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PubMed1978

[Environmental carcinogens: mechanisms of action and occurrence. Some aspects (author's transl)].

New aspects on the mechanism of action of known environmental carcinogens are described. These compounds are not active as such, but are bioactivated in the mammalian metabolism via chemically reactive intermediates to electrophilic reactants, forming with information-bearing biopolymeres covalent bonds. This change in the genetic code is in agreement with the mutation hypothesis of carcinogenesis. Aflatoxin B1, N-nitroso compounds and benzo(a)pyrene are taken as examples. "Threshold levels", e.g. no-effect-levels derived from animal experiments with all their inherent limitations, are compared with data from human exposure to benzo(a)pyren, aflatoxine, N-nitroso compounds and vinyl chloride. The difficulties of such risk evaluations are discussed.

Aflatoxins↗
PubMed1986

Effect of donor age on the levels of activity of rat, hamster and human liver S9 preparations in the Salmonella mutagenicity assay.

Liver S9 fractions were prepared from male and female Syrian Golden hamsters and Sprague-Dawley rats, 1, 3, 6 and 12 months of age, which were either uninduced (corn-oil treated) or induced with Aroclor 1254 suspended in corn oil. These preparations were compared at varying protein levels for their ability to metabolize polycyclic aromatic hydrocarbons (benzo(a)pyrene, 3-methylcholanthrene, 7,12-dimethylbenzanthracene), aromatic amines (N-2-acetyl-aminofluorene, beta-naphthylamine, benzidine), and nitroso compounds (N-nitroso-diethylamine, nitrosopyrrolidine, nitrosodiethylmethylurea) to products mutagenic to Salmonella typhimurium. With 3-methylcholanthrene or benzo(a)pyrene in the presence of S9 preparations from Aroclor-treated male rats, the numbers of revertant colonies decreased with increasing age of the animals. Mutagenicity of aromatic amines was not affected by the age of the donor animals from which the S9 was prepared. The use of liver S9 from 1-month-old hamsters produced the highest number of revertant colonies with nitrosodiethylamine. This number decreased with preparations from animals of increasing age. The greatest number of revertant colonies with nitrosopyrrolidine occurred with preparations from male hamsters. A decrease in numbers of revertant colonies with increasing age was observed with the S9 preparation from Arcolor-treated male rats. Nitroso-diethylmethylurea was mutagenic only in the presence of S9 from male or female Aroclor-treated hamsters and the metabolic activity of the S9 preparations did not change with age. S9 preparations from livers of 50-70-year-old humans were compared for their ability to produce mutagenic metabolites at a number of protein levels.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Acetylaminofluorene↗
PubMed1993

High gastric juice ascorbic acid concentrations in members of a gastric cancer family.

Gastric juice ascorbic acid, total vitamin C, nitrite and N-nitroso-compound concentrations were determined in fasting gastric juice from four second generation members of a gastric cancer family, all of whom had Helicobacter pylori-associated chronic gastritis and intestinal metaplasia. Juice pH, nitrite and N-nitroso-compound concentrations were low. Juice ascorbate levels were comparable to those found in subjects with normal histology. The findings are contrary to our previous experience with juice ascorbate in H. pylori gastritis.

Adult↗
PubMed1980

Human relevance: epidemiology and occupational exposure.

This paper reviews briefly some industrial applications which may result in occupational exposure of the workforce to preformed N-nitroso compounds. It considers exposure to nitrate in more detail, discussing epidemiological evidence which lends support to the hypothesis that high nitrate ingestion is related to high mortality from gastric cancer, through the formation in vivo of carcinogenic N-nitroso compounds. It presents the preliminary findings in a census-based mortality study of industrial workers exposed to nitrate-containing dust in the manufacture of fertilizers.

Adult↗
PubMed1979

In vitro nitrosation of methapyrilene.

The reactions of sodium nitrite and methapyrilene were studied in aqueous solution at neutral pH and under simulated gastric fluid conditions. Reaction product formation was much more complex than nitrosation of the parent molecule dimethylamino moiety to form nitrosodimethylamine. Several new nitroso compounds were formed under the reaction conditions studied. The simultaneous incorporation of 2 moles of ascorbic acid/mole of nitrite ion prevented any destruction of methapyrilene under all conditions studied. The implications of these observations with respect to nitrosation theory, the general carcinogenicity of nitroso compounds, and methapyrilene dosage formulation are discussed.

Aminopyridines↗
PubMed2000

Evaluation of fecal mutagenicity and colorectal cancer risk.

Colorectal cancer is one of the most common internal malignancies in Western society. The cause of this disease appears to be multifactorial and involves genetic as well as environmental aspects. The human colon is continuously exposed to a complex mixture of compounds, which is either of direct dietary origin or the result of digestive, microbial and excretory processes. In order to establish the mutagenic burden of the colorectal mucosa, analysis of specific compounds in feces is usually preferred. Alternatively, the mutagenic potency of fecal extracts has been determined, but the interpretation of these more integrative measurements is hampered by methodological shortcomings. In this review, we focus on exposure of the large bowel to five different classes of fecal mutagens that have previously been related to colorectal cancer risk. These include heterocyclic aromatic amines (HCA) and polycyclic aromatic hydrocarbons (PAH), two exogenous factors that are predominantly ingested as pyrolysis products present in food and (partially) excreted in the feces. Additionally, we discuss N-nitroso-compounds, fecapentaenes and bile acids, all fecal constituents (mainly) of endogenous origin. The mutagenic and carcinogenic potency of the above mentioned compounds as well as their presence in feces, proposed mode of action and potential role in the initiation and promotion of human colorectal cancer are discussed. The combined results from in vitro and in vivo research unequivocally demonstrate that these classes of compounds comprise potent mutagens that induce many different forms of genetic damage and that particularly bile acids and fecapentaenes may also affect the carcinogenic process by epigenetic mechanisms. Large inter-individual differences in levels of exposures have been reported, including those in a range where considerable genetic damage can be expected based on evidence from animal studies. Particularly, however, exposure profiles of PAH and N-nitroso compounds (NOC) have to be more accurately established to come to a risk evaluation. Moreover, lack of human studies and inconsistency between epidemiological data make it impossible to describe colorectal cancer risk as a result of specific exposures in quantitative terms, or even to indicate the relative importance of the mutagens discussed. Particularly, the polymorphisms of genes involved in the metabolism of heterocyclic amines are important determinants of carcinogenic risk. However, the present knowledge of gene-environment interactions with regard to colorectal cancer risk is rather limited. We expect that the introduction of DNA chip technology in colorectal cancer epidemiology will offer new opportunities to identify combinations of exposures and genetic polymorphisms that relate to increased cancer risk. This knowledge will enable us to improve epidemiological study design and statistical power in future research.

Amines↗
PubMed2004

Dietary cancer and prevention using antimutagens.

Many of the cancers common in the Western world, including colon, prostate and breast cancers, are thought to relate to dietary habits. Of the known risk factors, many will act through increasing the probability of mutation. Recognised dietary mutagens include cooked meat compounds, N-nitroso compounds and fungal toxins, while high meat and saturated fat consumption, increasing rates of obesity, and regular consumption of alcohol and tobacco are all dietary trends that could indirectly enhance the probability of mutation. However, there are significant difficulties in implementing and sustaining major dietary changes necessary to reduce the population's intake of dietary mutagens. Dietary antimutagens may provide a means of slowing progression toward cancer, and be more acceptable to the population. Consideration of genetic mechanisms in cancer development suggest several distinct targets for intervention. Strategies that reduce mutagen uptake may be the most simple intervention, and the one least likely to result in undesirable side effects. Certain (but not all) types of dietary fibres appear to reduce mutation through this mechanism, as may certain probiotics and large planar molecules such as chlorophyllin. Antioxidants have been suggested to scavenge free radicals, and prevent their interactions with cellular DNA. Small molecule dietary antioxidants include ascorbic acid, Vitamin E, glutathione, various polyphenols and carotenoids. We found a statistically significant relationship between colon cancer incidence and soil selenium status across different regions of New Zealand. Additionally, a study of middle-aged men suggested that blood selenium levels lower than 100 ng/ml were inadequate for repair or surveillance of oxidative (and other) DNA damage. We suggest that selenium will be an important antimutagen, at least in New Zealand, possibly through antioxidant effects associated with selenium's role in enzymes associated with endogenous repair of DNA damage. Modulation of xenobiotic metabolizing enzymes is well recognised as cancer-protective, and is a property of various flavonoids and a number of sulfur-containing compounds. Many fruits and vegetables contain compounds that will protect against mutation and cancer by several mechanisms. For example, kiwifruit has antioxidant effects and may also affect DNA repair enzymes. Dietary folate may be a key factor in maintenance of methylation status, while enhanced overall levels of vitamins and minerals may retard the development of genomic instability. The combination of each of these factors could provide a sustainable intervention that might usefully delay the development of cancer in New Zealand and other populations. Although there are a range of potentially antimutagenic fruits, vegetables and cereals available to these populations, current intake is generally below the level necessary to protect from dietary or endogenous mutagens. Dietary supplementation may provide an alternative approach.

Adolescent↗
PubMed1989

The initiator tRNA acceptance assay as a short-term test for carcinogens. 5. Results with 42 cytostatic drugs.

The activity of 42 cytostatic drugs used for the treatment of human cancer was tested by the initiator tRNA acceptance assay for carcinogens. Of 17 drugs carcinogenic for rodents, 16 (94.1%) gave a positive response in the assay and six (85.7%) out of seven non-carcinogens showed no activity. The predictive value of the test for cytostatics was 91.7%. Treatment of tRNA with several cytostatics resulted in an inhibition of its acceptance for L-methionine. Cyclophosphamide, dibromdulcitol, 5-deoxy-5-fluorouridine and vincristine also inhibited, in addition to this, the charging of unfractionated tRNA from rat liver with L-alanine, L-lysine, L-phenylalanine and L-valine. Some drugs apparently react with the same target nucleoside which is common for all species of tRNA (probably the terminal adenosine residue that is esterified with amino acids). Such compounds do not yield reliable results in the initiator tRNA acceptance assay since this inhibitory effect interferes with the stimulating effect characteristic for carcinogens. However, results of the present study agree well with those obtained earlier with different classes of compounds (N-nitroso compounds, mycotoxins, etc.) and indicate that this newly developed assay may be a useful alternative also for the testing of carcinogenicity of cytostatic drugs.

Amino Acids↗
PubMed2006

Reproductive effects of hexahydro-1,3,5-trinitroso-1,3,5-triazine in deer mice (Peromyscus maniculatus) during a controlled exposure study.

Contamination with hexahydro-1,3,5-trinitro-1,3,5-triazine (Royal Demolition Explosive [RDX]) has been identified at areas of explosive manufacturing, processing, storage, and usage. Thus, the potential exists for exposure to N-nitroso compounds, hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine, hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine, and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX), formed via anaerobic transformation of RDX. Following exposure, reproductive toxicity of TNX was evaluated in three consecutive litters of deer mice (Peromyscus maniculatus). Hexahydro-1,3,5-trinitroso-1,3,5-triazine was administered ad libitum via drinking water at four doses: 0 (control), 1, 10, and 100 microg/L. Endpoints investigated included reproductive success, offspring survival, offspring weight gain, offspring organ weights, and liver TNX residues. Data from the present study indicate that TNX bioaccumulates in the liver and is associated with postpartum mortality, dose-dependent decrease in body weight from birth to weaning, and decrease in kidney weight of deer mice offspring.

Animals↗
PubMed1991

[Current knowledge on the formation of nitric oxide in endothelial cells of blood vessels, in nerve cells and macrophages as well as its significance in vascular dilatation, information transmission and damage of tumor cells].

The vasculature endothelium cells and the nerve cells of several regions of the brain and the autonomous nerve system contain a nitric oxide (NO)-synthase, that forms NO from arginine. The NO-synthase is stimulated by bradykinin, histamine and acetylcholine and is especially active in the coronary and brain vessels. In the vasculature smooth muscle NO activates the guanylate cyclase: The increase in the concentration of cGMP induces a relaxation and in this way a vasodilatation. In the nerve cells NO is active as a neuromodulator. The activation of macrophages by gamma-interferon or by lipopolysaccharides induces the formation of a NO-synthase, that has other properties than the enzyme of the endothelium cells. The macrophages secrete NO and inhibit the metabolism of tumour cells, especially enzymes of the respiratory chain and of the citric acid cycle as well as the DNA-synthesis. Trinitroglycerin and amyl nitrite form with thiol-compounds S-nitroso-compounds, the decomposition of these forms NO.

Amino Acid Oxidoreductases↗
PubMed1989

[Microbial mutagenicity testing of N-nitrosoiminostilbene and N-nitrosoiminodibenzyl, the nitrosation products of the drugs carbamazepine and trimipramine hydrochloride].

The active agents of the drugs Finlepsin and Herphonal, carbamazepine and trimipramine, were nitrosated under simulated human gastric conditions. For both formed N-nitroso compounds, N-nitroso iminostilbene (N-nitroso-5H-dibenz(b,f)azepine) and N-nitroso iminodibenzyl (N-nitroso-10,11-dihydro-5H-dibenz(b,f)azepine), tests for mutagenic potency in the Ames-test gave negative results.

Carbamazepine↗
PubMedDate not supplied

[Surveillance of health status in an agrarian environment: proposal for a method. 1. Epidemiological data].

In order to evaluate the risk of the exposure of the pesticides and N-nitroso compounds in the agricultural environment not only farm-hands have to be considered but also their families. So it is necessary to prepare survey methodologies to examine the state of health of all individuals who are exposed to same kind of risk (pesticides and nitroso compounds), even if in different ways and intensity. We have therefore chosen four farms situated on the same territory which cultivate vegetables. Three, of these farms, made wide use of pesticides and fertilizers, the fourth one was used as a "control farm" because it did not employ any chemicals. For every farm data about the neighbouring territory, the climate, the kind of cultivation, the pesticides and other employed chemicals were collected. Every subject (in all 25) residing in the farm was interviewed with a standard questionnaire about personal data, the duties performed on the farm, the way in which chemicals were used, their medical history as well as the life style. Samples of blood were drawn periodically in different seasons, over a two year period, to determine both nitrosoamine (NA) and the enzymes which reveal hepatic damage: Alkaline phosphatase (ALP), Leucinoaminopeptidase (LAP), Gamma-glutamyltransferase (GGT) and Acetylcholinesterase (Ach). We have observed that: a. the most frequent pathologies concern skin (16% of the people) and liver (12% of the people), which are favourite targets for agricultural chemicals though the serum enzymes did not show any important change; b. 8% of the subjects had acute pesticide poisoning; we therefore observed neither particular precautionary safety measures, nor a particular knowledge of acute and chronic toxic effects depending on the use of pesticides. So we suggest: 1) that the Sanitary Authorities control the state of health not only of the farm-hands but also of their families, if exposed to risk; this can be realized through the strict collaboration of the Occupational Physician and the Family doctor; 2) capillary action of health education regarding agricultural risks; 3) to increase research to find more sensitive and efficient biological indicators in order to evaluate the hazards of agricultural chemicals.

Adult↗
PubMed2005

Meat, meat cooking methods and preservation, and risk for colorectal adenoma.

Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Processed meats contain N-nitroso compounds. Meat intake may increase cancer risk as HCAs, PAHs, and N-nitroso compounds are carcinogenic in animal models. We investigated meat, processed meat, HCAs, and the PAH benzo(a)pyrene and the risk of colorectal adenoma in 3,696 left-sided (descending and sigmoid colon and rectum) adenoma cases and 34,817 endoscopy-negative controls. Dietary intake was assessed using a 137-item food frequency questionnaire, with additional questions on meats and meat cooking practices. The questionnaire was linked to a previously developed database to determine exposure to HCAs and PAHs. Intake of red meat, with known doneness/cooking methods, was associated with an increased risk of adenoma in the descending and sigmoid colon [odds ratio (OR), 1.26; 95% confidence interval (95% CI), 1.05-1.50 comparing extreme quintiles of intake] but not rectal adenoma. Well-done red meat was associated with increased risk of colorectal adenoma (OR, 1.21; 95% CI, 1.06-1.37). Increased risks for adenoma of the descending colon and sigmoid colon were observed for the two HCAs: 2-amino-3,8-dimethylimidazo[4,5]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (OR, 1.18; 95% CI, 1.01-1.38 and OR, 1.17, 95% CI, 1.01-1.35, respectively) as well as benzo(a)pyrene (OR, 1.18; 95% CI, 1.02-1.35). Greater intake of bacon and sausage was associated with increased colorectal adenoma risk (OR, 1.14; 95% CI, 1.00-1.30); however, total intake of processed meat was not (OR, 1.04; 95% CI, 0.90-1.19). Our study of screening-detected colorectal adenomas shows that red meat and meat cooked at high temperatures are associated with an increased risk of colorectal adenoma.

Adenoma↗
PubMed1992

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

6-Nitroso-1,2-benzopyrone and 3-nitrosobenzamide, two C-nitroso compounds that inactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 2.4.2.30] at one zinc-finger site, completely suppressed the proliferation of leukemic and other malignant human cells and subsequently produced cell death. Tumoricidal concentrations of the drugs were relatively harmless to normal bone marrow progenitor cells and to superoxide formation by neutrophil granulocytes. The cellular mechanism elicited by the C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesium-dependent endonuclease. This endonuclease is maintained in a latent form by poly(ADP-ribosyl)ation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. ADPRT is thus identified as a critical regulatory enzyme component of a DNA-binding multiprotein system that plays a central function in defining DNA structures in the intact cell.

Animals↗
PubMed1992

Chromosomal aberrations and sister-chromatid exchanges induced by N-nitroso-2-acetylaminofluorene and their modifications by arsenite and selenite in Chinese hamster ovary cells.

The frequencies of chromosomal aberrations (CA) and sister-chromatid exchanges (SCE) in Chinese hamster cells were significantly increased by the direct-acting mutagen N-nitroso-2-acetylaminofluorene (N-NO-AAF) at the concentration of 0.1 mM. N-NO-AAF was prepared by nitrosation of the protohepatocarcinogen 2-acetylaminofluorene. The induced CA, which included chromatid breaks, chromatid exchanges, chromosome breaks, and chromosome ring formation were significantly potentiated by the presence of sodium arsenite (10 microM), but not by hydroxyurea (20 mM) or cytosine arabinoside (25 microM). On the other hand, the clastogenic effect of N-NO-AAF was effectively inhibited by sodium selenite (100 microM). Arsenite (10 microM) was shown to be moderately active in CA induction which was partially blocked by the presence of selenite (10 nM). N-Nitroso compounds such as N-nitroso-N-methylurea, N-nitroso-N-ethylurea and N-methyl-N'-nitro-N-nitrosoguanidine were equally or more active in the induction of CA and SCE in CHO cells when compared with N-NO-AAF. The cell cycle was significantly delayed by the intervention of N-NO-AAF.

2-Acetylaminofluorene↗
PubMed1991

New brands of oral snuff.

Snuff dipping is causally related to cancer of the oral cavity and pharynx. The most powerful carcinogens in snuff are nitroso compounds, particularly the tobacco-specific N-nitrosamines (TSNA). Concentrations of TSNA in snuff exceed the known concentrations of carcinogenic nitrosamines in any other consumer product by two to three orders of magnitude. During the last decade a gradual decrease in TSNA has occurred in the two leading snuff brands in the USA (about 90% of the market). Of two recently introduced snuff brands one has relatively low levels of nitroso compounds while the other contains the highest concentrations of nitrosamines ever reported in smokeless tobacco. This observation suggests that control of nitrosamines in snuff brands on the US market is desirable.

Alkaloids↗
PubMed1982

[Comparative studies of the nitrosation behavior of drugs by constant pH value and under simulated stomach conditions].

The nitrosation behaviour of 60 orally administered drugs used in the GDR have been investigated. Only those pharmaceuticals were selected whose active agents are assessed as being nitrosatable by their chemical structures. Amounts of active components and nitrite, dissolved in the gastric juice, did not exceed the concentrations permissible for human stomachs in vivo. After one-hour incubation at pH 2.0 and 37 degrees C ten drugs (Aminophenazone, Ampicilline, Clomipramine, Desipramine, Ethambutole, Imipramine, Noramidopyrinmethansulfonate, Oxacilline, Phenoxymethylpenicilline, Piperazine) proved to be nitrosatable using a colorimetric measuring method. Two of the N-nitroso compounds have been identified as known carcinogens. Structure analysis of the remaining ones is not yet finished. Results still more conforming to in vivo conditions have been obtained for all ten nitrosatable drugs by means of a model system simulating the conditions of the human stomach. The pH changes attending the shifts of pH occurring in the course of the digestive process have a distinct effect on the nitrosation reactions. It is only on such measurements of drug nitrosation that decisions on oral application, calculation of the burdening of the organism by N-nitroso compounds, or estimation of risk should be based.

Aminopyrine↗
PubMed1993

Ultrastructural hepatic alterations in hamsters and jirds after experimental infection with the liver fluke Opisthorchis viverrini.

Changes in the hepatocytes of male hamsters (Mesocricetus auratus) and jirds (Meriones unguiculatus) at 220 days after experimental infection with the liver fluke Opisthorchis viverrini were studied by light and electron microscopy. The hepatocytes of the control group were characterized by an intracellular compartmentation. A globular nucleus was located centrally. The main features of the perinuclear zone were the cisternae of the rough endoplasmic reticulum (RER) and interjacent mitochondria, lysosomes, and peroxisomes. The peripheral cell region was dominated by glycogen fields and scattered lipid droplets, which were surrounded by anastomosing tubules of the smooth endoplasmic reticulum (SER). An immense proliferation of the SER was striking in the hepatocytes of animals infected with O. viverrini. Coincidentally, the intracellular compartmentation disappeared. Glycogen rosettes, RER, lysosomes, and lipid droplets were distributed irregularly all over the cell, the latter being observed more frequently than in control animals. The nuclei showed lobe-like protrusions and were enlarged. The mitochondria were often dumbbell-shaped and showed pathologic degenerations up to lysis. Our results resemble those of numerous investigations concerning hepatocellular alterations caused by N-nitroso compounds. Therefore, these observations suggest a synergistic effect for trematode infection and N-nitroso compounds in the pathogenesis of opisthorchiasis. The cellular alterations observed in the hepatocytes of Opisthorchis-infected animals together with the accumulation of intermediate filaments seen in the adjacent bile-duct epithelia and in the epithelium of the gall-bladder seem to indicate a disturbance of the cell metabolism and might be related to a neoplastic transformation.

Animals↗