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PubMed1981

Variation of the frameshift activity of a mutagen (ICR-191) following nitrosation in human gastric juice.

The acridine half-mustard mutagen ICR-191 elicits peculiar frameshift mutations in S. typhimurium, which are greatly decreased in the presence of rat liver preparations. Following in vitro preincubation of ICR-191 with sodium nitrite and human gastric juice, these patterns of mutation are replaced by frameshift errors requiring metabolic activation and showing a different molecular specificity.

Aminacrine↗
PubMed1983

Mutagenic activity of N-nitrosomethamphetamine and N-nitrosoephedrine.

The mutagenicity of N-nitrosomethamphetamine (NMA) and N-nitrosoephedrine (NEP), which were synthesized in our laboratory, was examined by the modified pre-incubation method of Ames assay using Salmonella typhimurium TA100 and TA98. Both nitroso compounds showed significant mutagenic activity in the presence of hamster S9.

Animals↗
PubMed1987

The influence of urinary tract infection on the incidence of urinary tract tumors in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide induced carcinogenesis in male Sprague-Dawley rats.

Epidemiological studies have demonstrated an association between urinary tract infection and the development of bladder cancer. The present study aimed at evaluating the influence of urinary tract infection in male Sprague-Dawley rats exposed to a sub-carcinogenic dose of N-[4-(nitro-2-furyl)-thiazolyl]formamide (FANFT). A single injection of Escherichia coli into the bladder resulted in a persistent upper urinary tract infection in a high percentage of the rats. Thirty-two percent of the rats exposed to FANFT and E. coli infection developed urinary tract tumors, all but one occurring in the renal pelvis. Urinary tract tumors were not found in rats treated with FANFT or E. coli alone. The present results support that inflammation resulting from infection is actively involved in urinary tract tumorigenesis and may support the epidemiological studies showing an association between infection and human urinary tract cancer. The formation of dimethylnitrosamine or other nitroso compounds from nitrates in the urine or increased cell proliferation due to chronic inflammation or both may be important pathogenetic factors in tumor development.

Animals↗
PubMed1994

Endogenous formation of N-nitrosoproline and other N-nitrosamino acids in tobacco users.

The endogenous formation of N-nitroso compounds in tobacco users, namely chewers of tobacco + lime, betel quid with tobacco, and without tobacco, was determined by N-nitrosoproline test. Twenty-four- or six-hour urine samples were collected from volunteers for 3 days: day 1 without proline, day 2 after ingesting 100 mg proline three times a day and day 3 after ingesting 100 mg proline together with 100 mg ascorbic acid three times a day. The urine samples were analysed for the following N-nitrosamino acids: N-nitrosoproline, N-nitrososarcosine, N-nitrosopropionic acid, N-nitrosobutyric acid, N-nitrosothiozolidine-4-carboxylic acid, and N-methyl nitrosothiozolidine-4-carboxylic acid using gas chromatography-thermal energy analyser. It was observed that chewers of tobacco + lime excreted high basal levels of N-nitrosoproline on day 1 as compared with betel quid chewers with tobacco and without tobacco and those in the 'no habit' group. Levels of N-nitrosoproline on day 2 were 15.14 +/- 4.51 microns/mole creatinine in the tobacco + lime group, 3.55 +/- 1.22 microns/mole creatinine in the betel quid tobacco group, 4.72 +/- 1.35 microns/mole creatinine in the betel quid group while levels were 3.34 +/- 0.83 microns/mole creatinine in the 'no habit' group. A decrease in the N-nitrosoproline levels was observed in all the four groups on ingestion of ascorbic acid. This preliminary study suggests that there is a statistically significant increase in endogenous nitrosation in tobacco + lime chewers as compared with those with no habit, and ascorbic acid has an anti-nitrosating action in vivo.

Adult↗
PubMed1996

Molecular and genetic events in schistosomiasis-associated human bladder cancer: role of oncogenes and tumor suppressor genes.

Carcinoma of the urinary bladder is the most common malignancy in many tropical and subtropical countries and is mainly due to endemic schistosomal infection. Schistosomiasis-associated bladder cancer defines a characteristic pathology and cellular and molecular biology that differs from urothelial carcinoma of non-schistosomal origin. N-Nitroso compounds are suspected etiologic agents in the process of bladder cancer induction during schistosomiasis. Elevated levels of DNA alkylation damage have been detected in schistosome-infected bladders and are accompanied by an inefficient capacity of DNA repair mechanisms. Consequently, high frequency of G --> A transition mutations were observed in the H-ras gene and at the CpG sequences of the p53 tumor suppressor gene. Genetic changes have also been detected in the c-erbB-1 and c-erbB-2 oncogenes and in the cdkn2 and Rb tumor suppressor genes. The potential application of these mutational patterns in providing a biological marker suitable for the biomonitoring and early detection of this neoplasm could indicate new avenues of approach that might alleviate the problem in the future. It can also assist in elucidating the mechanisms by which schistosomiasis augments human bladder cancers.

Amino Acid Sequence↗
PubMed1986

Efflux of cyclic guanosine 3',5'-monophosphate from cerebellar slices stimulated by L-glutamate or high K+ or N-methyl-N'-nitro-N-nitrosoguanidine.

The efflux of cyclic guanosine 3',5'-monophosphate (cGMP) was studied from rat cerebellar slices which were stimulated by L-glutamate (1 mM), or by depolarizing concentrations of K+ (60 mM) or by the nitroso compound, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Via different mechanisms these agents stimulated cGMP synthesis producing several fold elevation of the cGMP content of the tissue slices. Simultaneously with the elevation of the intracellular (intra slice) concentrations of cGMP, a temperature-and time-dependent efflux of cGMP into the medium took place. This efflux was maximal at 5 min and could be inhibited by the known inhibitor of anion transport, probenecid, in a concentration-dependent manner. The results suggest the presence of an efflux system for cGMP, which may participate together with the well-characterized 3',5'-cyclic nucleotide phosphodiesterases in reduction of elevated cGMP levels.

Animals↗
PubMed1982

Activation of purified guanylate cyclase by nitric oxide requires heme. Comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung.

Bovine lung soluble guanylate cyclase was purified to apparent homogeneity in a form that was deficient in heme. Heme-deficient guanylate cyclase was rapidly and easily reconstituted with heme by reacting enzyme with hematin in the presence of excess dithiothreitol, followed by removal of unbound heme by gel filtration. Bound heme was verified spectrally and NO shifted the absorbance maximum in a manner characteristic of other hemoproteins. Heme-deficient and heme-reconstituted guanylate cyclase were compared with enzyme that had completely retained heme during purification. NO and S-nitroso-N-acetylpenicillamine only marginally activated heme-deficient guanylate cyclase but markedly activated both heme-reconstituted and heme-containing forms of the enzyme. Restoration of marked activation of heme-deficient guanylate cyclase was accomplished by including 1 microM hematin in enzyme reaction mixtures containing dithiothreitol. Preformed NO-heme activated all forms of guanylate cyclase in the absence of additional heme. Guanylate cyclase activation was observed in the presence of either MgGTP or MnGTP, although the magnitude of enzyme activation was consistently greater with MgGTP. The apparent Km for GTP in the presence of excess Mn2+ or Mg2+ was 10 microM and 85-120 microM, respectively, for unactivated guanylate cyclase. The apparent Km for GTP in the presence of Mn2+ was not altered but the Km in the presence of Mg2+ was lowered to 58 microM with activated enzyme. Maximal velocities were increased by enzyme activators in the presence of either Mg2+ or Mn2+. The data reported in this study indicate that purified guanylate cyclase binds heme and the latter is required for enzyme activation by NO and nitroso compounds.

Animals↗
PubMed1989

Interaction of carbaryl and N-nitrosocarbaryl with microsomal monooxygenase activities.

The in vitro interactions of carbaryl and carcinogenic N-nitrosocarbaryl with rat liver microsomal monooxygenase activities are compared. The inhibitory effect of the nitroso-compound is demonstrated to be non-competitive on aminopyrine N-demethylase, p-nitroanisole O-demethylase and aniline hydroxylase. The nature of the inhibition induced by the parent amide is found to be competitive on aminopyrine N-demethylase and p-nitroanisole O-demethylase. Correspondingly, in vitro studies of the metabolism of the two compounds were carried out: they both yield formaldehyde. Moreover, N-nitrosocarbaryl is denitrosated through a NO-cytochrome P-450 complex during microsomal metabolism. The toxic effects and biological activities of the two compounds are discussed on the basis of data of metabolic studies and different patterns of enzyme inhibition.

Animals↗
PubMed1994

Reactive radical intermediates formed from illuminated nifedipine.

Nifedipine, (1,4-dihydro-2,6,dimethyl-4-(2-nitrophenyl)-3, 5-pyridinedicarboxylic acid dimethyl ester) a calcium channel blocker widely used in treatment of hypertension, is strongly photolabile. This may represent a problem in patients taking nifedipine and in handling of nifedipine samples. Reactive radical intermediates were determined and characterized in the process of nifedipine illumination using EPR spectroscopy. On illumination of nifedipine by daylight or by a mercury lamp, a nitroxide radical, RIIL-NIFNO.X was observed (in the first step), in various solvents like benzene, cyclohexane, methanol, acetonitrile, dimethylsulphoxide, or aqueous suspensions of liposomes. RIIL-NIF represents the nifedipine skeleton centered with phenyl group, and X is an EPR silent substituent. The generation of RIIL-NIFNO.X is coupled with the formation of nitroso compound, RIIL-NIFNO, as characterized by UV-visible spectroscopy. In a further step, RIIL-NIFNO abstracts hydrogen from nifedipine skeleton under the formation of RIIL-NIFNO.H radical. In addition to this, in system containing RIIL-NIFNO and unsaturated lipids, nitroxide radicals RIIL-NIFNO.RLIPIDS are formed probably via a pseudo Diels-Alder mechanism (RLIPIDS represents lipidic skeleton). The unusually easy photochemical activation of nifedipine is probably stimulated by photosensitization of its nitro group interacting with suitably positioned hydrogen or carboxylic methyl ester group from the pyridinyl ring.

Electron Spin Resonance Spectroscopy↗
PubMedDate not supplied

Chemical induction of brain tumors in rats by nitrosoureas: molecular biology and neuropathology.

Nitrosourea-induced rat brain tumors are among the best investigated experimental systems for neuropathological, biochemical, diagnostic and therapeutic research in neurooncology. This review summarizes data concerning molecular biology, neuropathology, in vitro studies, transplantation models and antigen expression of experimental gliomas in inbred rat strains. Systemic application of nitroso-compounds, i.e., ENU and MNU, leads to the alkylation of DNA bases, which, due to a specific repair deficiency, persist in the nervous system remarkably longer than in other organs. The hypothesis is that alkylated bases cause base-mispairing and point mutations followed by uncontrolled expression of oncogenes and growth factor receptors, resulting in permanent cell proliferation. Thus, nitrosoureas are considered to be biological hazards, especially as potent endogenous and exogenous neurotoxins. Neuropathology and growth characteristics of these experimental tumors are comparable to human malignant gliomas. Similar to the human WHO grade III and IV tumors, they reveal cellular pleomorphism, elevated mitotic activity, proliferation of blood vessels, blood-brain barrier disturbances, necrosis and invasiveness. Nitrosourea-induced brain tumors have been used in investigations concerning glioma growth and regression, brain edema, glioma immunology, metabolism, regional biochemistry, and experimental therapy. The studies included conventional morphology, immunohistochemistry, -cytochemistry and -electronmicroscopy, morphometry, cell culture, hybridoma technology, tumor transplantation and regional imaging by autoradiography, bioluminescence, magnetic resonance and immunoscintigraphy.

Animals↗
PubMed1990

Isolation of a Bacillus subtilis mutant defective in constitutive O6-alkylguanine-DNA alkyltransferase.

A mutant of Bacillus subtilis defective in the constitutive activity of O6-alkylguanine-DNA alkyltransferase was isolated from a strain (ada-1) deficient in the adaptive response to DNA alkylation. Cells carrying the mutation dat-1 which was responsible for the defect in constitutive activity exhibited hypersensitivity for lethality and mutagenesis when challenged with methyl-nitroso compounds. The constitutive activity is independent of the adaptive response, and seems to function as a basal defense against environmental alkylating agents.

Alkyl and Aryl Transferases↗
PubMed2006

ATP-generating glycolytic substrates prevent N-nitrosofenfluramine-induced cytotoxicity in isolated rat hepatocytes.

The relationship between cytotoxicity induced by N-nitrosofenfluramine and mitochondrial or glycolytic adenosine triphosphate (ATP) synthesis-dependent intracellular bioenergetics was studied in isolated rat hepatocytes. The supplementation of fructose, an ATP-generating glycolytic substrate, to hepatocyte suspensions prevented N-nitrosofenfluramine-induced cell injury accompanied by the formation of cell blebs, abrupt loss of intracellular ATP and reduced glutathione and mitochondrial membrane potential (DeltaPsi), and the accumulation of oxidized glutathione and malondialdehyde, indicating lipid peroxidation, during a 2h incubation period. Fructose (1-20mM) resulted in concentration-dependent protection against the cytotoxicity of N-nitrosofenfluramine at a concentration of 0.6mM, a low toxic dose. Pretreatment with xylitol, another glycolytic substrate, at concentration of 15mM also prevented the cytotoxicity caused by the nitroso compound, but neither glucose nor sucrose exhibited protective effects. In addition, fructose inhibited N-nitrosofenfluramine (0.5 and 0.6mM)-induced DNA damage, as evaluated in the comet assay, indicating that nuclei as well as mitochondria are target sites of the compound. These results indicate that (a) the onset of N-nitrosofenfluramine-induced cytotoxicity in rat hepatocytes is linked to mitochondrial failure, and that (b) the insufficient supply of ATP in turn limits the activities of all energy-requiring reactions and consequently leads to acute cell death.

Adenosine Triphosphate↗
PubMed2004

Increased breath nitrous oxide after ingesting nitrate in patients with atrophic gastritis and partial gastrectomy.

BACKGROUND: Toxic nitrite and N-nitroso compounds due to gastric bacterial growth are often detected in the stomach of patients with atrophic gastritis and partial gastrectomy. The aim of this study is to investigate whether breath N2O, a major metabolite of denitrification, detected after ingestion of nitrate is associated with atrophic gastritis and partial gastrectomy. METHODS: Nine young, 16 normal older, nine atrophic gastritis and six partial gastrectomy subjects ingested 100 g lettuce, equal to 130 mg nitrate, and breath N2O was measured at 15-min intervals for 5 h. N2O was analyzed using an infrared-photoacoustic analyzer, and atrophic gastritis was diagnosed by pepsinogen test. RESULTS: The mean breath N2O concentrations were higher in the following order at all times: partial gastrectomy>atrophic gastritis>normal>young. The maximum N2O concentrations in the patients with partial gastrectomy and atrophic gastritis were 1655 +/- 296 and 1350 +/- 200 (mean +/- S.E.) ppb, respectively, which were higher than that of the normal subjects, 827 +/- 91 ppb (P < 0.05). The maximum N2O concentration in young people was 527 +/- 86 ppb, which was lower than that of the normal older people (P < 0.051). CONCLUSION: These higher N2O concentrations in gastric patients reflect bacterial growth in the stomach due to the reduction of gastric acid.

Adolescent↗
PubMed2005

Binding of gaseous Fe(III)-heme cation to model biological molecules: direct association and ligand transfer reactions.

The binding of a variety of ligands with Fe(III)-heme(+) ion, prosthetic group of heme proteins, has been studied in the gas phase by ESI-FT-ICR mass spectrometry. The ligands have been selected among substrate molecules of heme proteins (e.g., NO, nitroso compounds) or among model compounds acting for the functional groups that are present in the protein backbone (e.g., amines, thioethers, nitriles, ketones, amides, etc.). Both the kinetic and the thermodynamic features of the addition reactions are reported. Fe(III)-heme(+) ions react faster with lone pair donor ligands as the reaction becomes increasingly thermodynamically favored (higher heme cation basicity of the ligand, HCB, namely -DeltaG degrees for the ligand addition reaction). In turn HCBs correlate in general with the gas phase basicity toward the proton of the various ligands. A ligand addition equilibrium is established with weaker ligands, methanol, acetonitrile and acetone, yielding absolute HCB values, whereas ligand transfer equilibriums allowed a scale of relative (and absolute) HCBs to be constructed. NO displays exceptional binding properties towards Fe(III)-heme(+), unrelated to the low gas phase basicity toward the proton of this molecule, which is clearly the basis for the paramount role of heme proteins in NO binding and regulation.

Cations↗
PubMed2005

Photochemistry of the [Fe4(mu3-S)3(NO)7]- complex in the presence of S-nucleophiles: a spectroscopic study.

Biological systems usually contain cysteine, glutathione or other sulfur-containing biomolecules. These S-nucleophiles were found to affect drastically the [Fe(4)(mu(3)-S)(3)(NO)(7)](-) photolysis pathway generating products completely different from that of the neat cluster, which produces Fe(II) and NO and S(2-). The effect is interpreted in terms of formation of a pseudo-cubane adduct, [Fe(4)(mu(3)-S)(3)(mu(3)-SR)(NO)(7)](2-), whose existence in equilibrium with the parent complex has no detectable influence on the spectral properties, whereas shifts the redox potential and induces photoconversion leading to the Fe(III) species and N(2)O. Characteristic bond lengths, bond angles and atomic Mulliken charges were calculated using semi-empirical quantum chemical methods for the RBS anion and a series of pseudo-cubane complexes with S-donor or N-donor ligands. The results justify the hypothesis of the adduct formation and show that only in case of S-ligands the higher contribution of the Fe(III)-NO(-) components in adduct than in RBS is observed, which on excitation can undergo heterolytic cleavage yielding Fe(III) and NO(-), converted rapidly into N(2)O. These results are crucial in understanding the physiological activity of RBS. Fe(III) formation can be detected only when the S-ligand enables formation of a stable Fe(III) compound; the effect was recorded in the presence of sulfide, thioglycolate, 2-mercaptopropionate, mercaptosuccinate, penicillamine, 2,3-dimercaptosuccinate, 2,3-dimercaptopropanol, and thiocyanate. For all these S-ligands the Fe(III) photoproducts were identified and characterised. In the case of other thiolates, their excess results in fast reduction of Fe(III) to Fe(II), whereas N(2)O can be still detected. Quantum yields of Fe(III) formation in the presence of the S-ligands are considerably higher than that of the Fe(II) photoproduction from neat [Fe(4)(mu(3)-S)(3)(NO)(7)](-).

Iron↗
PubMed2004

Epidemiology of brain tumors in childhood--a review.

Malignant brain tumors are the leading cause of cancer death among children and the second most common type of pediatric cancer. Despite several decades of epidemiologic investigation, the etiology of childhood brain tumors (CBT) is still largely unknown. A few genetic syndromes and ionizing radiation are established risk factors. Many environmental exposures and infectious agents have been suspected of playing a role in the development of CBT. This review, based on a search of the medical literature through August 2003, summarizes the epidemiologic evidence to date. The types of exposures discussed include ionizing radiation, N-nitroso compounds (NOC), pesticides, tobacco smoke, electromagnetic frequencies (EMF), infectious agents, medications, and parental occupational exposures. We have chosen to focus on perinatal exposures and review some of the recent evidence indicating that such exposures may play a significant role in the causation of CBT. The scientific community is rapidly learning more about the molecular mechanisms by which carcinogenesis occurs and how the brain develops. We believe that advances in genetic and molecular biologic technology, including improved histologic subtyping of tumors, will be of huge importance in the future of epidemiologic research and will lead to a more comprehensive understanding of CBT etiology. We discuss some of the early findings using these technologies.

Animals↗
PubMed2004

Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies.

Perinatal carcinogenesis as a cross-disciplinary concern is the subject of this special issue of Toxicology and Applied Pharmacology, which consists of a total of eight reviews or commentaries in the areas of epidemiology, risk assessment, and animal models. Some of the conclusions from these articles, and the Questions and Answers section that follows most of them, are summarized here. There is adequate reason to suspect that perinatal exposures contribute to human cancer risk, both childhood cancers, and those appearing later in life. The latter type of risk may actually be quantitatively the more important, and involve a wide range of types of effects, but has received only limited attention. With regard to childhood cancers, fetal irradiation and diethylstilbestrol exposure are known etiological agents, and it is likely, but not yet certain, there are additional external causes of a portion of these. Some current focal points of interest here include nitroso compounds, DNA topoisomerase inhibitors, viruses, anti-AIDS drugs, and endocrine disruptors. Regulatory agencies must rely heavily on animal data for estimation of human risk due to perinatal exposures to chemicals, and the quantity and quality of these data presently available for this purpose are greatly limiting. Correctly designed conventional animal studies with suspect chemicals are still needed. Furthermore, genetically engineered mouse models for childhood cancers, especially medulloblastoma, have become available, and could be used for screening of candidate causative agents for this cancer type, and for better understanding of gene-environment interactions.

Animals↗