Ultraviolet-sensitive mutants of Neurospora. II. Radiation studies.
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Cell Survival↗
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Results for “Nitroso Compounds”
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Determination of volatile nitrosamines in cheese and cured meat products. Model study of a temperature- and pH-dependent artefact formation phenomenon in alkaline medium.
The present paper describes how the formation of artefactual nitrosodimethylamine (NDMA) may jeopardize attempts at determining volatile nitrosamines in cheese by the mineral oil technique (MOT) or the glycerol isolation technique (GIT). When such isolation techniques were performed at an initial pH of about 11 and a final temperature of 100 degrees C (compared to 70 degrees C), up to about 10 micrograms NDMA per kg was formed. In a meat product, which was examined for comparison, even more extensive artefact formation (up to 70 micrograms NDMA per kg) was found. The addition of 10 mg/kg morpholine, as a readily nitrosatable substrate, to this meat product resulted (under the most unfavourable conditions) in formation of 250 micrograms/kg artefactual nitrosomorpholine. Alkalization of samples before nitrosamine analysis is a widely practised method to prevent artefact formation and has been emphatically recommended by an international working group, convened by the International Agency for Research on Cancer (Lyon). The mechanism of this peculiar artefact formation, which is strongly temperature- and pH-dependent, is not as yet known. It may however involve transnitrosation by C-, S- or O-nitroso compounds, e.g. nitrosophenols, nitrosothiols, alkyl nitrites, sugar nitrite esters, or lipid-nitrite reaction products. Several parameters of initial pH, final temperature and use of inhibitors under which the phenomenon will or will not occur are discussed. The artefact formation described here occurs mostly at pH values which are common to laboratory situations, but which are rare as for as the preparation of food in the household is concerned. Therefore, the effect does not appear to imply a risk to the consumer's health.
Cheese↗
DNA-repair methyltransferase as a molecular device for preventing mutation and cancer.
Alkylation of DNA at the 0(6) position of guanine is regarded as one o f the most critical events leading to induction of mutations and cancers in organisms. Once 0(6)-methylguanine is formed, it can pair with thymine during DNA replication, the result being a conversion of the guanine.cytosine to an adenine.thymine pair in DNA, and such mutations are often found in tumors induced by alkylating agents. To counteract such effects, organisms possess a mechanism to repair 0(6)-methylguanine in DNA. An enzyme, 0(6)-methylguanine-DNA methyltransferase, is present in various organism, from bacteria to human cells, and appears to be responsible for preventing the occurrence of such mutations. The enzyme transfers methyl groups from 0(6)-methylguanine and other methylated moieties of the DNA to its own molecule, thereby repairing DNA lesions in a single-step reaction. To elucidate the role of methyltransferase in preventing cancers, animal models with altered levels of enzyme activity were generated. Transgenic mice carrying the foreign methyltransferase gene with functional promoters had higher levels of methyltransferase activity and showed a decreased susceptibility to N-nitroso compounds in regard to liver carcinogenesis. Mouse lines deficient in the methyltransferase gene, which were established by gene targeting, exhibited an extraordinarily high sensitivity to an alkylating carcinogen.
Amino Acid Sequence↗
[Animal experiments to assess the risk of cancer in the stomach after vagotomy (author's transl)].
To assess the possible risk of cancer in the operated stomach, the influence of truncal vagotomy combined with different operative drainage procedures (pyloroplasty, gastro-enterostomy without entero-anastomosis, Roux-en-Y gastro-enterostomy) was studied in animal experiments. The aim of the study was to determine whether, compared to controls an earlier and higher incidence of precancerous epithelial lesions or cancers in the stomach occurs in vagotomized animals after oral administration of carcinogens (MNNG). To consider conditions, that may predispose to in vivo formation of carcinogenic N-nitroso compounds, bacterial flora and intragastric nitrite concentration were measured and compared in the various operative groups. The severity of induced epithelial lesions and the quantity of bacterial growth and nitrite concentration in the gastric juice were influenced, apart from the reduction of acid output after vagotomy, mainly by prolonged gastric stasis or the degree of enterogastric reflux. The results suggest that there is probably no increased risk of cancer following vagotomy, if sufficient gastric clearance is guaranteed and enterogastric reflux is largely excluded.
Animals↗
Nitrosation of benzoxazolinone.
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Benzoxazoles↗
Human vitamin C requirements.
The importance of vitamin C is reflected in its multifunctional roles which include participation in collagen and carnitine syntheses, promotion of iron absorption and the more recently discovered participation in noradrenaline synthesis, inactivation of free radical chain reactions, prevention of N-nitroso compound formation and more. Given the many extra-antiscorbutic functions of the vitamin, the Recommended Dietary Allowances (RDA) should not just prevent deficiency disease but should aim at providing sufficient amounts for all vitamin C-dependent functions to operate at full capacity. The concept of vitamin C tissue saturation is best able to meet this demand. The use of kinetic models has shown that the body pool is saturated with a daily intake of 100 mg vitamin C in non-smokers and 140 mg in smokers, amounts that may be regarded as optimal RDA values. Certain disease states may be accompanied by still higher vitamin C requirements but the exact amounts are not yet known.
Animals↗
[Nutrition and the etiology of colon cancer: from descriptive epidemiology to dietary prevention].
Colon cancer is one of the most frequent forms of cancer in the Federal Republic of Germany and in most Western countries, but is, however, generally rare in Africa, Asia, and Latin America. Based on epidemiological investigations, differing dietary practices are considered to be main reason for these differences. A high fat and protein consumption was identified as a risk factor, while a high fibre content of the diet was found to be protective. Existing hypotheses of the etiology of colon cancer, which are based on the two-stage initiation-promotion model, regard interactions between initiators, promotors, and inhibitors as decisive for the final outcome of colon cancer. Possible initiators are pyrolysis products of protein-rich food (meat or fish), generated by heating, and products of metabolism of intestinal bacteria (e.g. faecal mutagens, N-nitroso compounds, transformation products of bile acids). Fats probably exert their influence only at the promotional stage. The diet-dependent bacterial formation of deoxycholic and lithocholic acids is a possible mechanism which has been experimentally substantiated. The protective effect of a diet rich in fibre seems to be mediated in particular by dilution and adsorption of harmful compounds. Further protective factors in human diet may be calcium, selenium, vitamin A and beta-carotene. In this paper, evidence, both supporting and refuting the existing hypotheses, is discussed, as well as the possibilities of dietary prevention of colon cancer.
Colonic Neoplasms↗
Metabolism of N-methyl-N'-nitro-N-nitrosoguanidine in rats.
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Animals↗
Nitrite from inflammatory cells--a cancer risk factor in ulcerative colitis?
Elevated levels of luminal nitrite and a lowered luminal pH were found in 77 percent of patients with acute ulcerative colitis. No luminal nitrite was found in healthy control subjects. Nitrites are a secretory product of activated macrophages and neutrophils of the lamina propria, whereas the lowered luminal pH is due to diminished bicarbonate formation by impaired colonocytes. A hypothesis is put forward that nitrites, lowered pH, and bacterial amines are conducive to formation of carcinogenic n-nitroso compounds, which reflect a cancer risk in patients with ulcerative colitis dependent on the type and extent of inflammatory cell activation as well as metabolic impairment of colonic epithelial cells.
Animals↗
Evidence for partial exocrine acinar differentiation in experimentally induced pancreatic ductal/ductular cell tumors.
The pancreatic carcinomas induced in Syrian hamsters by a nitroso compound are of a ductal/ductular cell type. Electron microscopic examination of such tumors has revealed the presence of an occasional isolated acinar cell within the tumor. Based on their cellular characteristics, these acinar cells seem to have derived from ductular cell precursors. When we used a monoclonal antibody which specifically recognizes hamster acinar cells, a larger number of cells bearing acinar cell membrane markers were found in many tumors by an indirect immunofluorescence technique. Since most of these positively reacting cells did not exhibit the characteristic cytological features of acinar cells, such as rough endoplasmic reticulum and zymogen granules, differentiation of precursor cells to acinar cells may possibly occur at the cell membrane level. The presence of a few acinar cells within exocrine pancreatic tumors implies that acinar differentiation or retrodifferentiation can occur in pancreatic neoplasms.
Adenocarcinoma↗
Development of an H. pylori-infected animal model and gastric cancer: recent progress and issues.
Gastric cancer is one of the most common malignancies in the world. Gastric carcinogenesis is multifactorial. Although some environmental factors, such as excessive intake of salt and N-nitroso compounds in foods, are involved in this process, Helicobacter pylori has been closely linked to an increased risk of the development of gastric adenocarcinoma. The IARC/WHO in 1994 concluded that H. pylori is a definite carcinogen in humans based on seroepidemiological evidence. H. pylori infection is associated with both intestinal and diffuse types of gastric cancer. Strong evidence has accumulated that H. pylori infection has been active in the development of gastric adenocarcinoma in the Mongolian gerbil (MG) model after long term infection and with or without treatment using low-dose chemical carcinogens. There are several criticisms of these reports. The most troublesome issue is the diagnostic criteria for gastric cancer in MGs, especially for well-differentiated cancers induced by H. pylori infection. Hence, common criteria for the diagnosis of gastric cancer in MGs is required. Another scientific approach is to find genetic-evidence to confirm the diagnosis. Such evidence could indicate directly that H. pylori infection itself is a promoter, initiator, or both in the development of gastric adenocarcinoma.
Adenocarcinoma↗
Excitotoxicity of quinolinic acid: modulation by endogenous antagonists.
Quinolinic acid (QUIN), a product of tryptophan metabolism by the kynurenine pathway, produces excitotoxicity by activation of NMDA receptors. Focal injections of QUIN can deplete the biochemical markers for dopaminergic, cholinergic, gabaergic, enkephalinergic and NADPH diaphorase neurons, which differ in their sensitivity to its neurotoxic action. This effect of QUIN differs from that of other NMDA receptor agonists in terms of its dependency on the afferent glutamatergic input and its sensitivity to the receptor antagonists. The enzymatic pathway yielding QUIN produces metabolites that inhibit QUIN-induced neurotoxicity. The most active of these metabolites, kynurenic acid (KYNA), blocks NMDA and non-NMDA receptor activity. Treatment with kynurenine hydroxylase and kynureinase inhibitors increases levels of endogenous KYNA in the brain and protects against QUIN-induced neurotoxicity. Other neuroprotective strategies involve reduction in QUIN synthesis from its immediate precursor, or endogenous synthesis of 7-chloro-kynurenic acid, a NMDA antagonist, from its halogenated precursor. Several other tryptophan metabolites--quinaldic acid, hydroxyquinaldic acid and picolinic acid--also inhibit excitotoxic damage but their presence in the brain is uncertain. Picolinic acid is of interest since it inhibits excitotoxic but not neuroexcitatory responses. The mechanism of its anti-excitotoxic action is unclear but might involve zinc chelation. Neurotoxic actions of QUIN are modulated by nitric oxide (NO). Treatment with inhibitors of NO synthase can augment QUIN toxicity in some models of excitotoxicity suggesting a neuroprotective potential of endogenous NO. In recent studies, certain nitroso compounds which could be NO donors, have been reported to reduce the NMDA receptor-mediated neurotoxicity. The existence of endogenous compounds which inhibit excitotoxicity provides a basis for future development of novel and effective neuroprotectants.
Journal Article↗
[Adenocarcinoma of the stomach with heterotopic ossification. Case report and discussion of the pathogenesis].
Heterotopic ossification of gastric adenocarcinomas is very rarely observed in humans. In rats such lesions could be induced by ingestion of nitroso compounds. We describe the case of a 70-year-old patient with an extended, initially spleen-infiltrating tubular adenocarcinoma of the stomach with a mucinous component, heterotopic ossifications and pronounced regressive alterations after neoadjuvant chemotherapy. Various speculations regarding the pathogenesis of heterotopic ossifications in gastrointestinal adenocarcinomas are discussed.
Adenocarcinoma↗
Epidemiology and etiology of gliomas.
Gliomas of astrocytic, oligodendroglial and ependymal origin account for more than 70% of all brain tumors. The most frequent (65%) and most malignant histological type is the glioblastoma. Since the introduction of computerized tomography and magnetic resonance imaging, the incidence rates of brain tumors have been rather stable, with a tendency of higher rates in highly developed, industrialized countries. Some reports indicate that Caucasians have higher incidence than black or Asian populations, but to some extent, this may reflect socio-economic differences and under-ascertainment in some regions, rather than a significant difference in genetic susceptibility. With the exception of pilocytic astrocytomas, the prognosis of glioma patients is still poor. Less than 3% of glioblastoma patients are still alive at 5 years after diagnosis, higher age being the most significant predictor of poor outcome. Brain tumors are a component of several inherited tumor syndromes, but the prevalence of these syndromes is very low. Several occupations, environmental carcinogens, and diet (N-nitroso compounds) have been reported to be associated with an elevated glioma risk, but the only environmental factor unequivocally associated with an increased risk of brain tumors, including gliomas, is therapeutic X-irradiation. In particular, children treated with X-irradiation for acute lymphoblastic leukemia show a significantly elevated risk of developing gliomas and primitive neuroectodermal tumor (PNET), often within 10 years after therapy. TP53 mutations are frequent in low-grade gliomas and secondary glioblastomas derived therefrom. Approximately 60% of mutations are located in the hot spot codons 248 and 273, and the majority of these are G:C-->A:T transitions at CpG sites. TP53 mutations are significantly more frequent in low-grade astrocytomas with promoter methylation of the O(6)-methylguanine-DNA methyltransferase repair gene, suggesting that, in addition to deamination of 5-methylcytosine, exogenous or endogenous alkylation in the O(6) position of guanine may contribute to the formation of these mutations.
Age Factors↗
Repair of DNA lesion O6-methylguanine in hepatocellular carcinogenesis.
Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the promutagenic DNA base lesion, O6-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating agents such as N-nitroso compounds can produce O6-methylguanine in cellular DNA. Unrepaired, O6-methylguanine can lead to the formation of G --> A transition mutations, a known mechanism of human oncogene activation and tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O6-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte DNA. The paramount importance of O6-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased hepatic levels of repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O6-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from animal models, this suggested a mechanism in which persistence of O6-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O6-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of O6-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively measure O6-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular carcinoma.
Alkylating Agents↗
Comparison of nitrate levels in raw water and finished water from historical monitoring data on Iowa municipal drinking water supplies.
Nitrate contamination of water sources is a concern where large amounts of nitrogen fertilizers are regularly applied to soils. Ingested nitrate from dietary sources and drinking water can be converted to nitrite and ultimately to N-nitroso compounds, many of which are known carcinogens. Epidemiologic studies of drinking water nitrate and cancer report mixed findings; a criticism is the use of nitrate concentrations from retrospective drinking water data to assign exposure levels. Residential point-of-use nitrate data are scarce; gaps in historical data for municipal supply finished water hamper exposure classification efforts. We used generalized linear regression models to estimate and compare historical raw water and finished water nitrate levels (1960s-1990s) in single source Iowa municipal supplies to determine whether raw water monitoring data could supplement finished water data to improve exposure assessment. Comparison of raw water and finished water samples (same sampling date) showed a significant difference in nitrate levels in municipalities using rivers; municipalities using other surface water or alluvial groundwater had no difference in nitrate levels. A regional aggregation of alluvial groundwater municipalities was constructed based on results from a previous study showing regional differences in nitrate contamination of private wells; results from this analysis were mixed, dependent upon region and decade. These analyses demonstrate using historical raw water nitrate monitoring data to supplement finished water data for exposure assessment is appropriate for individual Iowa municipal supplies using alluvial groundwater, lakes or reservoirs. Using alluvial raw water data on a regional basis is dependent on region and decade.
Cities↗
Sites of alkylation of poly(U) by agents of varying carcinogenicity and stability of products.
Several alkylating agents of widely varying reported carcinogenicity (dimethylsulfate, diethylsulfate, ethylmethanesulfonate, methylnitrosourea, ethylnitrosourea and ethylnitrosoguanidine) were reacted with poly(U) at pH values ranging from 4.5 to 7.5. All nucleophilic centers (internal phosphate groups, ribose hydroxyls, and O2, N-3 and O4 sites of the uracil base) were found reactive, though to different extents, at neutrality and in slightly acid solution. The distribution of products is a function of the alkylating agent and pH. The nitroso compounds are more reactive toward oxygens than are dialkylsulfates and alkylalkanesulfonates. The ratio of N : O alkyl products is strongly pH dependent, primarily due to the N-3 being most reactive at the higher pH values, while the diester is most reactive at the lower pH values. The extent of reaction of the O2, O4 or 2'-O or ribose is not greatly affected over the pH range tested. At pH 5.0 alkyl ribophosphotriesters mainly lose alchol to re-form a stable phosphodiester. With increasing OH- concentration, the favored reaction is chain scission at the 3'-O-P bond.
Alkylating Agents↗
Macrophage-mediated N-nitrosation of thioproline and proline.
Thioproline (Thiazolidine-4-carboxylic acid) and proline were nitrosated by stimulated mouse macrophages in vitro. A macrophage cell line (J774.1, 1.0 x 10(6)/well, 1 ml) was incubated with Escherichia coli lipopolysaccharide, interferon-gamma and thioproline (5 mM) or proline (5 mM). After 72 hr incubation at 37 degrees C, 4 microM N-nitrosothioproline was produced. The amount of N-nitrosoproline was much lower than that of N-nitrosothioproline. Thioproline and proline inhibited the formation of carcinogenic N-nitrosomorpholine. N-nitrosothioproline and N-nitrosoproline are found as major N-nitroso compounds in human urine. Macrophage mediated N-nitrosation may contribute to the formation of these N-nitrosamino acids in the human body.
Animals↗