent a risk factor for NPC in Maghrebian populations.

Algeria↗

Effects of amino acid-derived luminal metabolites on the colonic epithelium and physiopathological consequences.

Depending on the amount of alimentary proteins, between 6 and 18 g nitrogenous material per day enter the large intestine lumen through the ileocaecal junction. This material is used as substrates by the flora resulting eventually in the presence of a complex mixture of metabolites including ammonia, hydrogen sulfide, short and branched-chain fatty acids, amines; phenolic, indolic and N-nitroso compounds. The beneficial versus deleterious effects of these compounds on the colonic epithelium depend on parameters such as their luminal concentrations, the duration of the colonic stasis, the detoxication capacity of epithelial cells in response to increase of metabolite concentrations, the cellular metabolic utilization of these metabolites as well as their effects on colonocyte intermediary and oxidative metabolism. Furthermore, the effects of metabolites on electrolyte movements through the colonic epithelium must as well be taken into consideration for such an evaluation. The situation is further complicated by the fact that other non-nitrogenous compounds are believed to interfere with these various phenomenons. Finally, the pathological consequences of the presence of excessive concentrations of these compounds are related to the short- and, most important, long-term effects of these compounds on the rapid colonic epithelium renewing and homeostasis.

Amino Acids↗

Synthesis and solid-state molecular structures of nitrosoalkane complexes of iron porphyrins containing methanol, pyridine, and 1-methylimidazole ligands.

Nitrosoalkanes belong to the family of C-nitroso compounds and are known to bind to the iron center in heme proteins. We have prepared and characterized a series of new nitrosoalkane heme model complexes of the form (por)Fe(RNO)(L) (por=porphyrinato dianion; R=isopropyl; L=MeOH, pyridine, 1-methylimidazole) by infrared and 1H NMR spectroscopy and X-ray crystallography. Within the set of octaethylporphyrinato (OEP) compounds, the infrared stretching frequencies of the NO groups decrease in the order (OEP)Fe(iPrNO)(MeOH).MeOH (1433 cm-1) > (OEP)Fe(iPrNO)(py) (1429 cm-1) > (OEP)Fe(iPrNO)(1-MeIm) (1423 cm-1), reflecting the increased backdonation of electron density in the 1-methylimidazole derivative. The molecular structures of the compounds as determined by crystallography reveal N-binding of the nitrosoalkane ligands to the formally ferrous metal centers.

Heme↗

Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole.

Ten healthy volunteers were studied before, during, and after treatment with omeprazole 30 mg daily for two weeks. On the 14th night mean nocturnal (2100-0700) intragastric acidity was significantly decreased by 75% (p less than 0.001). At 0700, 22 hours after the last dose of omeprazole, there were significant increases in the bacterial count and the nitrite and N-nitrosamine concentrations in the gastric juice (p less than 0.001). Three days later these changes had resolved. Short term treatment of healthy volunteers with omeprazole is associated with a short lived increase in the gastric bacterial flora, with endogenous production of N-nitroso compounds.

Adult↗

[Mutagenicity of gastric juice in patients with chronic gastritis].

Mutagenicity of fasting gastric juice from 108 chronic gastritis patients in high- and low-risk areas of stomach cancer was assayed using in vitro SCE test in cultured human lymphocytes and micronucleus test in cultured Chinese hamster V79 cell. The results showed that mutagenicity could be found in this gastric juice. The positive rate of these two tests, SCE/cell, micronucleated cell rate and micronucleus rate were significantly higher in high-risk area than in low-risk area (P less than 0.01). There was a tendency that the mutagenic activity was higher in high pH than in low pH gastric juice and in males than in females. In high-risk area, the mutagenicity of gastric juice was obviously higher in younger than in elder aged group. Because no S9 was added in this test system, the results seem to suggest that the mutagenicity found in the gastric juice of patients with chronic gastritis might be, at least in part, related to direct-acting N-nitroso-compounds synthesized in the stomach.

Adult↗

Current trends in the biological monitoring of exposure to carcinogens.

The biological monitoring of exposure to carcinogens and mutagens has gained a lot of research interest recently. Biological monitoring data, in conjunction with environmental monitoring data, will provide information for the needed exposure assessment for directing preventive actions. For the reviewed carcinogens aromatic amines, benzene, ethylene oxide, aflatoxins, N-nitroso compounds, polynuclear aromatic hydrocarbons, and alkylating anticancer drugs, there are methods which are already routine in practice, whereas some promising methods are still used only for research purposes.

Aflatoxins↗

Chemical nature of nitric oxide storage forms in rat vascular tissue.

Endothelial NO production results in local formation of adducts that may act as storage forms of NO. Because little is known about their chemical nature, concentrations, and possible role in vascular biology, we sought to characterize those species basally present in rat aorta, using two independent approaches. In the first approach, tissue homogenates were analyzed by using chemiluminescence- and ion-chromatography-based techniques that allow trace-level quantification of NO-related compounds in complex biological matrices. In the second approach, NO stores were characterized by their ability to release NO when illuminated with light and subsequently relax vascular smooth muscle (photorelaxation). The latter included a careful assessment of action spectra for photorelaxation, taking into account the light-scattering properties of the tissue and the storage depletion rates induced by exposure to controlled levels of light. Biochemical analyses revealed that aortic tissues contained 10 +/- 1 microM nitrite, 42 +/- 7 microM nitrate, 40 +/- 6 nM S-nitroso, and 33 +/- 6 nM N-nitroso compounds (n = 4-8). The functional data obtained suggest that the NO photolytically released in the tissue originated from species with photophysical properties similar to those reported for low-molecular-weight S-nitrosothiols, as well as from nitrite. The relative contribution of these potential NO stores to the extent of photorelaxation was consistent with their concentrations detected biochemically in vascular tissue when their photoactivity was taken into account. We conclude that intravascular nitroso species and nitrite both have the potential to release physiologically relevant quantities of NO independent of enzymatic control by NO synthase.

Animals↗

In vitro and in vivo vasodilating activity of nitroso derivatives gem -substituted with electron-withdrawing groups.

A series of nitroso compounds gem -substituted with electron-withdrawing groups (R(2)C(X)NO, R=alkyl, X=NO(2), CN, Cl), were studied for their in vitro and in vivo vasodilating properties as well as for their ability to activate soluble guanylate cyclase (sGC) in RFL-6 cells. All the compounds, with the sole exception of chloro derivative, display good in vitro vasodilating action and are able to increase the basal level of cGMP. Their potencies as vasodilators decrease in the presence of oxyhaemoglobin, a scavenger of nitric oxide (NO). The haemodynamic profile of the most interesting compounds, assessed in anaesthetized pigs, is also in line with a release of NO from these compounds.

Action Potentials↗

Induction of liver tumors in Wistar rats by sodium nitrite given in pellet diet.

Sodium nitrate was given to male noninbred Wistar rats at levels of 800 ppm and 1,600 ppm in a pellet diet for 646 experimental days. The first tum or was found on day 441 in the liver of a rat given a diet containing 800 ppm sodium nitrite. On day 646, liver tumors were found in 1 of 22 rats (4.5%) on an 800-ppm sodium nitrite diet and in 5 of 19 rats (26.3%) on a 1,600-ppm sodium nitrite diet. The incidence of liver tumors in the rats fed 1,600 ppm sodium nitrite was significantly different from that in controls as judged by the t-test (P < 0.05). A hepatocellular carcinoma and a hemangioendothelial sarcoma of the liver were found on day 646 in 2 rats fed 1,600 ppm sodium nitrite. One mammary tumor but no liver tumors were found in the 19 control rats. The concentration of sodium nitrite decreased after preparation of the pellet diet, but it was still at least 70% of the initial amount when the pellets were given to the rats. Volatile N-nitroso compounds, especially dimehylnitrosamine, at ppm levels were detected in the pellet diet with a gas chromatography-thermal energy analyzer.

Adenoma↗

Dietary and tobacco risk factors for adult onset glioma in the San Francisco Bay Area (California, USA)

The roles of diet and tobacco in the etiology of primary brain cancer are controversial. In this report, we compare dietary and cigarette smoking histories among 434 adults newly diagnosed with glioma in the San Francisco Bay Area (California, USA) between 1991 and 1994 with frequency age, gender, and ethnicity-matched population-based controls. Data were obtained on use of vitamin supplements and mean weekly consumption of each of 24 food groups. Adjusted for age, family income, and education, for both men and women, cases had higher mean weekly consumption of cured meats and other cured foods, lower consumption of high vitamin A and C fruits and vegetables, and higher average intakes of beer and other alcohol than controls. Men with brain cancer were twice as likely as control men to report high consumption of cured foods and low consumption of foods rich in vitamin C (odds ratio [OR] = 2.0, 95 percent confidence interval [CI] = 1.2-3.5). This association was less pronounced and not statistically significant in women (OR = 1.5, CI = 0.8-2.7). Similarly, men with brain cancer were twice as likely as controls to have high nitrite and low vitamin C consumption. Among men only, cases were 1.8 times more likely than controls to report smoking unfiltered cigarettes (CI = 0.9-3.4). Moreover, among smokers cases smoked unfiltered cigarettes almost twice as long as controls (P = 0.04) and cases' average total pack-years also significantly exceeded controls. Although these findings support the hypothesis that N-nitroso compounds might be a factor in adult glioma, they are compatible with other dietary hypotheses. In particular, these results also favor the hypothesis that total body burden of oxidants may play a role in brain cancer causation.

Adult↗

Impairment of respiration and oxidative phosphorylation by redox cyclers 2-nitrosofluorene and menadione.

The present study was designed to investigate the effects of 2-nitrosofluorene (NOF), a metabolite of carcinogenic 2-acetylaminofluorene, on mitochondrial respiration and oxidative phosphorylation. NOF reacts with the NADH:ubiquinone oxidoreductase (complex I) and consumes oxygen in a rotenone-insensitive manner. Unlike menadione, which is able to bypass the rotenone-block and to restore ATP-formation, NOF-induced electron flow was almost completely uncoupled. In normal respiration both redox-cyclers decreased the respiratory control and P/O ratios at low concentrations (2-20 nmol/mg) in NADH-dependent oxidation. With succinate as substrate, only NOF was significantly active. In contrast to NOF, the hydroxamic acid N-hydroxy-2-acetylaminofluorene (N-OH-AAF) impaired mitochondrial energy conversion only at much higher concentrations (80 nmol/mg). At concentrations > 10 nmol/mg, NOF inhibited electron flow through the respiratory chain in NADH- and succinate-dependent oxidation, as determined by dinitrophenolate-uncoupled respiration. The small protective effect of L-cysteine indicates that covalent binding of the nitroso-compound to SH-groups may not explain sufficiently the inhibitory effect of NOF. The results support the notion that redox cyclers impair oxidative phosphorylation by establishing alternative pathways for electron transport in the respiratory chain.

2,4-Dinitrophenol↗

Inhibition of nitrosamine formation by ascorbic acid.

Nitrosation occurs under a wide variety of conditions by reaction of most types of amines with any of a large number of nitrosating species. Nitrite can be formed in vivo via bacterial reduction of nitrate and by activated macrophages and endothelial cells. The mechanism of nitrite formation by mammalian cells is via enzymatic oxidation of arginine to NO followed by oxidation to N2O3 and N2O4. Nitrosatable amines are found in many foods and some, eg, dimethylamine, are synthesized in the body. Precursors of N-nitroso compounds are thus almost constantly present together under favorable reaction conditions in vivo and there is, consequently, considerable interest concerning possible human health risks arising from endogenous formation of this class of compounds. Among many nitrosation inhibitors, most attention has focused on ascorbic acid, which reacts with many nitrosating agents and which is virtually nontoxic. This presentation discusses the chemistry of ascorbic acid inhibition of nitrosation reactions.

Amines↗

Assessment of the risks associated with the use of chemical carcinogens in biomedical research.

Estimates of occupational exposure to chemical carcinogens in biomedical research based on environmental monitoring data, efficiency of containment devices, and accident data suggest that workers may be exposed to a few tenths of a microgram of these carcinogens per work day. Environmental exposure to carcinogenic polycyclic aromatic hydrocarbons and N-nitroso compounds exceeds one microgram per day. Because occupational exposure to chemical carcinogens in the laboratory can be readily controlled and because environmental exposure appears to be greater than the occupational exposure that does occur, the relative risk of occupational exposure does not seem to constitute a major health problem.

Air Pollutants, Occupational↗

Pickled vegetables in the aetiology of oesophageal cancer in Hong Kong Chinese.

Oesophageal cancer is common in Chinese populations, but individual-based epidemiological studies have provided little explanation. A case control study with 400 cases and 1598 controls (800 hospital and 798 general practice) was conducted among Hong Kong Chinese. In multivariate analyses, statistically significant effects on risk were detected for several potentially preventable exposures with high attributable risks (ARs). These included preference for consuming drinks or soups at high temperature (AR = 14%), infrequent consumption of green leafy vegetables (AR = 15%) and citrus fruits (AR = 26%), ingestion of pickled vegetables (AR = 29%), tobacco smoking (AR = 44%), and alcohol drinking (AR = 48%). On the assumption of multiplicative risk, the combined AR due to these exposures was 89%. This is the first case control study to show an association between pickled vegetable consumption and oesophageal cancer risk. The finding considerably strengthens the evidence for carcinogenicity of N-nitroso compounds in man and helps to explain the very high risk among Chinese.

Aged↗