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Sample records for bulky carcinogen-dna adducts

  1. Bulky carcinogen-DNA adducts and exposure to environmental and occupational sources of polycyclic aromatic hydrocarbons. Influence of susceptibility genotypes on adduct level

    Energy Technology Data Exchange (ETDEWEB)

    Sabro Nielsen, P.

    1996-12-31

    PAH exposure, whether it is of occupational or environmental origin, is thought to result in an elevated risk of cancer especially in the lungs. DNA damage is considered an important step in the carcinogenic effect of PAH. Hence, methods that elucidate the steps in the carcinogenic process are important to understand the action of PAH. It may prove useful in the exposure assessment and in combination with classical epidemiological methods give better basis for risk estimation. The objective in this thesis was to evaluate the feasibility of the {sup 32}P-postlabeling method to detect carcinogen-DNA adducts for assessing exposure to DNA damaging compounds in different occupationally and environmentally exposed groups. The studies included groups, that have an elevated cancer risk due to occupational exposure to PAH. Exposure levels were supposed to be relatively low according to reports on occupational and environmental air quality programs. Another aim was to evaluate the influence of polymorphisms in metabolizing enzyme genes on DNA adduct levels. A third objective was to establish some kind of baseline DNA adduct level for individuals with supposed low exposure, and compare it to the more exposed groups. A fourth aim in these studies was to examine if biomarkers of genotoxic exposure could be useful in epidemiological studies to identify groups at risk and thereby contribute with better exposure estimates in the study of PAH related cancer risk. (EG).

  2. Bulky carcinogen-DNA adducts and exposure to environmental and occupational sources of polycyclic aromatic hydrocarbons. Influence of susceptibility genotypes on adduct level

    International Nuclear Information System (INIS)

    PAH exposure, whether it is of occupational or environmental origin, is thought to result in an elevated risk of cancer especially in the lungs. DNA damage is considered an important step in the carcinogenic effect of PAH. Hence, methods that elucidate the steps in the carcinogenic process are important to understand the action of PAH. It may prove useful in the exposure assessment and in combination with classical epidemiological methods give better basis for risk estimation. The objective in this thesis was to evaluate the feasibility of the 32P-postlabeling method to detect carcinogen-DNA adducts for assessing exposure to DNA damaging compounds in different occupationally and environmentally exposed groups. The studies included groups, that have an elevated cancer risk due to occupational exposure to PAH. Exposure levels were supposed to be relatively low according to reports on occupational and environmental air quality programs. Another aim was to evaluate the influence of polymorphisms in metabolizing enzyme genes on DNA adduct levels. A third objective was to establish some kind of baseline DNA adduct level for individuals with supposed low exposure, and compare it to the more exposed groups. A fourth aim in these studies was to examine if biomarkers of genotoxic exposure could be useful in epidemiological studies to identify groups at risk and thereby contribute with better exposure estimates in the study of PAH related cancer risk. (EG)

  3. CARCINOGEN-DNA ADDUCTS: INTRODUCTION, LITERATURE SUMMARY, AND RECOMMENDATIONS

    Science.gov (United States)

    The report summarizes the literature concerning adducts formed by xenobiotics with DNA and/or protein and discusses their feasibility as a monitoring tool for use in exposure and risk assessment. The report is divided into three segments. The first segment provides an introductio...

  4. Biomarkers for Exposure to Ambient Air Pollution - Comparison of Carcinogen-DNA Adduct Levels with Other Exposure Markers and Markers for Oxidative Stress

    DEFF Research Database (Denmark)

    Autrup, Herman; Daneshvar, Bahram; Dragsted, Lars Ove;

    1999-01-01

    Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts....../10(8) nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmol/mg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark. In contrast, significantly higher levels of AAS in hemoglobin (55.8 pmol/mg protein), malondialdehyde in plasma (0. 96...... nmol/ml plasma), and polycyclic aromatic hydrocarbon (PAH)-albumin adduct (3.38 fmol/ microg albumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative...

  5. Biomarkers for exposure to ambient air pollution--comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress

    DEFF Research Database (Denmark)

    Autrup, H; Daneshvar, B; Dragsted, L O;

    1999-01-01

    Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts....../10(8) nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmol/mg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark. In contrast, significantly higher levels of AAS in hemoglobin (55.8 pmol/mg protein), malondialdehyde in plasma (0. 96...... nmol/ml plasma), and polycyclic aromatic hydrocarbon (PAH)-albumin adduct (3.38 fmol/ microg albumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative...

  6. Biomarkers for exposure to ambient air pollution - Comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress

    DEFF Research Database (Denmark)

    Autrup, Herman; Daneshvar, Bahram; Dragsted, Lars Ove;

    1999-01-01

    Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts....../10(8) nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmol/mg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark. In contrast, significantly higher levels of AAS in hemoglobin (55.8 pmol/mg protein), malondialdehyde in plasma (0.......96 nmol/ml plasma), and polycyclic aromatic hydrocarbon (PAH)-albumin adduct (3.38 fmol/mu g albumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative...

  7. Environmental, Dietary, Maternal, and Fetal Predictors of Bulky DNA Adducts in Cord Blood

    DEFF Research Database (Denmark)

    Pedersen, Marie; Mendez, Michelle A; Schoket, Bernadette;

    2015-01-01

    BACKGROUND: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. OBJECTIVE: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates....

  8. Effect of acetylator genotype on the levels of carcinogen-DNA adducts in inbred hamsters treated with 2-aminofluorene

    International Nuclear Information System (INIS)

    A genetic polymorphism in N-acetyltransferase has been described previously in humans and in animal models that is known to affect an individual's susceptibility to certain drug toxicities and diseases including bladder cancer. In hamsters, the polymorphism is known to regulate the conversion of carcinogenic 2-aminofluorene to its amide and of N-hydroxy-2-aminofluorene to a reactive electrophile that forms a covalently-bound adduct with DNA; an event thought to initiate the tumorigenic process. A single dose of 2-aminofluorene (60 mg/kg body wt., i.p) was administered to homozygous rapid- (rr) and homozygous slow-acetylator (ss) hamsters, and the levels of aminofluorene-DNA adducts in bladder and liver were evaluated by a 32P-postlabeling assay. Only a non-acetylated aminofluorene-DNA adduct was detected in the DNA samples. In this study, no differences were detected between the levels of hepatic 2-aminofluorene-DNA adducts in males or females or between the rr or ss hamsters. In contrast, the levels of 2-amino-fluorene-adducts in bladder DNA were 5-fold higher in the male rr than in the ss hamsters, and were 2-fold higher in the male rr than in the female rr animals

  9. AlkB recognition of a bulky DNA base adduct stabilized by chemical cross-linking

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    E.coli AlkB is a direct DNA/RNA repair protein that oxidatively reverses N1 alkylated purines and N3 alkylated pyrimidines to regular bases.Previous crystal structures have revealed N1-methyl adenine(1-meA) recognition by AlkB and a unique base flipping mechanism,but how the AlkB active site can accommodate bulky base adducts is largely unknown.Employing a previously developed chemical cross-linking technique,we crystallized AlkB with a duplex DNA containing a caged thymine base(cagedT).The structure revealed a flexible hairpin lid and a reorganized substrate recognition loop used by AlkB to accommodate cagedT.These observations demonstrate,at the molecular level,how bulky DNA adducts may be recognized and processed by AlkB.

  10. Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother–newborns

    International Nuclear Information System (INIS)

    Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006–2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet was estimated on the basis of maternal food frequency questionnaire (FFQ) completed by the end of pregnancy. Biomarkers were detected in paired blood samples through the dioxin-responsive chemical-activated luciferase expression (CALUX)® bioassay, 32P-postlabelling technique and cytokinesis-block MN assay. Maternal preference for meats with dark surface were significantly associated with higher bulky DNA adducts in both maternal (β 95%CI; 0.46 (0.08, 0.84)) and cord blood (β 95%CI; 0.46 (0.05, 0.86)) before and after adjustment for potential confounders. No other significant associations between the 18 dietary variables and the biomarkers measured in maternal and fetal samples were identified. The present study suggests that maternal intake of meats with dark surface contributes to the bulky DNA adduct levels in maternal and umbilical cord blood. Relationship between food preparation and bulky DNA adducts appear to be captured by a FFQ while potential associations for other biomarkers might be more complex or need larger sample size.

  11. Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother-newborns

    Energy Technology Data Exchange (ETDEWEB)

    Pedersen, Marie, E-mail: mpedersen@creal.cat [Section of Environmental Health, Department of Public Health, University of Copenhagen, CSS, Oester Farimagsgade, Copenhagen K (Denmark); Halldorsson, Thorhallur I., E-mail: lur@ssi.dk [Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland Reykjavik (Iceland); Center for Fetal Programming, Department of Epidemiology, Statens Serum Institute, Copenhagen (Denmark); Autrup, Herman, E-mail: ha@mil.au.dk [School of Public Health, Department of Environmental and Occupational Medicine, Aarhus University, Aarhus (Denmark); Brouwer, Abraham, E-mail: Bram.Brouwer@bds.nl [BioDetection Systems B.V., Amsterdam (Netherlands); Besselink, Harrie, E-mail: Harrie.Besselink@bds.nl [BioDetection Systems B.V., Amsterdam (Netherlands); Loft, Steffen, E-mail: stl@sund.ku.dk [Section of Environmental Health, Department of Public Health, University of Copenhagen, CSS, Oester Farimagsgade, Copenhagen K (Denmark); Knudsen, Lisbeth E., E-mail: liek@sund.ku.dk [Section of Environmental Health, Department of Public Health, University of Copenhagen, CSS, Oester Farimagsgade, Copenhagen K (Denmark)

    2012-06-01

    Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006-2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet was estimated on the basis of maternal food frequency questionnaire (FFQ) completed by the end of pregnancy. Biomarkers were detected in paired blood samples through the dioxin-responsive chemical-activated luciferase expression (CALUX){sup Registered-Sign} bioassay, {sup 32}P-postlabelling technique and cytokinesis-block MN assay. Maternal preference for meats with dark surface were significantly associated with higher bulky DNA adducts in both maternal ({beta} 95%CI; 0.46 (0.08, 0.84)) and cord blood ({beta} 95%CI; 0.46 (0.05, 0.86)) before and after adjustment for potential confounders. No other significant associations between the 18 dietary variables and the biomarkers measured in maternal and fetal samples were identified. The present study suggests that maternal intake of meats with dark surface contributes to the bulky DNA adduct levels in maternal and umbilical cord blood. Relationship between food preparation and bulky DNA adducts appear to be captured by a FFQ while potential associations for other biomarkers might be more complex or need larger sample size.

  12. Lifestyle, Environmental, and Genetic Predictors of Bulky DNA Adducts in a Study Population Nested within a Prospective Danish Cohort

    DEFF Research Database (Denmark)

    Eriksen, K. T.; Sørensen, M.; Autrup, H.;

    2010-01-01

    Danish cohort. At enrollment, blood samples were collected and information on lifestyle, including dietary and smoking habits, obtained. Previously, bulky DNA adducts were measured in 245 individuals who developed lung cancer and 255 control members of the cohort. Of these 500 individuals, data on 375...... individuals were included in this study, excluding 125 cases, which developed lung cancer within the first 3 yr after blood sampling. Bulky DNA adduct levels were measured by 32P-postlabeling technique and polymorphisms in carcinogen metabolism and DNA repair genes were determined. Potential predictors of...

  13. Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother-newborns

    DEFF Research Database (Denmark)

    Pedersen, Marie; Halldorsson, Thorhallur I; Autrup, Herman;

    2012-01-01

    Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei...... (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006-2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet...... was estimated on the basis of maternal food frequency questionnaire (FFQ) completed by the end of pregnancy. Biomarkers were detected in paired blood samples through the dioxin-responsive chemical-activated luciferase expression (CALUX)(®) bioassay, (32)P-postlabelling technique and cytokinesis...

  14. Biomarkers for exposure to ambient air pollution - Comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress

    DEFF Research Database (Denmark)

    Autrup, Herman; Daneshvar, Bahram; Dragsted, Lars Ove; Gamborg, Mikael; Hansen, Åse Marie; Loft, Steffen; Okkels, Henrik; Nielsen, Flemming; Nielsen, Per Sabro; Raffn, Edith; Wallin, Håkan; Knudsen, Lisbeth Ehlert

    1999-01-01

    = 0.001). Significant correlations were also observed between urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine and AAS in plasma (p = 0.001) and PAM-albumin adducts (p = 0.002). The influence of the glutatione S-transferase (GST) M1 deletion on the correlation between the biomarkers was studied in the...

  15. Recovery of bulky DNA adducts by the regular and a modified 32P-postlabelling assay; influence of the DNA-isolation method.

    OpenAIRE

    Kovács, Katalin; Anna, Lívia; Rudnai, Péter; Schoket, Bernadette

    2011-01-01

    Bulky DNA adducts are widely used as biomarkers of human exposure to complex mixtures of environmental genotoxicants including polycyclic aromatic hydrocarbons. The 32P-postlabelling method is highly sensitive for the detection of bulky DNA adducts, but its relatively low throughput poses limits to its use in large-scale molecular epidemiological studies. The objectives of this study were to compare the impact of DNA-sample preparation with a commercial DNA-isolation kit or with the classical...

  16. Bulky DNA adducts in white blood cells: a pooled analysis of 3600 subjects

    Czech Academy of Sciences Publication Activity Database

    Ricceri, F.; Godschalk, R. W.; Peluso, M.; Philips, D. H.; Agudo, A.; Georgiadis, P.; Loft, S.; Tjonneland, A.; Raaschau-Nielsen, O.; Palli, D.; Perera, F.; Vermeulen, R.; Taioli, E.; Šrám, Radim; Munnia, A.; Rosa, F.; Allione, A.; Matullo, G.; Vineis, P.

    2010-01-01

    Roč. 19, č. 12 (2010), s. 3174-3181. ISSN 1055-9965 Grant ostatní: European Union ECNIS(XE) FOOD-CT-2005-513943 Institutional research plan: CEZ:AV0Z50390512 Keywords : DNA adducts * biomarkers of exposure * air pollution Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.190, year: 2010

  17. Structural Basis for Bulky-Adduct DNA-Lesion Recognition by the Nucleotide Excision Repair Protein Rad14.

    Science.gov (United States)

    Simon, Nina; Ebert, Charlotte; Schneider, Sabine

    2016-07-25

    Heterocyclic aromatic amines react with purine bases and result in bulky DNA adducts that cause mutations. Such structurally diverse lesions are substrates for the nucleotide excision repair (NER). It is thought that the NER machinery recognises and verifies distorted DNA conformations, also involving the xeroderma pigmentosum group A and C proteins (XPA, XPC) that act as a scaffold between the DNA substrate and several other NER proteins. Here we present the synthesis of DNA molecules containing the polycyclic, aromatic amine C8-guanine lesions acetylaminophenyl, acetylaminonaphthyl, acetylaminoanthryl, and acetylaminopyrenyl, as well as their crystal structures in complex with the yeast XPA homologue Rad14. This work further substantiates the indirect lesion-detection mechanism employed by the NER system that recognises destabilised and deformable DNA structures. PMID:27223336

  18. Increased micronuclei and bulky DNA adducts in cord blood after maternal exposures to traffic-related air pollution

    DEFF Research Database (Denmark)

    Pedersen, M.; Wichmann, J.; Autrup, H.;

    2009-01-01

    highest among mother-newborn pairs who lived near medium-traffic-density (> 400-2500 vehicle km/24 h; p <0.01) places. MN frequencies among newborns from women who lived at high-traffic-density homes ( > 2500 vehicle km/24 h) were significantly increased (p = 0.02). This trend remained after adjusting for......Exposure to traffic-related air pollution in urban environment is common and has been associated with adverse human health effects. In utero exposures that result in DNA damage may affect health later in life. Early effects of maternal and in utero exposures to traffic-related air pollution were...... assessed through the use of validated biomarkers in blood cells from mother-newborn pairs. A cross-sectional biomonitoring study with healthy pregnant women living in the Greater Copenhagen area, Denmark, was conducted. Bulky DNA adducts and micronuclei (MN) were measured in blood from 75 women and 69...

  19. 32P-postlabeling assay for carcinogen-DNA adducts: description of beta shielding apparatus and semi-automatic spotting and washing devices that facilitate the handling of multiple samples

    International Nuclear Information System (INIS)

    The utilization of the 32P-postlabeling assay in combination with TLC for the sensitive detection and estimation of aromatic DNA adducts has been increasing. The procedure consists of 32P-labeling of carcinogen-adducted 3'-nucleotides in the DNA digests using γ-32P ATP and polynucleotide kinase, separation of 32P-labeled adducts by TLC, and their detection by autoradiography. During both 32P-labeling and initial phases of TLC, a relatively high amount of γ-32P ATP is handled when 30 samples are processed simultaneously. We describe the design of acrylic shielding apparatus, semi-automatic TLC spotting devices, and devices for development and washing of multiple TLC plates, which not only provide substantial protection from exposure to 32P beta radiation, but also allow quick and easy handling of a large number of samples. Specifically, the equipment includes: (i) a multi-tube carousel rack having 15 wells to hold capless Eppendorf tubes and a rotatable lid with an aperture to access individual tubes; (ii) a pipette shielder; (iii) two semi-automatic spotting devices to apply radioactive solutions to TLC plates; (iv) a multi-plate holder for TLC plates; and (v) a mechanical device for washing multiple TLC plates. Item (i) is small enough to be held in one-hand, vortexed, and centrifuged to mix the solutions in each tube while beta radiation is shielded. Items (iii) to (iv) aid in the automation of the assay. (author)

  20. Analysis of biomarkers in a Czech population exposed to heavy air pollution. Part I. Bulky DNA adducts

    Czech Academy of Sciences Publication Activity Database

    Rössner ml., Pavel; Švecová, Vlasta; Schmuczerová, Jana; Milcová, Alena; Tabashidze, Nana; Topinka, Jan; Pastorková, Anna; Šrám, Radim

    2013-01-01

    Roč. 28, č. 1 (2013), s. 89-95. ISSN 0267-8357 R&D Projects: GA MŽP(CZ) SP/1B3/8/08; GA MŠk 2B08005; GA ČR GAP503/11/0084 Institutional research plan: CEZ:AV0Z50390703 Institutional support: RVO:68378041 Keywords : Air pollution * biomarkers * DNA adducts Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.497, year: 2013

  1. Resistance to Nucleotide Excision Repair of Bulky Guanine Adducts Opposite Abasic Sites in DNA Duplexes and Relationships between Structure and Function.

    Directory of Open Access Journals (Sweden)

    Zhi Liu

    Full Text Available The nucleotide excision repair of certain bulky DNA lesions is abrogated in some specific non-canonical DNA base sequence contexts, while the removal of the same lesions by the nucleotide excision repair mechanism is efficient in duplexes in which all base pairs are complementary. Here we show that the nucleotide excision repair activity in human cell extracts is moderate-to-high in the case of two stereoisomeric DNA lesions derived from the pro-carcinogen benzo[a]pyrene (cis- and trans-B[a]P-N2-dG adducts in a normal DNA duplex. By contrast, the nucleotide excision repair activity is completely abrogated when the canonical cytosine base opposite the B[a]P-dG adducts is replaced by an abasic site in duplex DNA. However, base excision repair of the abasic site persists. In order to understand the structural origins of these striking phenomena, we used NMR and molecular spectroscopy techniques to evaluate the conformational features of 11mer DNA duplexes containing these B[a]P-dG lesions opposite abasic sites. Our results show that in these duplexes containing the clustered lesions, both B[a]P-dG adducts adopt base-displaced intercalated conformations, with the B[a]P aromatic rings intercalated into the DNA helix. To explain the persistence of base excision repair in the face of the opposed bulky B[a]P ring system, molecular modeling results suggest how the APE1 base excision repair endonuclease, that excises abasic lesions, can bind productively even with the trans-B[a]P-dG positioned opposite the abasic site. We hypothesize that the nucleotide excision repair resistance is fostered by local B[a]P residue-DNA base stacking interactions at the abasic sites, that are facilitated by the absence of the cytosine partner base in the complementary strand. More broadly, this study sets the stage for elucidating the interplay between base excision and nucleotide excision repair in processing different types of clustered DNA lesions that are substrates of

  2. Detection of environmental carcinogens-DNA

    International Nuclear Information System (INIS)

    It has been estimated that majority of human cancer is due to environmental factors including pollutants in air, soil, water and food, work places exposure and personal habits such as smoking. After penetration in organism, xenobiotics could be directly excreted or are bio transformed by oxidation or reduction in more hydrophilic compounds which could be conjugate and then eliminated in urine. But in some case, the biotransformation leads to electrophilic compounds which interact with macromolecules such as DNA, forming addition products named adduct. The 32P post-labelling method, inspired by recent developments in the methodology for sequencing nucleic acids, is an extremely sensitive method for assessing and quantifying DNA adducts and is applicable to structurally diverse classes of chemicals. In the first study, we have analysed hepatic DNA from fish living in the River Rhone downstream and upstream from a polychlorinated biphenyl incineration plant. Our results suggest that fish are exposed to genotoxic chemicals. In another study, leave DNA from healthy and declining hop were analysed. The total adduct level is 3 time higher in declining hop. A comparison between DNA adducts from several vegetal cells cultured in presence of heptachlor and DNA adduct in declining hop, confirmed the implication of heptachlor. In these examples, our data indicate the usefulness of the 32 P-post labelling method to assess the contamination of the environment by genotoxic pollutants. Epidemiological data suggested that increasing exposure to airborne PAH contributes to increase risk cancer in this population. Exposure-dependent adducts were detected in while blood cells in coke oven workers. The adduct levels is function of the level of pollutant. In the last example we have analysed lung tissue from patient with cancer. We observed many adducts in peritumoral tissue, while few adducts could be detected in tumoral tissues. (author)

  3. Biomarkers of exposure to tobacco smoke and environmental pollutants in mothers and their transplacental transfer to the foetus. Part I: Bulky DNA adducts

    International Nuclear Information System (INIS)

    32P-postlabelling and PAH-ELISA using the antiserum no. 29 were employed to analyze DNA adducts in venous and umbilical cord blood and the placenta of 79 mothers giving birth to 80 living babies in Prague (Czech Republic). Ambient air exposure was measured by stationary measurements of basic air pollutants (PM2.5, c-PAHs) during the entire pregnancy. Tobacco smoke exposure was assessed by questionnaire data and by plasma cotinine levels. The total DNA adduct levels in the lymphocytes of mothers and newborns were elevated by 30-40% (p 8 nucleotides vs. 0.15 ± 0.06 adducts/108 nucleotides) with newborns indicated a 30-40% increase of adducts in mothers. Almost equal PAH-DNA adduct levels were detected by anti-BPDE-DNA ELISA in the placenta of tobacco smoke-exposed and -unexposed mothers. Our results suggest a protective effect of the placental barrier against the genotoxic effect of some tobacco smoke components between the circulation of mother and child. We found a correlation between adduct levels in the blood of mothers and newborns.

  4. Interaction between CYP1A1 polymorphisms and exposure to environmental tobacco smoke in the modulation of lymphocyte bulky DNA adducts and chromosomal aberrations

    Czech Academy of Sciences Publication Activity Database

    Georgiadis, P.; Topinka, Jan; Vlachodimitropoulos, D.; Stoikidou, M.; Gioka, M.; Stephanou, G.; Autrup, H.; Demopoulos, N. A.; Katsouyanni, K.; Šrám, Radim; Kyrtopoulos, S. A.

    2005-01-01

    Roč. 26, č. 1 (2005), s. 93-101. ISSN 0143-3334 Institutional research plan: CEZ:AV0Z50390512 Keywords : DNA adducts * aberrant cells Subject RIV: DI - Air Pollution ; Quality Impact factor: 5.108, year: 2005

  5. Biomarkers of exposure to tobacco smoke and environmental pollutants in mothers and their transplacental transfer to the foetus. Part I: Bulky DNA adducts

    Czech Academy of Sciences Publication Activity Database

    Topinka, Jan; Milcová, Alena; Líbalová, Helena; Nováková, Zuzana; Rössner ml., Pavel; Balascak, I.; Šrám, Radim

    2009-01-01

    Roč. 669, 1-2 (2009), s. 13-19. ISSN 0027-5107 R&D Projects: GA MŠk 2B06088 Institutional research plan: CEZ:AV0Z50390512 Keywords : DNA adducts * PAHs * complex mixtures Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.556, year: 2009

  6. Mechanochemical and solution synthesis, X-ray structure and IR and 31P solid state NMR spectroscopic studies of copper(I) thiocyanate adducts with bulky monodentate tertiary phosphine ligands.

    Science.gov (United States)

    Bowmaker, Graham A; Hanna, John V; Hart, Robert D; Healy, Peter C; King, Scott P; Marchetti, Fabio; Pettinari, Claudio; Skelton, Brian W; Tabacaru, Aurel; White, Allan H

    2012-07-01

    A number of adducts of copper(I) thiocyanate with bulky tertiary phosphine ligands, and some nitrogen-base solvates, were synthesized and structurally and spectroscopically characterised. CuSCN:PCy3 (1:2), as crystallized from pyridine, is shown by a single crystal X-ray study to be a one-dimensional polymer ...(Cy3P)2CuSCN(Cy3P)2CuSCN... (1) with the four-coordinate copper atoms linked end-on by S-SCN-N bridging thiocyanate groups. A second form (2), obtained from acetonitrile, was also identified and shown by IR and 31P CPMAS NMR spectroscopy to be mononuclear, with the magnitude of the dν(Cu) parameter measured from the 31P CPMAS and the ν(CN) value from the IR clearly establishing this compound as three-coordinate [(Cy3P)2CuNCS]. Two further CuSCN/PCy3 compounds CuSCN:PCy3 (1:1) (3), and CuSCN:PCy3:py (1:1:1) (4) were also characterized spectroscopically, with the dν(Cu) parameters indicating three- and four-coordinate copper sites, respectively. Attempts to obtain a 1:2 adduct with tri-t-butylphosphine have yielded, from pyridine, the 1:1 adduct as a dimer [(Bu(t)3P)((SCN)(NCS))Cu(PBu(t)3)] (5), while similar attempts with tri-o-tolylphosphine (from acetonitrile and pyridine (= L)) resulted in solvated 1:1:1 CuSCN:P(o-tol)3:L forms as dimeric [{(o-tol)3P}LCu((SCN)(NCS))CuL{P(o-tol)3}] (6 and 8). The solvent-free 1:1 CuSCN:P(o-tol)3 adduct (7), obtained by desolvation of 6, was characterized spectroscopically and dν(Cu) measurements from the 31P CPMAS NMR data are consistent with the decrease in coordination number of the copper atom from four (for 6) (P,N(MeCN)Cu,S,N) to three (for 7) (PCuS,N) upon loss of the acetonitrile of solvation. These results are compared with those previously reported for mononuclear and binuclear PPh3 adducts which demonstrate a clear tendency for the copper centre to remain four-coordinate. The IR spectroscopic measurements on these compounds show that bands in the far-IR spectra provide a much more definitive criterion for

  7. The N(2)-Furfuryl-deoxyguanosine Adduct Does Not Alter the Structure of B-DNA.

    Science.gov (United States)

    Ghodke, Pratibha P; Gore, Kiran R; Harikrishna, S; Samanta, Biswajit; Kottur, Jithesh; Nair, Deepak T; Pradeepkumar, P I

    2016-01-15

    N(2)-Furfuryl-deoxyguanosine (fdG) is carcinogenic DNA adduct that originates from furfuryl alcohol. It is also a stable structural mimic of the damage induced by the nitrofurazone family of antibiotics. For the structural and functional studies of this model N(2)-dG adduct, reliable and rapid access to fdG-modified DNAs are warranted. Toward this end, here we report the synthesis of fdG-modified DNAs using phosphoramidite chemistry involving only three steps. The functional integrity of the modified DNA has been verified by primer extension studies with DNA polymerases I and IV from E. coli. Introduction of fdG into a DNA duplex decreases the Tm by ∼1.6 °C/modification. Molecular dynamics simulations of a DNA duplex bearing the fdG adduct revealed that though the overall B-DNA structure is maintained, this lesion can disrupt W-C H-bonding, stacking interactions, and minor groove hydrations to some extent at the modified site, and these effects lead to slight variations in the local base pair parameters. Overall, our studies show that fdG is tolerated at the minor groove of the DNA to a better extent compared with other bulky DNA damages, and this property will make it difficult for the DNA repair pathways to detect this adduct. PMID:26650891

  8. Modulation of the Effect of Prenatal PAH Exposure on PAH-DNA Adducts in Cord Blood by Plasma Antioxidants

    OpenAIRE

    Kelvin, Elizabeth A.; Edwards, Susan; Jedrychowski, Wieslaw; Schleicher, Rosemary L.; Camann, David; Tang, Deliang; Perera, Frederica P.

    2009-01-01

    The fetus is more susceptible than the adult to the effects of certain carcinogens, such as polycyclic aromatic hydrocarbons (PAH). Nutritional factors, including antioxidants, have been shown to have a protective effect on carcinogen-DNA adducts and cancer risk in adults. We investigated whether the effect of prenatal airborne PAH exposure, measured by personal air monitoring during pregnancy, on the level of PAH-DNA adducts in a baby's cord blood is modified by the concentration of micronut...

  9. Benzo(a)pyrene diolepoxide-DNA adducts detected by synchronous fluorescence spectrophotometry.

    OpenAIRE

    Vahakangas, K.; Trivers, G; Rowe, M.; Harris, C. C.

    1985-01-01

    Using benzo(a)pyrene (BP) as a model carcinogen we are currently applying a fluorescence technique to detect the very low levels of carcinogen-DNA adducts in human populations due to environmental exposure. In synchronous fluorescence spectrophotometry for detection of BP-diol epoxide-DNA, excitation and emission wavelengths are scanned simultaneously with a fixed wavelength difference (delta lambda) of 34 nm. Compared to conventional fluorescence methods only one peak emerges because excitat...

  10. Sperm DNA oxidative damage and DNA adducts.

    Science.gov (United States)

    Jeng, Hueiwang Anna; Pan, Chih-Hong; Chao, Mu-Rong; Lin, Wen-Yi

    2015-12-01

    The objective of this study was to investigate DNA damage and adducts in sperm from coke oven workers who have been exposed to polycyclic aromatic hydrocarbons. A longitudinal study was conducted with repeated measurements during spermatogenesis. Coke-oven workers (n=112) from a coke-oven plant served the PAH-exposed group, while administrators and security personnel (n=67) served the control. Routine semen parameters (concentration, motility, vitality, and morphology) were analyzed simultaneously; the assessment of sperm DNA integrity endpoints included DNA fragmentation, bulky DNA adducts, and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo). The degree of sperm DNA fragmentation was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and sperm chromatin structure assay (SCSA). The PAH-exposed group had a significant increase in bulky DNA adducts and 8-oxo-dGuo compared to the control subjects (Ps=0.002 and 0.045, respectively). Coke oven workers' percentages of DNA fragmentation and denaturation from the PAH-exposed group were not significantly different from those of the control subjects (Ps=0.232 and 0.245, respectively). Routine semen parameters and DNA integrity endpoints were not correlated. Concentrations of 8-oxo-dGuo were positively correlated with percentages of DNA fragmentation measured by both TUNEL and SCSA (Ps=0.045 and 0.034, respectively). However, the concentrations of 8-oxo-dGuo and percentages of DNA fragmentation did not correlate with concentrations of bulky DNA adducts. In summary, coke oven workers with chronic exposure to PAHs experienced decreased sperm DNA integrity. Oxidative stress could contribute to the degree of DNA fragmentation. Bulky DNA adducts may be independent of the formation of DNA fragmentation and oxidative adducts in sperm. Monitoring sperm DNA integrity is recommended as a part of the process of assessing the impact of occupational and environmental toxins on sperm

  11. Role of retinoic acid in the modulation of benzo(a)pyrene-DNA adducts in human hepatoma cells: Implications for cancer prevention

    International Nuclear Information System (INIS)

    Carcinogen-DNA adducts could lead to mutations in critical genes, eventually resulting in cancer. Many studies have shown that retinoic acid (RA) plays an important role in inducing cell apoptosis. Here we have tested the hypothesis that levels of carcinogen-DNA adducts can be diminished by DNA repair and/or by eliminating damaged cells through apoptosis. Our results showed that the levels of total DNA adducts in HepG2 cells treated with benzo(a)pyrene (BP, 2 μM) + RA (1 μM) were significantly reduced compared to those treated with BP only (P = 0.038). In order to understand the mechanism of attenuation of DNA adducts, further experiments were performed. Cells were treated with BP (4 μM) for 24 h to initiate DNA adduct formation, following which the medium containing BP was removed, and fresh medium containing 1 μM RA was added. The cells were harvested 24 h after RA treatment. Interestingly, the levels of total DNA adducts were lower in the BP/RA group (390 ± 34) than those in the BP/DMSO group (544 ± 33), P = 0.032. Analysis of cell apoptosis showed an increase in BP + RA group, compared to BP or RA only groups. Our results also indicated that attenuation of BP-DNA adducts by RA was not primarily due to its effects on CYP1A1 expression. In conclusion, our results suggest a mechanistic link between cellular apoptosis and DNA adduct formation, phenomena that play important roles in BP-mediated carcinogenesis. Furthermore, these results help understand the mechanisms of carcinogenesis, especially in relation to the chemopreventive properties of nutritional apoptosis inducers.

  12. Measuring bulky waste arisings in Hong Kong

    International Nuclear Information System (INIS)

    All too often, waste authorities either assume that they know enough about their bulky waste stream or that it is too insignificant to deserve attention. In this paper, we use Hong Kong as an example to illustrate that official bulky waste figures can actually be very different from the reality and therefore important waste management decisions made based on such statistics may be wrong too. This study is also the first attempt in Hong Kong to outline the composition of bulky waste. It was found that about 342 tonnes/day of wood waste were omitted by official statistics owing to incomplete records on actual bulky waste flow. This is more than enough to provide all the feedstock needed for one regular-sized wood waste recycling facility in Hong Kong. In addition, the proportion of bulky waste in the municipal solid waste (MSW) streams in Hong Kong should be about 6.1% instead of the officially stated 1.43%. Admittedly, there are limitations with this study. Yet, present findings are suggestive of significant MSW data distortion in Hong Kong.

  13. Carcinogen-DNA interaction study by base sequence footprinting. Progress report, July 1, 1985-January 21, 1986

    International Nuclear Information System (INIS)

    Acetyl-aminofluorene (AAF) modified plasmid pSV2 CAT is being studied to learn how the adducts influence expression of chloramphenicol acetyltransferase (CAT) genes. phi X-174 RF DNA exhibits specific base sequence abnormalities induced by the formation of AAF adducts. The DNAase I sensitive state of AAF modified DNA sequences could presumably lead to enhanced expression of genes since it is a well-known characteristic of active or potentially active derepressed genes. DNAase I hypersensitive sites are necessary but not sufficient for transcription. We observed enhanced expression of CAT genes in CV-1 cells after transfection with modified plasmids, using electroporation to introduce the plasmids into the cells. 34 refs., 2 figs

  14. DNA adducts and cancer risk in prospective studies: a pooled analysis and a meta-analysis

    DEFF Research Database (Denmark)

    Veglia, Fabrizio; Loft, Steffen; Matullo, Giuseppe; Peluso, Marco; Munnia, Armelle; Perera, Frederica; Phillips, David H; Tang, Deliang; Autrup, Herman; Raaschou-Nielsen, Ole; Tjønneland, Anne; Vineis, Paolo

    2008-01-01

    Bulky DNA adducts are biomarkers of exposure to aromatic compounds and of the ability of the individual to metabolically activate carcinogens and to repair DNA damage. Their ability to predict cancer onset is uncertain. We have performed a pooled analysis of three prospective studies on cancer risk...... in which bulky DNA adducts have been measured in blood samples collected from healthy subjects (N = 1947; average follow-up 51-137 months). In addition, we have performed a meta-analysis by identifying all articles on the same subject published up to the end of 2006, including case-control studies....... In the pooled analysis, a weakly statistically significant increase in the risk of lung cancer was apparent (14% per unit standard deviation change in adduct levels, 95% confidence interval 1-28%; using the weighted mean difference method, 0.15 SD, units higher adducts in cases than in controls). The...

  15. DNA adduct measurements in zebra mussels, Dreissena polymorpha, Pallas

    International Nuclear Information System (INIS)

    The purpose of this study was to examine PAH accumulation and bulky DNA adduct formation in the digestive gland of zebra mussels exposed in their habitat or in controlled laboratory conditions to complex mixture of PAH. DNA adducts were measured using a 32P-postlabelling protocol with nuclease P1 enrichment adapted from Reddy and Randerath [Reddy, M.V., Randerath, K., 1986. Nuclease P1-mediated enhancement of sensitivity of 32P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551]. Specimens collected in the upper part of the Seine estuary were shown to accumulate higher levels of PAH (up to 1.6 μg g-1 dry weight) in comparison to individuals from the reference site (0.053 μg g-1 dry weight). The former exhibited elevated levels of DNA adducts (up to 4.0/108 nucleotides) and higher diversity of individual adducts with five distinct spots being specifically detected in individuals originating from the Seine estuary. Zebra mussels exposed for 5 days to 0.01% (v/v) of organic extract of sediment from the Seine estuary were shown to accumulate high amounts of PAH (up to 138 μg g-1 dry weight) but exhibited relatively low levels of DNA adducts. Exposure to benzo[a]pyrene led to a dose-dependent accumulation of B[a]P (up to 7063 μg g-1 dry weight) and a clear induction of DNA adduct formation in the digestive gland of mussels (up to 1.13/108 nucleotides). Comparisons with other bivalves exposed to the same model PAH, revealed similar levels of adducts and comparable adduct profiles with a main adduct spot and a second faint one. This study clearly demonstrated that zebra mussels are able to biotransform B[a]P and probably other PAH into reactive metabolites with DNA-binding activity. This work also demonstrated the applicability of the nuclease P1 enhanced 32P-postlabelling method for bulky adduct detection in the digestive gland of zebra mussels. DNA adduct measurement in zebra mussels could be a suitable biomarker to monitor PAH

  16. Carcinogen-DNA interaction study by base sequence footprinting. Final report, July 1, 1983-June 30, 1986

    International Nuclear Information System (INIS)

    Our previous studies on acetylaminofluorene (AAF) modified DNA demonstrated three kinds of structural changes in DNA of defined base sequence. For example, adduct formation by N-Aco-AAF was found at each guanine. We studied the interaction of IgG specific for AAF guanosine in an in vitro system using AAF modified phi X-174 rf DNA. We had expected to find protection against DNAase I digestion. Instead, when the DNA was immunobound to an inert matrix via the IgG, DNAase I digestion was enhanced 20 fold without changing the base sequence pattern of digestion. DNAase I hypersensitive sites are a necessary but not a sufficient condition for transcription. Moreover, some hypersensitive sites are stably propagated, independent of the continued presence of the inducer. Stability of these hypersensitive sites in the absence of their inducer suggests that they can be propagated. It appeared likely that distortion of DNA by a carcinogen adduct such as AAF, and the interaction of this modified DNA with a specific protein such as IgG or cellular proteins might inappropriately enhance the transcription of specific genes. That hypothesis will be tested; surprisingly, little is known about the early action of carcinogens on expression of specific genes. 34 refs., 2 figs., 1 tab

  17. A new sensitive 32P-postlabeling assay based on the specific enzymatic conversion of bulky DNA lesions to radiolabeled dinucleotides and nucleoside 5'-monophosphates

    International Nuclear Information System (INIS)

    A new sensitive 32P-postlabelling assay for DNA adducts has been developed. When DNA containing bulky adducts, X1, X2, .....Xn, is digested with nuclease P1 at pH 5, normal nucleotides are released as 5'-monophosphates, pN, while adducts are excised as 5'-phosphorylated dinucleotides, pXipN, because inter-nucleotide linkages on the 3' side of X resist attack by nuclease P1. Addition of prostatic acid phosphatase to such a digest results in 5'-dephosphorylation of the nucleotides to normal nucleosides, N, and adducted dinucleotides, XipN, carrying a 5'-terminal free hydroxyl group. The dinucleotides but not nucleosides are converted to 5'-32P-labeled dinucleotides,[32P]pXipN, by T4 polynucleotide kinase-catalyzed [32P]posphate transfer from [γ-32P]ATP. Upon mapping on polyethyleneimine-cellulose anion-exchange TLC, the labeled dinucleotide adducts produce characteristic autoradiographic fingerprints. Alternatively, they are further digested with snake venom phosphodiesterase to yield 5'-monophosphates, [32P]pXi and pN. TLC profiles of the monophosphate adducts are distinct from those of the dinucleotides. These reactions provide the basis of the new 32P-postlabeling scheme, which is compared in this paper with a previously reported protocol yielding adducts in the form of 5'-32P-labeled 3',5'-bisphosphates, [32P]pXip. (author)

  18. Bulky waste quantities and treatment methods in Denmark

    DEFF Research Database (Denmark)

    Larsen, Anna Warberg; Petersen, Claus; Christensen, Thomas Højlund

    2012-01-01

    Bulky waste is a significant and increasing waste stream in Denmark. However, only little research has been done on its composition and treatment. In the present study, data about collection methods, waste quantities and treatment methods for bulky waste were obtained from two municipalities. In...... addition a sorting analysis was conducted on combustible waste, which is a major fraction of bulky waste in Denmark. The generation of bulky waste was found to be 150–250 kg capita−1 year−1, and 90% of the waste was collected at recycling centres; the rest through kerbside collection. Twelve main fractions...

  19. Acetaldehyde adducts with hemoglobin.

    OpenAIRE

    Stevens, V.J.; Fantl, W J; Newman, C B; Sims, R V; Cerami, A.; Peterson, C M

    1981-01-01

    Clinical studies on the minor hemoglobins (hemoglobin A1a-c) have suggested that a novel adduct may form in people abusing alcohol. Such patients were found to have an elevated concentration of minor hemoglobins, but normal or subnormal amounts of glycosylated hemoglobin (hemoglobin A1c) as determined by radioimmunoassay, Acetaldehyde, a reactive metabolite of ethanol, was postulated to form adducts with hemoglobin A that change its chromatographic properties. At physiological concentrations,...

  20. Bulky PAH-DNA induced by exposure of a co-culture model of human alveolar macrophages and embryonic epithelial cells to atmospheric particulate pollution

    International Nuclear Information System (INIS)

    Because of their deep penetration in human lungs, fine airborne particulate matter were described as mainly responsible for the deleterious effects of exposure to air pollution on health. Organic constituents are adsorbed on particles surface and, after inhalation, some (polycyclic aromatic hydrocarbons, PAHs) can be activated into reactive metabolites and can bind to DNA. The formation of bulky DNA adducts has been researched after exposure of mono-and co-cultures of alveolar macrophages (AM) and human embryonic human lung epithelial (L132), to fine air pollution particulate matter Air samples have been collected with cascade impactor and characterized: size distribution (92.15% 2/g), inorganic (Fe, AI, Ca, Na, K, Mg, Pb, etc.) and organic compounds (PAHs, etc.). 32P post-labeling method was applied to detect bulky DNA adducts in AM and L132, in mono-and co-cultures, 72 h after their exposure to atmospheric particles at their Lethals and Effects concentrations or (LC or CE) to 50% (i.e. MA: EC50 = 74.63 μg/mL and L132: LC-5-0 = 75.36 μg/mL). Exposure to desorbed particles (MA: C1= 61.11 μg/mL and L132 : C2 = 61.71 μg/mL) and B[a]P (1 μM) were included. Bulky PAH-DNA adducts were detected in AM in mono-culture after exposure to total particles (Pt), to B[a]P and desorbed particles (Pd). Whatever the exposure, no DNA adduct was detected in L132 in mono-culture. These results are coherent with the enzymatic activities of cytochrome P450 l Al in AM and L132. Exposure of co-culture to Pt, or Pd induced bulky adducts to DNA in AM but not in L132. Exposure to B[a]P alone has altered the DNA of AM and L132, in co-culture. Exposure to Pt is closer to the environmental conditions, but conferred an exposure to amounts of genotoxic agents compared to studies using organic extracts. The formation of bulky DNA adducts was nevertheless observed in AM exposed to Pt, in mono- or co-culture, indicating that they were competent in terms of metabolic activation of PAHs. The DNA

  1. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon

    DEFF Research Database (Denmark)

    1979-01-01

    Aflatoxin B1 and benzo(a)pyrene were activated by both cultured human bronchus and human colon as measured by binding to cellular DNA and protein. The binding of aflatoxin B1 to DNA was dose dependent, and the level of binding was higher in cultured human bronchus than it was in the colon. When...... found in these two peaks, and the ratio of radioactivity between the peaks was nearly 1. In colonic DNA, the ratio between Structures 1 and 11 was approximately 2. These observations add aflatoxin B1 to the list of chemical procarcinogens metabolized by cultured human tissues and in which the carcinogen-DNA...... adducts are similar to the adducts formed in animal tissue susceptible to the carcinogenic action of aflatoxin B1....

  2. The effect of plant phenolics on the formation of 7,12-dimethylbenz[a]anthracene-DNA adducts and TPA-stimulated polymorphonuclear neutrophils chemiluminescence in vitro

    International Nuclear Information System (INIS)

    Phenolics, common plant constituents, form up an important part of human diet and are considered potential chemopreventive agents. In the present study, structurally diverse phenolics, such as tannic acid, protocatechuic acid, chlorogenic acid and resveratrol, were investigated for their inhibitory effects on covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) to DNA in vitro and the suppression of oxidative burst in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated human polymorphonuclear neutrophils (PMNs). 32P-postlabeling analysis of DNA incubated with DMBA in the presence of 3-methylcholanthrene (3-MC)-induced microsomes produced three major adducts derived from anti-, syn- and anti-dihydrodiol epoxides through reactions with dGuo and dAdo, respectively. Phenolic compounds at the concentration of 150 μM reduced the levels of all DMBA-DNA adducts by 55-98%. The most dramatic effect was observed in case of tannic acid, which completely inhibited the formation of DMBA-dAdo adducts. Chlorogenic acid was the least effective inhibitor of DMBA-DNA adducts formation particularly syn-DMBADE-dAdo (20%). Human neutrophils showed a significant dose-related decrease of TPA-induced chemiluminescence after pretreatment with phenolic compounds. The most effective inhibitors were tannic acid and resveratrol with IC50=5.19 and 5.76 μM, respectively. These results suggest that the suppression of reactive oxygen species (ROS) and carcinogen-DNA adducts formation may be important for anticarcinogenic activity of the examined phenolics

  3. DNA adducts as molecular dosimeters

    International Nuclear Information System (INIS)

    There is compelling evidence that DNA adducts play an important role in the actions of many pulmonary carcinogens. During the last ten years sensitive methods (antibodies and 32P-postlabeling) have been developed that permit detection of DNA adducts in tissues of animals or humans exposed to low levels of some genotoxic carcinogens. This capability has led to approaches designed to more reliably estimate the shape of the dose-response curve in the low dose region for a few carcinogens. Moreover, dosimetry comparisions can, in some cases, be made between animals and humans which help in judging the adequacy of animal models for human risk assessments. There are several points that need to be considered in the evaluation of DNA adducts as a molecular dosimeter. For example, DNA adduct formation is only one of many events that are needed for tumor development and some potent carcinogens do not form DNA adducts; i.e., TCDD. Other issues that need to be considered are DNA adduct heterogeneity, DNA repair, relationship of DNA adducts to somatic mutation and cell specificity in DNA adduct formation and persistence. Molecular epidemiology studies often require quantitation of adducts in cells such as lymphocytes which may or may not be reliable surrogates for adduct concentrations in target issues. In summary, accurate quantitation of low levels of DNA adducts may provide data useful in species to species extrapolation of risk including the development of more meaningful human monitoring programs

  4. DNA adduct measurements in zebra mussels, Dreissena polymorpha, Pallas. Potential use for genotoxicant biomonitoring of fresh water ecosystems.

    Science.gov (United States)

    Le Goff, J; Gallois, J; Pelhuet, L; Devier, M H; Budzinski, H; Pottier, D; André, V; Cachot, J

    2006-08-12

    The purpose of this study was to examine PAH accumulation and bulky DNA adduct formation in the digestive gland of zebra mussels exposed in their habitat or in controlled laboratory conditions to complex mixture of PAH. DNA adducts were measured using a 32P-postlabelling protocol with nuclease P1 enrichment adapted from Reddy and Randerath [Reddy, M.V., Randerath, K., 1986. Nuclease P1-mediated enhancement of sensitivity of 32P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551]. Specimens collected in the upper part of the Seine estuary were shown to accumulate higher levels of PAH (up to 1.6 microg g(-1) dry weight) in comparison to individuals from the reference site (0.053 microg g(-1) dry weight). The former exhibited elevated levels of DNA adducts (up to 4.0/10(8) nucleotides) and higher diversity of individual adducts with five distinct spots being specifically detected in individuals originating from the Seine estuary. Zebra mussels exposed for 5 days to 0.01% (v/v) of organic extract of sediment from the Seine estuary were shown to accumulate high amounts of PAH (up to 138 microg g(-1) dry weight) but exhibited relatively low levels of DNA adducts. Exposure to benzo[a]pyrene led to a dose-dependent accumulation of B[a]P (up to 7063 microg g(-1) dry weight) and a clear induction of DNA adduct formation in the digestive gland of mussels (up to 1.13/10(8) nucleotides). Comparisons with other bivalves exposed to the same model PAH, revealed similar levels of adducts and comparable adduct profiles with a main adduct spot and a second faint one. This study clearly demonstrated that zebra mussels are able to biotransform B[a]P and probably other PAH into reactive metabolites with DNA-binding activity. This work also demonstrated the applicability of the nuclease P1 enhanced 32P-postlabelling method for bulky adduct detection in the digestive gland of zebra mussels. DNA adduct measurement in zebra mussels could be a suitable

  5. Solid state phase detector replaces bulky transformer circuit

    Science.gov (United States)

    Moberly, C. L.

    1967-01-01

    Miniature solid state phase detector using MOSFETs is used in a phase lock loop with a sun-bit detector in an integrated data-link circuit. This replaces bulky transformer circuits. It uses an inverter amplifier, a modulator switch, and a buffer amplifier.

  6. Fullerene–Carbene Lewis Acid–Base Adducts

    KAUST Repository

    Li, Huaping

    2011-08-17

    The reaction between a bulky N-heterocylic carbene (NHC) and C60 leads to the formation of a thermally stable zwitterionic Lewis acid-base adduct that is connected via a C-C single bond. Low-energy absorption bands with weak oscillator strengths similar to those of n-doped fullerenes were observed for the product, consistent with a net transfer of electron density to the C60 core. Corroborating information was obtained using UV photoelectron spectroscopy, which revealed that the adduct has an ionization potential ∼1.5 eV lower than that of C60. Density functional theory calculations showed that the C-C bond is polarized, with a total charge of +0.84e located on the NHC framework and -0.84e delocalized on the C 60 cage. The combination of reactivity, characterization, and theoretical studies demonstrates that fullerenes can behave as Lewis acids that react with C-based Lewis bases and that the overall process describes n-doping via C-C bond formation. © 2011 American Chemical Society.

  7. Bulky mediastinal aspergillosis mimicking cancer in an immunocompetent patient.

    Science.gov (United States)

    Stern, Jean-Baptiste; Wyplosz, Benjamin; Validire, Pierre; Angoulvant, Adela; Fregeville, Aude; Caliandro, Raffaele; Gossot, Dominique

    2014-10-01

    We describe the case of a previously healthy 42-year-old woman who presented with a chronic cough and occasional night sweats. Radiologic exploration showed a bulky mediastinal mass surrounding the aortic arch, associated with a left subclavicular lymph node and a cerebral round lesion, mimicking a disseminated lung cancer. Surgical left subclavicular and computed tomography-guided mediastinal biopsy specimens showed granulomatous patterns. Mycologic culture of both samples grew Aspergillus flavus. Resolution was obtained after 9 months of oral voriconazole therapy. PMID:25282220

  8. Hafnium tetrachloride adducts with aminophenols

    International Nuclear Information System (INIS)

    Adducts of hafnium tetrachloride with aminophenols of a general composition of HfCl4x4L have been obtained by addition of ethyl acetate solutions of hafnium tetrachloride with solutions of o-aminophenol in dioxan, m-aminophenol in ethyl acetate and n-aminophenol in dioxan at a ratio Hf/L=1/2. In the investigated adducts, aminophenols are connected to hafnium both through an oxygen atom and a nitrogen atom, the latter's coordination being preferable. A thermal investigation of synthesized complexes has determined the quantity of heat evolving on addition of 4 moles of aminophenol to 1 mole of crystalline hafnium tetrachloride

  9. Effects of dietary fish oil on the depletion of carcinogenic PAH-DNA adduct levels in the liver of B6C3F1 mouse.

    Directory of Open Access Journals (Sweden)

    Guo-Dong Zhou

    Full Text Available Many carcinogenic polycyclic aromatic hydrocarbons (PAHs and their metabolites can bind covalently to DNA. Carcinogen-DNA adducts may lead to mutations in critical genes, eventually leading to cancer. In this study we report that fish oil (FO blocks the formation of DNA adducts by detoxification of PAHs. B6C3F1 male mice were fed a FO or corn oil (CO diet for 30 days. The animals were then treated with seven carcinogenic PAHs including benzo(apyrene (BaP with one of two doses via a single intraperitoneal injection. Animals were terminated at 1, 3, or 7 d after treatment. The levels of DNA adducts were analyzed by the (32P-postlabeling assay. Our results showed that the levels of total hepatic DNA adducts were significantly decreased in FO groups compared to CO groups with an exception of low PAH dose at 3 d (P = 0.067. Total adduct levels in the high dose PAH groups were 41.36±6.48 (Mean±SEM and 78.72±8.03 in 10(9 nucleotides (P = 0.011, respectively, for the FO and CO groups at 7 d. Animals treated with the low dose (2.5 fold lower PAHs displayed similar trends. Total adduct levels were 12.21±2.33 in the FO group and 24.07±1.99 in the CO group, P = 0.008. BPDE-dG adduct values at 7 d after treatment of high dose PAHs were 32.34±1.94 (CO group and 21.82±3.37 (FO group in 10(9 nucleotides with P value being 0.035. Low dose groups showed similar trends for BPDE-dG adduct in the two diet groups. FO significantly enhanced gene expression of Cyp1a1 in both the high and low dose PAH groups. Gstt1 at low dose of PAHs showed high levels in FO compared to CO groups with P values being 0.014. Histological observations indicated that FO played a hepatoprotective role during the early stages. Our results suggest that FO has a potential to be developed as a cancer chemopreventive agent.

  10. Oxidation of Isoeugenol by Salen Complexes with Bulky Substituents

    Directory of Open Access Journals (Sweden)

    Anika Salanti

    2010-03-01

    Full Text Available The catalytic properties of bulky water-soluble salen complexes in the oxidation of isoeugenol(2-methoxy-4-(1-propenyl phenol have been investigated in aqueous ethanol solutions in order to obtain a mixture of polymeric compounds through dehydrogenative polymerization. The average molecular weight of dehydrogenated polymers (DHPs was monitored by GPC and correlated to reaction conditions such as time, concentration of substrate, concentration of catalyst, type of oxidation agent, etc. The DHP synthesized by adopting the best reaction conditions was characterized by different analytical techniques (GPC, 13C-NMR, 31P-NMR and LC-MS to elucidate its structure. The lignin-like polymer resulting from isoeugenol radical coupling possesses valuable biological activity and finds applications in a variety of fields, such as packaging industry and cultural heritage conservation.

  11. The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions

    Science.gov (United States)

    Mullins, Elwood A.; Shi, Rongxin; Parsons, Zachary D.; Yuen, Philip K.; David, Sheila S.; Igarashi, Yasuhiro; Eichman, Brandt F.

    2015-11-01

    Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-π interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.

  12. Bulky PAH-DNA induced by exposure of a co-culture model of human alveolar macrophages and embryonic epithelial cells to atmospheric particulate pollution; Adduits encombrants a l'ADN dans des cocultures de cellules pulmonaires humaines exposees a une pollution atmospherique particulaire

    Energy Technology Data Exchange (ETDEWEB)

    Abbas, Imane; Garcon, Guillaume; Billet, Sylvain; Shirali, Pirouz [Universite Lille Nord de France - Lille (France); Unite de Chimie Environnementale et Interactions sur le Vivant, MREI, Universite du Littoral Cote d' Opale, Dunkerque (France); Andre, Veronique; Le Goff, Jeremie; Sichel, Francois [GRECAN, Universite de Caen Basse-Normandie et centre Francois Baclesse, Caen (France); Roy Saint-Georges, Francoise; Mulliez, Philippe [Service de Pneumologie, Hopital Saint-Philibert, GHICL, Lille (France)

    2012-01-15

    Because of their deep penetration in human lungs, fine airborne particulate matter were described as mainly responsible for the deleterious effects of exposure to air pollution on health. Organic constituents are adsorbed on particles surface and, after inhalation, some (polycyclic aromatic hydrocarbons, PAHs) can be activated into reactive metabolites and can bind to DNA. The formation of bulky DNA adducts has been researched after exposure of mono-and co-cultures of alveolar macrophages (AM) and human embryonic human lung epithelial (L132), to fine air pollution particulate matter Air samples have been collected with cascade impactor and characterized: size distribution (92.15% < 2.5{mu}.m), specific surface area (1 m{sup 2}/g), inorganic (Fe, AI, Ca, Na, K, Mg, Pb, etc.) and organic compounds (PAHs, etc.). {sup 32}P post-labeling method was applied to detect bulky DNA adducts in AM and L132, in mono-and co-cultures, 72 h after their exposure to atmospheric particles at their Lethals and Effects concentrations or (LC or CE) to 50% (i.e. MA: EC{sub 50} = 74.63 {mu}g/mL and L132: LC-5-0 = 75.36 {mu}g/mL). Exposure to desorbed particles (MA: C1= 61.11 {mu}g/mL and L132 : C2 = 61.71 {mu}g/mL) and B[a]P (1 {mu}M) were included. Bulky PAH-DNA adducts were detected in AM in mono-culture after exposure to total particles (Pt), to B[a]P and desorbed particles (Pd). Whatever the exposure, no DNA adduct was detected in L132 in mono-culture. These results are coherent with the enzymatic activities of cytochrome P450 l Al in AM and L132. Exposure of co-culture to Pt, or Pd induced bulky adducts to DNA in AM but not in L132. Exposure to B[a]P alone has altered the DNA of AM and L132, in co-culture. Exposure to Pt is closer to the environmental conditions, but conferred an exposure to amounts of genotoxic agents compared to studies using organic extracts. The formation of bulky DNA adducts was nevertheless observed in AM exposed to Pt, in mono- or co-culture, indicating that

  13. DNA adducts-chemical addons

    Directory of Open Access Journals (Sweden)

    T R Rajalakshmi

    2015-01-01

    Full Text Available DNA adduct is a piece of DNA covalently bond to a chemical (safrole, benzopyrenediol epoxide, acetaldehyde. This process could be the start of a cancerous cell. When a chemical binds to DNA, it gets damaged resulting in abnormal replication. This could be the start of a mutation and without proper DNA repair, this can lead to cancer. It is this chemical that binds with the DNA is our prime area of concern. Instead of performing the whole body analysis for diagnosing cancer, this test could be carried out for early detection of cancer. When scanning tunneling microscope is used, the DNA results can be obtained earlier. DNA adducts in scientific experiments are used as biomarkers.

  14. DNA adducts-chemical addons.

    Science.gov (United States)

    Rajalakshmi, T R; AravindhaBabu, N; Shanmugam, K T; Masthan, K M K

    2015-04-01

    DNA adduct is a piece of DNA covalently bond to a chemical (safrole, benzopyrenediol epoxide, acetaldehyde). This process could be the start of a cancerous cell. When a chemical binds to DNA, it gets damaged resulting in abnormal replication. This could be the start of a mutation and without proper DNA repair, this can lead to cancer. It is this chemical that binds with the DNA is our prime area of concern. Instead of performing the whole body analysis for diagnosing cancer, this test could be carried out for early detection of cancer. When scanning tunneling microscope is used, the DNA results can be obtained earlier. DNA adducts in scientific experiments are used as biomarkers. PMID:26015708

  15. The boron trifluoride nitromethane adduct

    Science.gov (United States)

    Ownby, P. Darrell

    2004-02-01

    The separation of the boron isotopes using boron trifluoride·organic-donor, Lewis acid·base adducts is an essential first step in preparing 10B enriched and depleted crystalline solids so vital to nuclear studies and reactor applications such as enriched MgB 2, boron carbide, ZrB 2, HfB 2, aluminum boron alloys, and depleted silicon circuits for radiation hardening and neutron diffraction crystal structure studies. The appearance of this new adduct with such superior properties demands attention in the continuing search for more effective and efficient means of separation. An evaluation of the boron trifluoride nitromethane adduct, its thermodynamic and physical properties related to large-scale isotopic separation is presented. Its remarkably high separation factor was confirmed to be higher than the expected theoretical value. However, the reportedly high acid/donor ratio was proven to be an order of magnitude lower. On-going research is determining the crystal structure of deuterated and 11B enriched 11BF 3·CD 3NO 2 by X-ray and neutron diffraction.

  16. Lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions

    Energy Technology Data Exchange (ETDEWEB)

    Nair, Jagadeesan [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); De Flora, Silvio [Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132 Genoa (Italy); Izzotti, Alberto [Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132 Genoa (Italy); Bartsch, Helmut [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany)]. E-mail: h.bartsch@dkfz.de

    2007-08-01

    Atherosclerosis and cancer are characterized by uncontrolled cell proliferation and share common risk factors, such as cigarette smoking, dietary habits and ageing. Growth of smooth muscle cells (SMCs) in atherosclerotic plaques may result from DNA damage, caused either by exogenous mutagens or by agents endogenously generated due to oxidative stress and lipid peroxidation (LPO). Hydroxy-2-nonenal (HNE), a major LPO product, binds covalently to cellular DNA to form the exocyclic etheno-DNA-base adducts, 1,N {sup 6}-ethenodeoxyadenine ({epsilon}dA) and 3,N {sup 4}-ethenodeoxycytosine ({epsilon}dC). By applying an ultrasensitive {sup 32}P-postlabeling-immunoaffinity method, {epsilon}dA and {epsilon}dC were quantified in abdominal aorta SMCs from 13 atherosclerotic patients and 3 non-smoking subjects without atherosclerotic lesions. The levels of etheno-adducts ranged for {epsilon}dA from 2.3 to 39.6/10{sup 8} dA and for {epsilon}dC from 10.7 to 157.7/10{sup 8} dC, with a high correlation between {epsilon}dA and {epsilon}dC (r = 0.84, P = 0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both {epsilon}dA (means 15.2 versus 7.3, P = 0.06) and {epsilon}dC (71.9 versus 51.6, not significant). {epsilon}dC levels were higher in either ex-smokers (P = 0.03) or smokers (P = 0.07) than in non-smokers. There was a poor correlation between either {epsilon}dA or {epsilon}dC and 8-hydroxy-2'-deoxyguanosine, whereas significant positive correlations were detected with the levels of several postlabeled bulky aromatic DNA adducts. In conclusion, two different types of DNA damage may be involved in atherosclerotic plaque formation and progression: (i) bulky aromatic compounds, to which aorta SMCs are chronically exposed in smokers, can either covalently bind to DNA, induce redox-cycling via quinone intermediates and/or activate local chronic inflammatory processes in the arterial wall; ii) this in turn leads to a self perpetuating

  17. Formation of adduct of cerium (4) thenoyltrifluoroacetonate

    International Nuclear Information System (INIS)

    Adduct formation of thenoyltrifluoroacetonate of Ce(4) [Ce(TTFA)4] with seven nitrogen- and oxygen-containing donor additional ligands is studied using the methods of IR-spectroscopy, derivatography, X-ray phase analysis. The presence of formation of Ce(TTFA)4 adducts with phosphorus-containing additional ligands tributyl phosphate (TBP), trioctylphosphine oxide (TOPO), triphenylphosphine oxide (TPPO); α, α'-dipyridyl (Dipy) and o-phenanthroline (Phen) is established. The adduct Ce(TTFA)4 stable to reduction is formed with Dipy, and in the case of Phen, TBP, TOPO, TPPO in the process of adduct formation the reduction of Ce(4) to Ce(3) takes place

  18. Tomography of actinides by photofission in bulky radioactive waste packages

    International Nuclear Information System (INIS)

    Quantifying actinides using non-destructive methods, in radioactive waste packages, is a great stake to turn packages towards appropriate storage facility. But the nature of radiations emitted by actinides (alpha radiations) makes the detection of those very difficult for large volume packages characterization. Indeed, the emitted radiation is too weak, either to be detected by emission tomography or to reach required sensitivities. Therefore, it is necessary to turn to an external probing source. Tomography based on detection of delayed neutrons induced by photofission, allows to probe bulky packages. We demonstrate the suitability of this method to an industrial stage. Firstly, we determine and qualify projection matrix which connects measures at reconstructed activity of tomographic picture. Thus, during measurements on a model and a real package, we carry out convincing tomographic reconstructions with real acquisition conditions. More, we prove that it is possible to take all disruptive chemical element into account, for tomographic reconstructions, in order to obtain the best image of activity. So, we propose a finalised tomographic device, integrating a shielding cell, and checking all the activity and distribution activity criterions fixed for acceptance of radioactive waste packages in superficial storage facility. (author)

  19. Surgical Management of Bulky Mediastinal Metastases in Follicular Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Zainal Adwin

    2016-01-01

    Full Text Available Follicular thyroid adenoma and carcinoma are very common. Benign and malignant lesions are usually indistinguishable from cytology alone and often require confirmatory resection. The spread of follicular carcinoma is usually hematogenous and is treated with surgery and adjuvant radioactive iodine. Very rarely, metastases occur in the mediastinum. Patients usually present with severe compressive symptoms. With proper treatment and follow-up, the prognosis for these type of thyroid malignancies is excellent. In the case presented here, our patient presented to the Universiti Kebangsaan Malaysia Medical Center with a progressively enlarging anterior neck swelling. The swelling had started 10 years before his presentation. We diagnosed him with an advanced thyroid malignancy with bulky mediastinal metastases. After extensive investigations and counseling, we chose to treat the patient with tumor excision and mediastinal metastases resection. Typically, mediastinal resection involves the removal of the sternum and use of an acrylic implant to recreate the sternum. In this case, the sternum and ribs were removed with subsequent myocutaneous flap coverage for the wound defect. Our experience represents an alternative treatment option in cases where implant use is unsuitable.

  20. DNA adducts-chemical addons

    OpenAIRE

    T. R. Rajalakshmi; N AravindhaBabu; Shanmugam, K. T.; Masthan, K. M. K.

    2015-01-01

    DNA adduct is a piece of DNA covalently bond to a chemical (safrole, benzopyrenediol epoxide, acetaldehyde). This process could be the start of a cancerous cell. When a chemical binds to DNA, it gets damaged resulting in abnormal replication. This could be the start of a mutation and without proper DNA repair, this can lead to cancer. It is this chemical that binds with the DNA is our prime area of concern. Instead of performing the whole body analysis for diagnosing cancer, this test could b...

  1. Bilateral failure of adduction following orbital decompression.

    OpenAIRE

    Kinsella, F; Kyle, P.; Stansfield, A

    1990-01-01

    We report a case of bilateral complete failure of adduction following bilateral translid antralethmoidal orbital decompression. We believe the probable mechanism is neuropraxia (temporary dysfunction) of the third cranial nerves' supply to the medial recti, owing to these nerves' occupying an anatomically abnormal position. Partial recovery of adduction occurred over the ensuing six months.

  2. Underlying structure of bulky oxide nodule on alumina-forming austenitic stainless steel

    International Nuclear Information System (INIS)

    The bulky oxide nodule and its underlying structure were investigated in an alumina-forming austenitic steel exposed to dry air at 1053 K for 336 h. Some bulky oxide nodules were found to be attached on globular phases in the matrix. By combined application of electron backscattering diffraction and energy dispersive X-ray spectroscopy, the bulky nodule was identified as Cr-rich M3O4 underlying which was Nb-rich MO2. Thermodynamic calculation suggested that the MO2 was transformed from the primary NbC near surface

  3. Modern induction chemotherapy before chemoradiation for bulky locally-advanced nonsmall cell lung cancer improves survival

    Directory of Open Access Journals (Sweden)

    Inaya Ahmed

    2016-01-01

    Conclusion: In patients with large tumors or bulky nodal NSCLC, carboplatin-based induction chemotherapy may be an important addition to definitive CCRT in the modern era. Our findings strongly support further investigation induction chemotherapy in this population.

  4. Hydrogen abstraction reactions by amide electron adducts

    International Nuclear Information System (INIS)

    Electron reactions with a number of peptide model compounds (amides and N-acetylamino acids) in aqueous glasses at low temperature have been investigated using ESR spectroscopy. The radicals produced by electron attachment to amides, RC(OD)NDR', are found to act as hydrogen abstracting agents. For example, the propionamide electron adduct is found to abstract from its parent propionamide. Electron adducts of other amides investigated show similar behavior except for acetamide electron adduct which does not abstract from its parent compound, but does abstract from other amides. The tendency toward abstraction for amide electron adducts are compared to electron adducts of several carboxylic acids, ketones, aldehydes and esters. The comparison suggests the hydrogen abstraction tendency of the various deuterated electron adducts (DEAs) to be in the following order: aldehyde DEA > acid DEA = approximately ester DEA > ketone DEA > amide DEA. In basic glasses the hydrogen abstraction ability of the amide electron adducts is maintained until the concentration of base is increased sufficiently to convert the DEA to its anionic form, RC(O-)ND2. In this form the hydrogen abstracting ability of the radical is greatly diminished. Similar results were found for the ester and carboxylic acid DEA's tested. (author)

  5. [DNA adducts in human female genital organs].

    Science.gov (United States)

    Postawski, Krzysztof; Przadka-Rabaniuk, Dorota; Monist, Marta; Baranowski, Włodzimierz

    2007-12-01

    DNA adducts, one of genetic damages markers, precede and finally can lead to oncogenic mutations. They appear in genome as a result of DNA bases damages caused by various and numerous environmental factors eg. ultraviolet light, ionic radiation, toxins and also endogenic substances, for example estrogens. It is believed that the creation of DNA adducts is a necessary but insufficient process for the neoplastic transformation of the cell. The following review presents concise knowledge about the DNA adducts creation and their sequels served in healthy and cancerous tissues of the female genital organs, on the base of the available data. PMID:18411923

  6. DNA polymerase eta participates in the mutagenic bypass of adducts induced by benzo[a]pyrene diol epoxide in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Alden C Klarer

    Full Text Available Y-family DNA-polymerases have larger active sites that can accommodate bulky DNA adducts allowing them to bypass these lesions during replication. One member, polymerase eta (pol eta, is specialized for the bypass of UV-induced thymidine-thymidine dimers, correctly inserting two adenines. Loss of pol eta function is the molecular basis for xeroderma pigmentosum (XP variant where the accumulation of mutations results in a dramatic increase in UV-induced skin cancers. Less is known about the role of pol eta in the bypass of other DNA adducts. A commonly encountered DNA adduct is that caused by benzo[a]pyrene diol epoxide (BPDE, the ultimate carcinogenic metabolite of the environmental chemical benzo[a]pyrene. Here, treatment of pol eta-deficient fibroblasts from humans and mice with BPDE resulted in a significant decrease in Hprt gene mutations. These studies in mammalian cells support a number of in vitro reports that purified pol eta has error-prone activity on plasmids with site-directed BPDE adducts. Sequencing the Hprt gene from this work shows that the majority of mutations are G>T transversions. These data suggest that pol eta has error-prone activity when bypassing BPDE-adducts. Understanding the basis of environmental carcinogen-derived mutations may enable prevention strategies to reduce such mutations with the intent to reduce the number of environmentally relevant cancers.

  7. 32P-adduct assay: Comparative recoveries of structurally diverse DNA adducts in the various enhancement procedures

    International Nuclear Information System (INIS)

    A (32)P-adduct assay for the measurement of low levels (1 adduct per 10(sup 7) nucleotides) of binding of carcinogens to DNA has been reported previously. In this procedure, DNA is enzymatically hydrolyzed to 3'-monophosphates of normal nucleosides and adducts, which are 5'-(32)P-labeled by T4 polynucleotide kinase and (lambda(32)P)ATP. Labeled adducts are resolved by TLC. Enrichment of adducts by extraction in 1-butanol or digestion with nuclease P1 prior to (32)P-labeling, however, increased the sensitivity of detection for many adducts to a level of 1 per 10(sup 9-10) nucleotides, although adduct recovery particularly in the latter assay depended on the chemical nature of adducts. The observation that chemical structure of an adduct may be detrimental in its recovery in the enzyme- and extraction-mediated enrichment procedures may serve as a probe in the structural characterization of adducts of unknown carcinogens

  8. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    International Nuclear Information System (INIS)

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across

  9. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    Energy Technology Data Exchange (ETDEWEB)

    Kiwamoto, R., E-mail: reiko.kiwamoto@wur.nl; Spenkelink, A.; Rietjens, I.M.C.M.; Punt, A.

    2015-01-01

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.

  10. Monitoring lipase-catalyzed interesterification for bulky fats modification with FT-IR/NIR spectroscopy

    DEFF Research Database (Denmark)

    Chang, Tinghong; Lai, Xuxin; Zhang, Hong;

    2005-01-01

    This work demonstrates the application of FT-IR and FT-NIR spectroscopy to monitor the enzymatic interesterification process for bulky fat modification. The reaction was conducted between palm stearin and coconut oil (70/30, w/w) with the catalysis of Lipozyme TL IM at 70°C in a batch reactor...

  11. Turning the Page: Forget about Those Bulky Backbreakers, Digital Textbooks Are the Future

    Science.gov (United States)

    Hill, Rebecca

    2010-01-01

    Remember when computers were mostly used in offices? They were big and bulky with about as much mobility as a beached whale. Forget about using them in the classroom. Forget about reading a book on them. Forget about an app, well, for anything. Today, computers are the number-one educational tool. In fact, no one can imagine a school without one.…

  12. Hip adduction and abduction strength profiles in elite soccer players

    DEFF Research Database (Denmark)

    Serner, Andreas; Petersen, Jesper; Madsen, Thomas Moller;

    2011-01-01

    An ipsilateral hip adduction/abduction strength ratio of more than 90%, and hip adduction strength equal to that of the contralateral side have been suggested to clinically represent adequate strength recovery of hip adduction strength in athletes after groin injury. However, to what extent side-......-to-side symmetry in isometric hip adduction and abduction strength can be assumed in soccer players remains uncertain....

  13. Hip adduction and abduction strength profiles in elite soccer players

    DEFF Research Database (Denmark)

    Thorborg, Kristian; Serner, Andreas; Petersen, Jesper;

    2011-01-01

    An ipsilateral hip adduction/abduction strength ratio of more than 90%, and hip adduction strength equal to that of the contralateral side have been suggested to clinically represent adequate strength recovery of hip adduction strength in athletes after groin injury. However, to what extent side-...

  14. Modelling informally collected quantities of bulky waste and reusable items in Austria

    International Nuclear Information System (INIS)

    Highlights: • Informal collectors from Hungary collect bulky waste and reusable items in Austria. • Two methodologies were applied to estimate the informally collected quantities. • Both approaches lead to an estimation of roughly 100,000 t p.a. informally collected. • The formal Austrian system collects 72 kg/cap/yr of bulky waste, WEE & scrap metal. • Informal collection amounts to approx. 12 kg/cap/yr. - Abstract: Disparities in earnings between Western and Eastern European countries are the reason for a well-established informal sector actively involved in collection and transboundary shipment activities from Austria to Hungary. The preferred objects are reusable items and wastes within the categories bulky waste, WEEE and metals, intended to be sold on flea markets. Despite leading to a loss of recyclable resources for Austrian waste management, these informal activities may contribute to the extension of the lifetime of certain goods when they are reused in Hungary; nevertheless they are discussed rather controversially. The aim of this paper is to provide objective data on the quantities informally collected and transhipped. The unique activities of informal collectors required the development and implementation of a new set of methodologies. The concept of triangulation was used to verify results obtained by field visits, interviews and a traffic counting campaign. Both approaches lead to an estimation of approx. 100,000 t per year of reusable items informally collected in Austria. This means that in addition to the approx. 72 kg/cap/yr formally collected bulky waste, bulky waste wood, household scrap (excluding packaging) and WEEE, up to a further 12 kg/cap/yr might, in the case that informal collection is abandoned, end up as waste or in the second-hand sector

  15. Modelling informally collected quantities of bulky waste and reusable items in Austria

    Energy Technology Data Exchange (ETDEWEB)

    Ramusch, R., E-mail: roland.ramusch@boku.ac.at; Pertl, A.; Scherhaufer, S.; Schmied, E.; Obersteiner, G.

    2015-10-15

    Highlights: • Informal collectors from Hungary collect bulky waste and reusable items in Austria. • Two methodologies were applied to estimate the informally collected quantities. • Both approaches lead to an estimation of roughly 100,000 t p.a. informally collected. • The formal Austrian system collects 72 kg/cap/yr of bulky waste, WEE & scrap metal. • Informal collection amounts to approx. 12 kg/cap/yr. - Abstract: Disparities in earnings between Western and Eastern European countries are the reason for a well-established informal sector actively involved in collection and transboundary shipment activities from Austria to Hungary. The preferred objects are reusable items and wastes within the categories bulky waste, WEEE and metals, intended to be sold on flea markets. Despite leading to a loss of recyclable resources for Austrian waste management, these informal activities may contribute to the extension of the lifetime of certain goods when they are reused in Hungary; nevertheless they are discussed rather controversially. The aim of this paper is to provide objective data on the quantities informally collected and transhipped. The unique activities of informal collectors required the development and implementation of a new set of methodologies. The concept of triangulation was used to verify results obtained by field visits, interviews and a traffic counting campaign. Both approaches lead to an estimation of approx. 100,000 t per year of reusable items informally collected in Austria. This means that in addition to the approx. 72 kg/cap/yr formally collected bulky waste, bulky waste wood, household scrap (excluding packaging) and WEEE, up to a further 12 kg/cap/yr might, in the case that informal collection is abandoned, end up as waste or in the second-hand sector.

  16. New adducts of Lapachol with primary amines

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Mirelly D.F.; Litivack-Junior, Jose T.; Antunes, Roberto V.; Silva, Tania M.S.; Camara, Celso A., E-mail: ccelso@dq.ufrpe.b [Universidade Federal Rural de Pernambuco (UFRPE), Recife, PE (Brazil). Dept. de Quimica

    2011-07-01

    New adducts of lapachol with neat primary aliphatic amines were obtained in a solvent-free reaction in good to reasonable yields (52 to 88%), at room temperature. The new compounds containing a phenazine moiety were obtained from suitable functionalized aminoalkyl compounds, including ethanolamine, 3-propanolamine, 2-methoxy-ethylamine, 3-methoxy-propylamine, n-butylamine and 2-phenetylamine. (author)

  17. STUDY ON GMA-DNA ADDUCTS

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    Objective. DNA modification fixed as mutations in the cells may be an essential factor in the initiation step of chemical carcinogenesis. In order to explore the mechanism of gene mutation and cell transformation induced by glycidyl methacrylate (GMA), the current test studied the characteristics of GMA-DNA adducts formation in vitro.Methods. In vitro test, dAMP, dCMP, dGMP, dTMP and calf thymus DNA were allowed to react with GMA (Glycidyl Methacrylate). After the reaction, the mixtures were detected by UV and subjected to reversed-phase HPLC on ultrasphere ODS reversed-phase column, the reaction products were eluted with a linear gradients of methanol (solvent A) and 10mmol/L ammonium formate, pH5.0 (solvent B). The synthesized adducts were then characterized by UV spectroscopy in acid (pH1.0), neutral (pH7.2), alkaline (pH11.0) and by mass spectroscopy.Results. The results showed that GMA could bind with dAMP, dCMP, dGMP and calf thymus DNA by covalent bond, and the binding sites were specific (N6 of adenine, N3 of cytosine). Meanwhile, a main GMA-DNA adduct in the reaction of GMA with calf thymus DNA was confirmed as N3-methacrylate-2-hydroxypropy1-dCMP.Conclusions. GMA can react with DNA and /or deoxynucleotide monophosphate and generate some adducts such as N6-methacrylate-2-hydroxypropyl-dAMP and N3-methacrylate-2-hydroxypropyl-dCMP, ets. Formation of GMA-DNA adducts is an important molecular event in gene mutation and cell transformation induced by GMA.

  18. Fluorescence spectroscopy in the analysis of deoxyribonucleic acid (DNA) adducts

    International Nuclear Information System (INIS)

    An important first step in the initiation of carcinogenesis by polycyclic aromatic hydrocarbons (PAH), is the formation of a covalently bound adduct between the metabolized PAH and one or more deoxyribonucleic acid bases. In vivo concentrations of these adducts are typically ∼1 adducted base per 108 normal DNA base pairs. In this paper methods of generating high resolution fluorescence spectra of adducts at these levels are described. Methods of overcoming factors such as photochemistry and nonphotochemical hole burning which limit detection limits are described. By generating line narrowed fluorescence spectra, it is possible to spectrally distinguish between various adduct possibilities

  19. Bulky DNA Adducts in Cord Blood, Maternal Fruit-and-Vegetable Consumption, and Birth Weight in a European Mother-Child Study (NewGeneris)

    DEFF Research Database (Denmark)

    Pedersen, Marie; Schoket, Bernadette; Godschalk, Roger W;

    2013-01-01

    Stedingk H, Törnqvist M, Sunyer J, Nielsen JK, Merlo DF, Mendez MA, Meltzer HM, Lukács V, Landström A, Kyrtopoulos SA, Kovács K, Knudsen LE, Haugen M, Hardie LJ, Gützkow KB, Fleming S, Fthenou E, Farmer PB, Espinosa A, Chatzi L, Brunborg G, Brady NJ, Botsivali M, Arab K, Anna L, Alexander J, Agramunt S...

  20. 32P-postlabelling methods for cyclic DNA adducts.

    Science.gov (United States)

    Watson, W P; Crane, A E; Steiner, S

    1993-01-01

    32P-Postlabelling procedures coupled with HPLC have been developed to detect and measure a range of cyclic DNA adducts formed by bifunctional genotoxic agents. The methods are based on reverse-phase HPLC, particularly column-switching HPLC, to enrich adduct 3'-monophosphates before labelling. Following 3'-dephosphorylation of the 3'5'-[5'-32P]bisphosphates with nuclease P1, the resulting 5'-[32P]monophosphate adducts are resolved, identified and characterized by co-chromatography with synthetic reference standards. The procedures have been applied to a number of cyclic adducts including those formed by chloroacetaldehyde, glycidaldehyde and malonaldehyde. In general, labelling efficiencies measured as chromatographed 5'-[32P]monophosphates were in the range 30-40%. However, the values for the malonaldehyde deoxyguanosine adduct were much lower. The techniques have been applied to studies on the formation of DNA adducts in the skin of male C3H mice treated cutaneously with glycidaldehyde. The HPLC-32P-postlabelling analysis of epidermal DNA hydrolysates indicated that a single major cyclic adduct was formed by reaction with deoxyadenosine residues in mouse skin DNA. The adduct was identified as a hydroxymethyl ethenodeoxyadenosine adduct by comparison with a synthetic standard. This adduct was highly fluorescent and it was possible to make quantitative comparisons of the amounts of adduct determined by either HPLC-32P-postlabelling or HPLC-fluorescence detection. PMID:8225493

  1. SHORT-TIME ANALYSIS FOR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH EARLY-STAGE BULKY CERVICAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    令狐华; 徐小蓉; 梅耀宇; 唐均英; 唐良萏; 孙彤

    2003-01-01

    Objective: To investigate the effect of adjuvant chemotherapy on early stage cervical cancer with bulky tumor. Methods: Between Mar 1998 and Aug 2002, 162 patients of cervical cancer with Ib~IIa stage were investigated. 21 patients with bulky tumors (≥4cm) were managed by cisplatin-based chemotherapy followed by radical hysterectomy and pelvic lymphadenectomy (Bulky-chemo group, BC group). The change of tumor size, the depth of stromal invasion, lymph node metastasis and the involvement of surgical specimens were assessed after operation and compared with those in 57 patients with bulky tumors (Bulky-nonchemo group, BN group) and 84 patients with the tumor size less than 4cm (small group, S group) who underwent surgery as the first step of treatment. Chemotherapy with the same regimen was offered for another 1~2 cycles after operation and the survival situation was followed up. Results: The tumor size of 21 patients in BC group were decreased to varying degrees after chemotherapy, 15 patients were shown as clinical effectiveness (71.43%). And the blood loss during operation (352.35(19.01ml) was significantly lower than that in BN group (619.05(35.58ml), t=4.37) and that in S group (568.07(45.23ml, t=3.36) patients. The incidence of lymph node metastasis (9/78) in patients with bulky tumors was greatly higher than those with tumor size less than 4cm (3/84, X2=4.416); its prevalence rate of deep wall infiltration (8/78) was also higher than that of the latter group (2/84), while with no statistical significance (X2=3.089). Histology showed that there was no case of marginal involvement in all patients. The ratio of both deep stromal invasion (1/21) and positive lymph node (2/21) in BC group was lower than that in BN group (7/57, 7/57 respectively), but neither with statistical significance (X2=0.0103 and 0.8193 respectively). Conclusion: Pre-operative chemotherapy can improve decreasing the primary tumor size and facilitate the following radical surgery. While

  2. Stereotactic Radiosurgery as Part of Multimodal Treatment in a Bulky Leptomeningeal Recurrence of Breast Cancer.

    Science.gov (United States)

    Bertke, Matthew H; Burton, Eric C; Shaughnessy, Joseph N

    2016-01-01

    Breast cancer metastatic to the brain and/or leptomeningeal spread of disease is a frequently encountered clinical situation, especially given the extended course of disease in these patients. Systemic therapies can often effectively prolong extracranial disease control, making effective strategies to control central nervous system-based disease even more critical. We present a case of bulky leptomeningeal relapse of breast cancer in the setting of prior whole brain radiation therapy. In order to treat the patient's bulky disease and leptomeningeal spread while avoiding the potential toxicities of repeat whole brain radiation, the patient was treated with frameless stereotactic radiosurgery and intrathecal chemotherapy. This is the first report of this treatment approach for leptomeningeal relapse of breast cancer. The patient had an excellent response to treatment and durable intracranial control. PMID:27081584

  3. RESPONSE OF EARLY STAGE BULKY CERVICAL SQUAMOUS CARCINOMA TO PREOPERATIVE ADJUVANT CHEMOTHERAPY

    Institute of Scientific and Technical Information of China (English)

    Hua Linghu; Xiao-rong Xu; Yao-yu Mei; Jun-ying Tang; Liang-dan Tang; Tong Sun

    2004-01-01

    Objective To investigate the potential role of preoperative adjuvant chemotherapy on early stage cervical squamouscarcinoma with bulky tumor.Methods One hundred and forty-five patients with cervical squamous cancer stages Ⅰb-Ⅱa were investigated, among which 17 patients with bulky tumors (≥4 cm) were managed by cisplatin-based chemotherapy for 1-2 courses followed by radical hysterectomy and pelvic lymphadenectomy (BC group). The change of tumor size, pelvic lymph nodes metastasis, cervical wall invasion, the involvement of surgical specimen margin, and the blood loss during operation were assessed after operation and compared with those in 51 patients with bulky tumors (BN group) and 77 patients with small local tumors (S group)who underwent surgery directly.Results (1) The tumor size of 17 patients in BC group were decreased in various degrees after chemotherapy, with 13 patients of clinical effectiveness (76.47%). And the responsiveness pertained to neither histological differentiation nor size of local tumors. (2) Post-operative histology has showed that patients in BC and BN group have higher incidence of lymph node metastasis and deep cervical infiltration (5/68 and 3/68, respectively) than in S group (1/77 and 1/77, respectively) while with no statistical significance. (3) Blood loss during operation in BC group was less than BN and S group. (4) Seventeen patients, including those underwent surgeries of vaginal prolongation and/or ovarian transposition, appeared disease-free survival within the follow-up time.Conclusions Most of patients with bulky early stage cervical squamous carcinoma are sensitive to cisplatin-based chemotherapy, which could greatly reduce local tumor size and in turn facilitate the following operation by well controlling blood loss.

  4. Bulky abdominal masses in pediatrics: iconographic essay; Massas abdominais volumosas em pediatria: ensaio iconografico

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Fabiano; Faria, Andreia V.; Kluge, Patricia D.; Volpato, Ricardo G.; Santos, Sergio L.M. dos; Caserta, Nelson M.G. [Universidade Estadual de Campinas, SP (Brazil). Faculdade de Ciencias Medicas]. E-mail: fabiano97@bol.com.br

    2005-04-15

    The ultrasound, computerized tomography and magnetic resonance findings of 19 patients with abdominal bulky masses diagnosed as hydronephrosis, Wilms' tumor, neuroblastoma, adrenal carcinoma, sarcoma, hemangioendothelioma, hepatoblastoma, mesenchymal hamartoma, hepatocellular carcinoma, choledochal cyst, splenic cyst, lymphoma, enteric cyst, teratoma, hydrometrocolpos and lipoma are presented. Imaging findings (including ultrasound, computerized tomography and magnetic resonance imaging) are important tools for the evaluation of abdominal masses in pediatric patients and can contribute to the diagnosis and evaluation of the extension of these diseases. (author)

  5. Acetaldehyde Adducts in Alcoholic Liver Disease

    Directory of Open Access Journals (Sweden)

    Mashiko Setshedi

    2010-01-01

    Full Text Available Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD, with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC. Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2–15% versus cirrhosis (15–20% is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC.

  6. Covalent adduction of nitrogen mustards to model protein nucleophiles.

    Science.gov (United States)

    Thompson, Vanessa R; DeCaprio, Anthony P

    2013-08-19

    Protein adducts have the potential to serve as unique biomarkers of exposure to compounds of interest. Many xenobiotics (or their metabolites) are electrophilic and therefore reactive with nucleophilic amino acid residues on proteins. Nitrogen mustards are reactive xenobiotics with potential use as chemical warfare agents (CWA) or agents of terrorist attack, in addition to being employed as chemotherapeutic agents. The present study utilized cysteine-, lysine-, and histidine-containing model peptides to characterize in vitro adduction of the nitrogen mustards mechloroethamine (HN-2) and tris-(2-chlorethyl)amine (HN-3) to these nucleophilic amino acid residues by means of liquid chromatography-tandem mass spectrometry. The study assessed the structure of adducts formed, the time course of adduct formation, concentration-response relationships, and temporal stability of adducts. Adduction was hypothesized to occur on all three model peptides via initial formation of a reactive aziridinium intermediate for both mechloroethamine and tris-(2-chlorethyl)amine, followed by covalent adduction to nucleophilic residues. While adduction was found to occur most readily with cysteine, it was also observed at lysine and histidine, demonstrating that adduction by mechloroethamine and tris-(2-chlorethyl)amine is possible at multiple nucleophilic sites. Following solid phase extraction cleanup, adducts formed with mechloroethamine were stable for up to three weeks. Adducts formed with tris-(2-chlorethyl)amine were less stable; however, hydrolyzed secondary adducts were observed throughout the three week period. This study demonstrates that the nitrogen mustards mechloroethamine and tris-(2-chlorethyl)amine form stable adducts with reactive protein nucleophiles other than cysteine. PMID:23859065

  7. Formation of PAH-DNA adducts after in vivo and vitro exposure of rats and lung cells to different commercial carbon blacks

    International Nuclear Information System (INIS)

    Objective: The current study was designed to test the possible release and bioavailability of polycyclic aromatic hydrocarbons (PAHs) from a set of commercial carbon blacks (CBs) as well as the ability of these PAHs to form bulky DNA adducts. Methods: In four commercial CBs (Printex 90, Sterling V, N330, Lampblack 101), leaching of PAH was examined through (1) release of parent PAHs in saline with or without surfactant, and (2) PAH adducts in lung epithelial cells (A549) or in rat lungs after exposure to two CBs (Printex 90, Sterling V) for 13 weeks (50 mg/m3). In vitro experiments were done with original and extracted particles, as well as organic extracts of CB in DMSO. As positive controls, B[a]P (0.03 μM) and a mixture of 16 PAHs (0.1 μM) were used. Results: No leaching of PAHs was measured in saline or surfactant-containing saline. In vitro incubations with CB particles (30-300 μg/cm2) revealed no adduct spots except for Sterling V. However, the spot was not concentration dependent and remains unidentified. Lung DNA from rats after inhalation of Printex 90 or Sterling V showed no spots related to PAH-DNA adduct formation compared to sham-exposed rats. Conclusion: The results suggest that PAHs are very tightly bound to these CBs. Only using organic extracts or particles of low-surface Sterling V, with high PAH content, PAHs may become available to form PAH-DNA adducts. However, the in vitro conditions showing this effect will not be encountered in vivo and renders this mechanism in particle-induced lung cancer at in vivo exposures highly unlikely

  8. Mutagenesis by site-specific arylamine adducts in plasmid DNA: Enhancing replication of the adducted strand alters mutation frequency

    International Nuclear Information System (INIS)

    Site specifically modified plasmids were used to determine the mutagenic effects of single arylamine adducts in bacterial cells. A synthetic heptadecamer bearing a single N-(guanin-8-yl)-2-aminofluorene (AF) or N-(guanin-8-yl)-2-(acetylamino)fluorene (AAF) adduct was used to introduce the adducts into a specific site in plasmid DNA that contained a 17-base single-stranded region complementary to the modified oligonucleotide. Following transformation of bacterial cells with the adduct-bearing DNA, putative mutants were detected by colony hybridization techniques that allowed unbiased detection of all mutations at or near the site of the adduct. The site-specific AF or AAF adducts were also placed into plasmid DNA that contained uracil residues on the strand opposite that bearing the lesions. The presence of uracil in one strand of the DNA decreases the ability of the bacterial replication system to use the uracil-containing strand, thereby favoring the use of the strand bearing the adducts. In a comparison of the results obtained with site specifically modified DNA, either with or without uracil, the presence of the uracil increased the mutation frequencies of the AF adduct by >7-fold to 2.9% and of the AAF adduct by >12-fold to 0.75%. The AF adduct produced primarily single-base deletions in the absence of uracil but only base substitutions in the uracil-containing constructs. The AAF adduct produced mutations only in the uracil-containing DNA, which included both frame shifts and base substitutions. Mutations produced by both adducts were SOS dependent

  9. External Beam Radiotherapy Followed by 90Y Ibritumomab Tiuxetan in Relapsed or Refractory Bulky Follicular Lymphoma

    International Nuclear Information System (INIS)

    Purpose: We combined external beam radiotherapy (EBRT) with yttrium-90 ibritumomab tiuxetan (90Y-IT) in an attempt to improve therapeutic response in patients with relapsed or refractory bulky follicular lymphoma (RRBFL). Methods and Materials: Between February 2006 and September 2007, 11 patients with RRBFL were treated with EBRT followed by 90Y-IT. Bulky disease (BD) was defined as >5 cm. EBRT was delivered to BD as 2,400 cGy in eight fractions using computed tomography (CT)-based planning. BD was contoured as the gross tumor volume. A planning margin of 1 to 2 cm was added depending on anatomical location. After recovery of complete blood counts (CBC), 90Y-IT was administered at a dose of 0.3 or 0.4 mCi/kg depending on platelet counts. Hematologic toxicity was monitored through weekly CBC. Response was measured by positron emission tomography/CT or CT 3-4 months after 90Y-IT. Results: Only 2 patients required prolonged breaks between EBRT and 90Y-IT. The median time after 90Y-IT for platelets to recover to >100,000/ml was 55 days (range, 41-128 days). Platelet counts for 1 patient, who had received 4 previous chemotherapy regimens, never reached 100,000/ml. The complete and overall responses to combined therapy as measured 3-4 months after 90Y-IT were 64%. No patients relapsed within the EBRT field. With a median follow-up of 36.1 months, 6 patients have relapsed, 2 of whom have died. Median progression-free survival was 17.5 months. Conclusions: In contrast to prior failure analysis data for RRBFL patients treated with 90Y-IT alone, a brief course of EBRT prevented relapse in sites of BD. EBRT used to pretreat bulky sites may improve clinical outcomes and potentially extend survival when combined with 90Y-IT.

  10. Properties of ferrocene derivative C60 adduct

    International Nuclear Information System (INIS)

    Properties of ferrocene derivative C60 adduct were investigated by thermal analyses, x-ray diffraction, 57Fe Moessbauer spectroscopy in order to examine interaction of iron with fullerene. Thermal treatment may be applied to remove organic groups to obtain sample containing C60Fe with C60 arranged in the fcc lattice and iron dispersed between fullerenes. We performed calculations based on the semi-empirical quantum chemistry model P M3 for a few exohedral complexes with Fe at various sites relatively to C60

  11. 18. Adduct detection in human monitoring for carcinogen exposure

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Determination of the covalently bound products (adducts) of carcinogens with DNA or proteins may be used for the monitoring of exposure to these compounds. Protein adducts are generally stable and are not enzymatically repaired, and the use of these for cxposure monitoring is normally carried out with globin or albumin, because

  12. Intramolecular Tetrylene Lewis Adducts: Synthesis and Reactivity.

    Science.gov (United States)

    Schneider, Julia; Krebs, Kilian M; Freitag, Sarah; Eichele, Klaus; Schubert, Hartmut; Wesemann, Lars

    2016-07-01

    A series of benzyl(diphenylphosphino) and o-phenyl(diphenlyphosphino) substituted germylenes and plumbylenes were synthesized by nucleophilic substitution between the respective lithium reagent and tetrylene halide. The Lewis pairs were characterized by X-ray crystallography and NMR spectroscopy. The reactivity of the tetrylenes was investigated with respect to azide addition. In the germylene case, the germaniumimide was formed as the kinetically controlled product, which rearranges upon heating to give the phosphinimide. The stannylene and plumbylene derivatives react with adamantylazide to give the azide adducts. 1-Pentene reacts diastereoselectively with the phosphagermirane to give a cyclic addition product. Trimethysilylacetylene shows an addition with the benzylphosphino-substituted germylene and plumbylene to give the cycloheteropentene molecules. The addition product between phenylacetylene and the four membered Ge-P adduct shows after addition at room temperature a 1,4-phenylmigration to give a cyclic phosphine. Alkylnitrene insertion into a Ge-C bond of the alkyne addition product of the phosphagermirane was found in reaction with adamantylazide. PMID:27273819

  13. DNA adduct formation by alachlor metabolites

    International Nuclear Information System (INIS)

    The extent of DNA adduct formation by alachlor [ArN(CH2OCH3)C(O)CH2Cl wherein Ar is 2,6-diethylphenyl] and its metabolites is used as a guide to deduce the causal agent(s) in the carcinogenicity of this major herbicide. [14C-phenyl]Alachlor is compared to its two metabolic cleavage products, [14C-phenyl] 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) [ArNHC(O)CH2Cl] and [14C-phenyl]2,6-diethylaniline (DEA) (ArNH2), and to [14C-methoxy]alachlor in various in vitro and in vivo systems. Horseradish peroxidase and hydrogen peroxide activate DEA, but not CEDPA or alachlor, for formation of adducts with calf thymus DNA, which probably involves 2,6-diethylnitrosobenzene (ArNO) as an intermediate. Mouse liver microsomes and NADPH are both required to enhance the binding from each labeled preparation to calf thymus DNA; 4-fold higher labeling is observed from [14C-methoxy]- than from [14C-phenyl]alachlor. This 4-fold preferential DNA labeling from the 14C-methoxy compound is likewise found in the liver of mice treated intraperitoneally. Mouse liver protein and hemoglobin are also labeled, in vivo, with [14C-phenyl]alachlor, -CDEPA and -DEA, and, as with the DNA, the labeling of these proteins is 1.5- to 2-fold higher with [14C-methoxy]alachlor

  14. Benzenesulfonamides incorporating bulky aromatic/heterocyclic tails with potent carbonic anhydrase inhibitory activity.

    Science.gov (United States)

    Bozdag, Murat; Alafeefy, Ahmed M; Vullo, Daniela; Carta, Fabrizio; Dedeoglu, Nurcan; Al-Tamimi, Abdul-Malek S; Al-Jaber, Nabila A; Scozzafava, Andrea; Supuran, Claudiu T

    2015-12-15

    Three series of sulfonamides incorporating long, bulky tails were obtained by applying synthetic strategies in which substituted anthranilic acids, quinazolines and aromatic sulfonamides have been used as starting materials. They incorporate long, bulky diamide-, 4-oxoquinazoline-3-yl- or quinazoline-4-yl moieties in their molecules, and were investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides showed excellent inhibitory effects against the four isoforms, with KIs of 7.6-322nM against hCA I, of 0.06-85.4nM against hCA II; of 6.7-152nM against hCA IX and of 0.49-237nM against hCA XII; respectively. However no relevant isoform-selective behavior has been observed for any of them, although hCA II and XII, isoforms involved in glaucoma-genesis were the most inhibited ones. The structure-activity relationship for inhibiting the four CAs with these derivatives is discussed in detail. PMID:26639945

  15. Improved control of bulky prostate carcinoma with sequential estrogen and radiation therapy

    International Nuclear Information System (INIS)

    Patients with bulky prostate cancer have usually been treated by palliative measures because the likelihood of tumor control with definitive irradiation has been low and the development of distant metastases high. The addition of estrogen to irradiation has not been shown to be of value. However, the method of estrogen administration may have been the cause for the apparent lack of benefit. In this study estrogen was used for two months prior to and concurrent with irradiation. Between 1975 and 1980, 25 patients with bulky prostate cancer received sequential estrogen and irradiation, 12 patients irradiation alone and six patients irradiation after having become refractory to long-term estrogen use. Eighteen of 25 (72%) treated by sequential estrogen and irradiation, 14/17 (82%) with estrogen responsive cancer and 4/8 (50%) with estrogen resistant cancer had a complete tumor response. Six of 11 (55%) patients treated by irradiation alone and 2/6 (33%) treated by irradiation for estrogen refractory cancer had a complete tumor response. Distant metastases was observed in 15% of patients when the primary tumor was controlled and 30% when there was persistent or recurrent local disease. The results with the use of estrogen prior to and concurrent with irradiation is encouraging. Estrogen may shrink the cancer and allow for a more favorable geometry for external irradiation

  16. Bulky Macroporous TiO2 Photocatalyst with Cellular Structure via Facile Wood-Template Method

    Directory of Open Access Journals (Sweden)

    Qingfeng Sun

    2013-01-01

    Full Text Available We report a bulky macroporous TiO2 particles with cellular structure prepared in the presence of wood slices as template. Firstly, TiO2 sol was coated onto the wood slices by repeated dip-coating process. Then, after calcinations at 550°C, the wood template could be removed, and the bulky TiO2 structure was obtained. The prepared samples were characterized by scanning electron microscopy (SEM, X-ray diffraction (XRD, energy dispersive spectroscopy (EDS, and transmission electron microscope (TEM techniques. XRD pattern confirmed the crystalline phase of the wood-templated TiO2 is anatase phase. And interestingly, from the observation of SEM image, the wood-templated TiO2 inherited the initial cellular structures of birch lumber (B. albosinensis Burk, and numerous macropores were observed in the sample. Meanwhile, the wood-templated TiO2 presented a superior photocatalytic ability to decompose Rhodamine B (RhB under ultraviolet irradiation.

  17. Catalytic behaviour in the ring-opening polymerisation of organoaluminiums supported by bulky heteroscorpionate ligands.

    Science.gov (United States)

    Castro-Osma, Jose A; Alonso-Moreno, Carlos; Lara-Sánchez, Agustín; Otero, Antonio; Fernández-Baeza, Juan; Sánchez-Barba, Luis F; Rodríguez, Ana M

    2015-07-21

    A series of alkyl organoaluminium complexes based on bulky heteroscorpionate ligands were designed as catalysts for the ring-opening polymerisation of cyclic esters. Thus, the treatment of AlX3 (X = Me, Et) with bulky acetamide or thioacetamide heteroscorpionate ligands nbptamH (1) [nbptamH = N-naphthyl-2,2-bis(3,5-dimethylpyrazol-1-yl)thioacetamide], fbpamH (2) [fbpamH = N-fluorenyl-2,2-bis(3,5-dimethylpyrazol-1-yl)acetamide], ptbptamH (3) [ptbptamH = N-phenyl-2,2-bis(3,5-di-tert-butylpyrazol-1-yl)thioacetamide], ntbptamH (4) [ntbptamH = N-naphthyl-2,2-bis(3,5-di-tert-butylpyrazol-1-yl)thioacetamide], ptbpamH (5) [ptbpamH = N-phenyl-2,2-bis(3,5-di-tert-butylpyrazol-1-yl)acetamide] and (S)-mtbpamH (6) [(S)-mtbpamH = (S)-(−)-N-α-methylbenzyl-2,2-bis(3,5-di-tert-butylpyrazol-1-yl)acetamide] for 1 hour at 0 °C afforded the dialkyl aluminium complexes [AlX2{κ(2)-nbptam}] (X = Me 7, Et 8), [AlX2{κ(2)-fbpam}] (X = Me 9, Et 10), [AlX2{κ(2)-ptbptam}] (X = Me 11, Et 12), [AlX2{κ(2)-ntbptam}] (X = Me 13, Et 14), [AlX2{κ2(-)ptbpam}] (X = Me 15, Et 16) and [AlX2{κ(2)-(S)-mtbpam}] (X = Me 17, Et 18). The structures of the complexes were determined by spectroscopic methods and the X-ray crystal structure of 14 was also established. The alkyl-containing aluminium complexes 7–18 can act as efficient single-component initiators for the ring-opening polymerisation of ε-caprolactone and rac-lactide. The polymerisations are living, as evidenced by the narrow polydispersities of the isolated polymers and the linear nature of the number average molecular weight versus conversion plot. Finally, a comparative study of ring-opening polymerisation for new bulky heteroscorpionate aluminium initiators and the less congested aluminium analogues is reported. PMID:25534594

  18. Redshift or adduct stabilization -- a computational study of hydrogen bonding in adducts of protonated carboxylic acids

    DEFF Research Database (Denmark)

    Olesen, Solveig Gaarn; Hammerum, Steen

    2009-01-01

    always yield consistent predictions, as illustrated by the hydrogen bonds formed by the E and Z OH groups of protonated carboxylic acids. The delta-PA and the stabilization of a series of hydrogen bonded adducts indicate that the E OH group forms the stronger hydrogen bonds, whereas the bond length...... carboxylic acids are different. The OH bond length and IR redshift afford the better measure of hydrogen bond strength....

  19. Biocatalytic Reductions of Baylis - Hillman Adducts

    Energy Technology Data Exchange (ETDEWEB)

    A Walton; W Conerly; Y Pompeu; B Sullivan; J Stewart

    2011-12-31

    Baylis-Hillman adducts are highly useful synthetic intermediates; to enhance their value further, we sought enantiocomplementary alkene reductases to introduce chirality. Two solutions emerged: (1) a wild-type protein from Pichia stipitis (OYE 2.6), whose performance significantly outstrips that of the standard enzyme (Saccharomyces pastorianus OYE1), and (2) a series of OYE1 mutants at position 116 (Trp in the wild-type enzyme). To understand how mutations could lead to inverted enantioselectivity, we solved the X-ray crystal structure of the Trp116Ile OYE1 variant complexed with a cyclopentenone substrate. This revealed key protein-ligand interactions that control the orientation of substrate binding above the FMN cofactor.

  20. Synthesis and characterization of bulky mesoporous silica Pd-MCM-41

    International Nuclear Information System (INIS)

    Bulky palladium catalyst supported on mesoporous silica MCM-41 (Pd-MCM-41) was successfully synthesized by hydrothermal hot-pressing method. In this study, the structure of the palladium species in Pd-MCM-41 bulk before and after heat-treatment process was revealed by X-ray diffraction (XRD), X-ray absorption near edge structure (XANES) and transmission electron microscopy (TEM). Also, the microstructure and mesoporous property of Pd-MCM-41 bulk was discussed. As a result, it was revealed that these dense Pd-MCM-41 bulks possessed a high surface area of over 1000 m2/g and the structure of palladium of Pd-MCM-41 bulk is almost equal to palladium (0) metal. (author)

  1. Distance-Dependent Attractive and Repulsive Interactions of Bulky Alkyl Groups.

    Science.gov (United States)

    Hwang, Jungwun; Li, Ping; Smith, Mark D; Shimizu, Ken D

    2016-07-01

    The stabilizing and destabilizing effects of alkyl groups on an aromatic stacking interaction were experimentally measured in solution. The size (Me, Et, iPr, and tBu) and position (meta and para) of the alkyl groups were varied in a molecular balance model system designed to measure the strength of an intramolecular aromatic interaction. Opposite stability trends were observed for alkyl substituents at different positions on the aromatic rings. At the closer meta-position, smaller groups were stabilizing and larger groups were destabilizing. Conversely, at the farther para-position, the larger alkyl groups were systematically more stabilizing with the bulky tBu group forming the strongest stabilizing interaction. X-ray crystal structures showed that the stabilizing interactions of the small meta-alkyl and large para-alkyl groups were due to their similar distances and van der Waals contact areas with the edge of opposing aromatic ring. PMID:27159670

  2. Photoinduced and thermal denitrogenation of bulky triazoline crystals: insights into solid-to-solid transformation.

    Science.gov (United States)

    de Loera, Denisse; Stopin, Antoine; Garcia-Garibay, Miguel A

    2013-05-01

    The photoinduced and thermal denitrogenation of crystalline triazolines with bulky substituents leads to the quantitative formation of aziridines in clean solid-to-solid reactions despite very large structural changes in the transition from reactant to product. Analysis of the reaction progress by powder X-ray diffraction, solid-state (13)C CPMAS NMR, solid-state FTIR spectroscopy, and thermal analysis has revealed that solid-to-solid reactions proceed either through metastable phases susceptible to amorphization or by mechanisms that involve a reconstructive phase transition that culminates in the formation of the stable phase of the product. While the key for a solid-to-solid transformation is that the reaction occurs below the eutectic temperature of the reactant and product two-component system, experimental evidence suggests that those reactions will undergo a reconstructive phase transition when they take place above the glass transition temperature. PMID:23547729

  3. Protein adduct formation as a molecular mechanism in neurotoxicity.

    Science.gov (United States)

    Lopachin, Richard M; Decaprio, Anthony P

    2005-08-01

    Chemicals that cause nerve injury and neurological deficits are a structurally diverse group. For the majority, the corresponding molecular mechanisms of neurotoxicity are poorly understood. Many toxicants (e.g., hepatotoxicants) of other organ systems and/or their oxidative metabolites have been identified as electrophiles and will react with cellular proteins by covalently binding nucleophilic amino acid residues. Cellular toxicity occurs when adduct formation disrupts protein structure and/or function, which secondarily causes damage to submembrane organelles, metabolic pathways, or cytological processes. Since many neurotoxicants are also electrophiles, the corresponding pathophysiological mechanism might involve protein adduction. In this review, we will summarize the principles of covalent bond formation that govern reactions between xenobiotic electrophiles and biological nucleophiles. Because a neurotoxicant can form adducts with multiple nucleophilic residues on proteins, the challenge is to identify the mechanistically important adduct. In this regard, it is now recognized that despite widespread chemical adduction of tissue proteins, neurotoxicity can be mediated through binding of specific target nucleophiles in key neuronal proteins. Acrylamide and 2,5-hexanedione are prototypical neurotoxicants that presumably act through the formation of protein adducts. To illustrate both the promise and the difficulty of adduct research, these electrophilic chemicals will be discussed with respect to covalent bond formation, suspected protein sites of adduction, and proposed mechanisms of neurotoxicity. The goals of future investigations are to identify and quantify specific protein adducts that play a causal role in the generation of neurotoxicity induced by electrophilic neurotoxicants. This is a challenging but critical objective that will be facilitated by recent advances in proteomic methodologies. PMID:15901921

  4. Synthesis and Electroluminescent Properties of Julolidine-π-Juloidine Type Materials with the Bulky Adamantane Groups

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kum Hee; Yoon, Seung Soo [Sungkyunkwan Univ., Suwon (Korea, Republic of); Lee, Seok Jae; Kim, Young Kwan [Hongik Univ., Seoul (Korea, Republic of)

    2012-11-15

    A main problem of red emitting material, which contributes to their low EL performances, is the concentration quenching due to the effective self aggregation and the consequent formation of excimers. To avoid this drawback and thus improve the EL properties of red fluorescent OLED devices, many synthetic efforts have been conducted to develop new emitting materials with the structural motifs to suppress self-aggregation by the weakening intermolecular attractive interactions. Particularly, the introduction of bulky moieties in the emitters would provide the steric hindrance between emitting materials in solid state devices and thus reduce the self-aggregation. Nevertheless, EL performances of red materials still need to be improved for the practical applications. In conclusion, we designed and synthesized three julolidine-π-juloidine type emitting materials (1-3) with the bulky adamantane groups. To study their electroluminescent properties, the multilayered OLED devices with the structure of ITO/NPB (40 nm)/ADN : 1-3 (x%) (20 nm)/Alq{sub 3} (40 nm)/Liq (2 nm)/Al were fabricated. All devices using emitters 1-3 showed the efficient emissions, in which their EL performances depend on the structure of emitters sensitively. Particularly, a device using emitter 3 exhibited the efficient orange-red emission with the luminous and power efficiencies of 4.79 cd/A and 1.76 lm/W at 20 mA/cm{sup 2}, respectively. The CIE coordinates of this device was (0.57, 0.42) at 7.0 V.

  5. Quantitation of DNA adducts by stable isotope dilution mass spectrometry

    OpenAIRE

    Tretyakova, Natalia; Goggin, Melissa; Janis, Gregory

    2012-01-01

    Exposure to endogenous and exogenous chemicals can lead to the formation of structurally modified DNA bases (DNA adducts). If not repaired, these nucleobase lesions can cause polymerase errors during DNA replication, leading to heritable mutations potentially contributing to the development of cancer. Due to their critical role in cancer initiation, DNA adducts represent mechanism-based biomarkers of carcinogen exposure, and their quantitation is particularly useful for cancer risk assessment...

  6. Multiple DNA adducts in lymphocytes of smokers and nonsmokers determined by 32P-postlabeling analysis

    International Nuclear Information System (INIS)

    Identification of DNA adducts in peripheral lymphocytes could serve as a means of monitoring human exposure to potential genotoxic agents. In the study, DNA from peripheral lymphocytes of smokers and nonsmokers was examined for adducts by the P1 nuclease 32P-post-labeling technique. Thin layer chromatography (TLC) maps from both groups revealed multiple DNA adducts which ranged from no adducts for one individual to six adducts for a different individual. The total DNA adduct concentrations were approximately one adduct in 10 to the seventh-10 to the eighth power normal nucleotides. Comparison of the adduct TLC profiles revealed individual variation in both pattern and level of DNA adducts. The type and amount of adduct was not influenced by smoking history and remained unchanged in four out of six subjects who were resampled after a one month interval. One adduct detected in lymphocyte DNA co-migrated on TLC with an adduct derived by in vitro incubation of lymphocytes with benzo(a)pyrene (B(a)P). The 3H-nucloside values were consistent with values obtained by 32P-postlabeling of the same sample (correlation coefficient of 0.88). No relationship was apparent between the capacity of lymphocytes to form a (3H)-B(a)P-derived adduct in vitro and the concentration of the adduct, or total adducts present in untreated lymphocytes

  7. Single-Component Conductors: A Sturdy Electronic Structure Generated by Bulky Substituents.

    Science.gov (United States)

    Filatre-Furcate, Agathe; Bellec, Nathalie; Jeannin, Olivier; Auban-Senzier, Pascale; Fourmigué, Marc; Íñiguez, Jorge; Canadell, Enric; Brière, Benjamin; Ta Phuoc, Vinh; Lorcy, Dominique

    2016-06-20

    While the introduction of large, bulky substituents such as tert-butyl, -SiMe3, or -Si(isopropyl)3 has been used recently to control the solid state structures and charge mobility of organic semiconductors, this crystal engineering strategy is usually avoided in molecular metals where a maximized overlap is sought. In order to investigate such steric effects in single component conductors, the ethyl group of the known [Au(Et-thiazdt)2] radical complex has been replaced by an isopropyl one to give a novel single component molecular conductor denoted [Au(iPr-thiazdt)2] (iPr-thiazdt: N-isopropyl-1,3-thiazoline-2-thione-4,5-dithiolate). It exhibits a very original stacked structure of crisscross molecules interacting laterally to give a truly three-dimensional network. This system is weakly conducting at ambient pressure (5 S·cm(-1)), and both transport and optical measurements evidence a slowly decreasing energy gap under applied pressure with a regime change around 1.5 GPa. In contrast with other conducting systems amenable to a metallic state under physical or chemical pressure, the Mott insulating state is stable here up to 4 GPa, a consequence of its peculiar electronic structure. PMID:27266960

  8. Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

    Science.gov (United States)

    Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

    2015-09-01

    Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. PMID:26213237

  9. Covalent thiol adducts arising from reactive intermediates of cocaine biotransformation.

    Science.gov (United States)

    Schneider, Kevin J; DeCaprio, Anthony P

    2013-11-18

    Exposure to cocaine results in the depletion of hepatocellular glutathione and macromolecular protein binding in humans. Such cocaine-induced responses have generally been attributed to oxidative stress and reactive metabolites resulting from oxidative activation of the cocaine tropane nitrogen. However, little conclusive data exists on the mechanistic pathways leading to protein modification or the structure and specificity of cocaine-derived adduction products. We now report a previously uncharacterized route of cocaine bioactivation leading to the covalent adduction of biological thiols, including cysteine and glutathione. Incubation of cocaine with biological nucleophiles in an in vitro biotransformation system containing human liver microsomes identified a monooxygenase-mediated event leading to the oxidation of, and subsequent sulfhydryl addition to, the cocaine aryl moiety. Adduct structures were confirmed using ultra-high performance liquid chromatography coupled to high resolution, high mass accuracy mass spectrometry. Examination of assays containing transgenic bactosomes expressing single human cytochrome P450 isoforms determined the role of P450s 1A2, 2C19, and 2D6 in the oxidation process resulting in adduct formation. P450-catalyzed aryl epoxide formation and subsequent attack by free nucleophilic moieties is consistent with the resulting adduct structures, mechanisms of formation, and the empirical observation of multiple structural and stereo isomers. Analogous adduction mechanisms were maintained across all sulfhydryl-containing nucleophile models examined; N-acetylcysteine, glutathione, and a synthetic cysteine-containing hexapeptide. Predictive in silico calculations of molecular reactivity and electrophilicity/nucleophilicity were compared to the results of in vitro assay incubations in order to better understand the adduction process using the principles of hard and soft acid and base (HSAB) theory. This study elucidated a novel metabolic

  10. Organocatalytic removal of formaldehyde adducts from RNA and DNA bases

    Science.gov (United States)

    Karmakar, Saswata; Harcourt, Emily M.; Hewings, David S.; Lovejoy, Alexander F.; Kurtz, David M.; Ehrenschwender, Thomas; Barandun, Luzi J.; Roost, Caroline; Alizadeh, Ash A.; Kool, Eric T.

    2015-09-01

    Formaldehyde is universally used to fix tissue specimens, where it forms hemiaminal and aminal adducts with biomolecules, hindering the ability to retrieve molecular information. Common methods for removing these adducts involve extended heating, which can cause extensive degradation of nucleic acids, particularly RNA. Here, we show that water-soluble bifunctional catalysts (anthranilates and phosphanilates) speed the reversal of formaldehyde adducts of mononucleotides over standard buffers. Studies with formaldehyde-treated RNA oligonucleotides show that the catalysts enhance adduct removal, restoring unmodified RNA at 37 °C even when extensively modified, while avoiding the high temperatures that promote RNA degradation. Experiments with formalin-fixed, paraffin-embedded cell samples show that the catalysis is compatible with common RNA extraction protocols, with detectable RNA yields increased by 1.5-2.4-fold using a catalyst under optimized conditions and by 7-25-fold compared with a commercial kit. Such catalytic strategies show promise for general use in reversing formaldehyde adducts in clinical specimens.

  11. Isolation, identification, and assay of [3H]-porfiromycin adducts of EMT6 mouse mammary tumor cell DNA: effects of hypoxia and dicumarol on adduct patterns.

    Science.gov (United States)

    Tomasz, M; Hughes, C S; Chowdary, D; Keyes, S R; Lipman, R; Sartorelli, A C; Rockwell, S

    1991-07-01

    [3H]-(N-la-methyl) Porfiromycin (POR) was employed to detect and identify the radiolabeled mono- and bis-adducts formed in living EMT6 mouse mammary tumor cells under different conditions. To provide authentic standard adducts, calf-thymus DNA was treated with POR under reductive activation, then digested to nucleosides and POR-nucleoside adducts. The three major adducts formed were isolated by HPLC and authenticated. Two were mono-adducts, composed of deoxyguanosine linked at its N2-position to C-1 of POR and of 10-decarbamoyl POR. The third was a bis-adduct, in which POR was crosslinked to two deoxyguanosines at their N2-positions. DNA from [3H]-POR treated EMT6 cells was digested an analyzed by HPLC. DNA-associated label was located in thymidine and in two mono-adducts and one bis-adduct identical to those described above. Label in thymidine resulted from N-demethylation of POR and reincorporation of label into new thymidylate residues. Adducts were formed more abundantly in hypoxia than in air. In addition, the mono-adduct to crosslink ratios were different, approximately 1:1 and 2:1 for hypoxic and aerobic cells, respectively. The different patterns of alkylation in air and hypoxia may be related to the greater toxicity of POR in hypoxia. When cells were treated simultaneously with POR and dicumarol, adduct levels were lower, and a new, unknown adduct was observed primarily under hypoxia; these changes may be related to the altered toxicity of POR in the presence of dicumarol. The HPLC assay detected simultaneously the full array of stable mono- and bis-adducts in DNA with good sensitivity (greater than or equal to 2 x 10(6) adducts/nucleotide) and excellent reproducibility. This assay should be generally applicable to all cells and tissues when MC or POR with high specific radioactivity can be employed. PMID:1714285

  12. Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B(a)PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers

    Energy Technology Data Exchange (ETDEWEB)

    Sofia Pavanello; Alessandra Pulliero; Ewa Siwinska; Danuta Mielzynska; Erminio Clonfero [University of Padova, Padova (Italy). Occupational Health Section, Department of Environmental Medicine and Public Health

    2005-07-01

    It is important to identify the potential genetic-susceptible factors that are able to modulate individual responses to exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). In the present study we evaluated the influence of four polymorphisms of nucleotide excision repair (NER) genes and that of glutathione S-transferase {mu}1 (GSTM1-active or -null) on benzo(a)pyrene diol epoxide (B(a)PDE)-DNA adduct levels from the lympho-monocyte fraction (LMF) of highly PAH benzo(a)pyrene -exposed Polish coke oven workers with individual urinary post-shift excretion of 1-pyrenol exceeding the proposed biological exposure index. The bulky {+-}-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-B(a)PDE)-DNA adduct levels were detected by high-performance liquid chromatography fluorescence analysis and genotypes by polymerase chain reaction. We found that workers with the low DNA repair capacity of XPC-PAT+/+ and XPA-A23A genotypes had increased anti-B(a)PDE-DNA adduct levels, DNA adducts were also raised in workers without GSTM1 activity. Workers with unfavourable XPC-PAT+/+ and XPA-A23A NER genotypes, alone or combined with GSTM1-null genotype were in the tertile with the highest adduct level. The increase in anti-B(a)PDE-DNA adduct levels was related in a multiple linear regression analysis to PAH exposure lack of GSTM1 activity and to low DNA repair capacity of the XPC-PAT+/+ genotype. The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found. The modulation of anti-B(a)PDE-DNA adducts in the LMF by GSTM1-null and some low-activity NER genotypes may be considered as a potential genetic susceptibility factor capable of modulating individual responses to PAH genotoxic exposure and the consequent risk of cancer in coke oven workers.

  13. Conformational preferences of DNA following damage by aristolochic acids: Structural and energetic insights into the different mutagenic potential of the ALI and ALII-N(6)-dA adducts.

    Science.gov (United States)

    Kathuria, Preetleen; Sharma, Purshotam; Abendong, Minette N; Wetmore, Stacey D

    2015-04-21

    Aristolochic acids (AAI and AAII), produced by the Aristolochiaceae family of plants, are classified as group I (human) carcinogens by the International Agency for Research on Cancer. These acids are metabolized in cells to yield aristolactams (ALI and ALII, respectively), which further form bulky adducts with the purine nucleobases. Specifically, the adenine lesions are more persistent in cells and have been associated with chronic renal diseases and related carcinogenesis. To understand the structural basis of the nephrotoxicity induced by AAs, the ALI-N(6)-dA and ALII-N(6)-dA lesions are systematically studied using computational methods. Density functional theory calculations indicate that the aristolactam moiety intrinsically prefers a planar conformation with respect to adenine. Nucleoside and nucleotide models suggest that the anti and syn orientations about the glycosidic bond are isoenergetic for both adducts. Molecular dynamics simulations and free energy calculations reveal that the anti base-displaced intercalated conformation is the most stable conformer for both types of AL-N(6)-dA adducted DNA, which agrees with previous experimental work on the ALII-N(6)-dA adduct and thereby validates our approach. Interestingly, this conformer differs from the dominant conformations adopted by other N6-linked adenine lesions, including those derived from polycyclic aromatic hydrocarbons. Furthermore, the second most stable syn base-displaced intercalated conformation lies closer in energy to the anti base-displaced intercalated conformation for ALI-N(6)-dA compared to ALII-N(6)-dA. This indicates that a mixture of conformations may be detectable for ALI-N(6)-dA in DNA. If this enhanced conformational flexibility of double-stranded DNA persists when bound to a lesion-bypass polymerase, this provides a possible structural explanation for the previously observed greater nephrotoxic potential for the ALI versus ALII-N(6)-dA adduct. In addition, the structural

  14. Synthesis and Olfactory Evaluation of Bulky Moiety-Modified Analogues to the Sandalwood Odorant Polysantol®

    Directory of Open Access Journals (Sweden)

    Adolfo Sánchez

    2009-07-01

    Full Text Available Five new bulky moiety-modified analogues of the sandalwood odorant Polysantol® have been synthesized by aldol condensation of appropriate aldehydes with butanone, deconjugative α-methylation of the resulting α,β-unsaturated ketones, and reduction of the corresponding β,γ-unsaturated ketones. The final compounds were evaluated organoleptically and one of them seemed to be of special interest for its natural sandalwood scent.

  15. P53 overexpression is associated with bulky tumor and poor local control in T1 glottic cancer

    International Nuclear Information System (INIS)

    Purpose: To study the role of two possible prognostic factors, p53 and tumor bulk, and their interaction with other tumor and treatment variables in early-stage laryngeal cancer patients treated with curative radiotherapy. Methods: One hundred two patients with T1N0M0 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy were analyzed. p53 status in pretreatment biopsy specimens was assessed by immunohistochemistry (IHC) using mouse monoclonal antibody DO-7. Tumors were classified as small surface lesions or bulky tumors. All tumor-related and treatment-related variables which might influence the outcome were analyzed. Local control after definitive radiotherapy was the end point of the study. Results: The local control at 5 years for the entire group of patients was 78% (80/102) and 91% (93/102) after surgical salvage. p53 overexpression by IHC was seen in 37% (38/102) of patients. Tumors were classified as small volume in 69 (68%) and bulky in 33 (32%) patients. Five-year local control was 48% for p53-positive patients as compared to 94% for p53-negative patients (p = 0.0001). Tumor bulk was the other important prognostic factor, with 5-year local control of 91% for small tumors and 48% for bulky tumors (p = 0.0001). Patients who had both p53 positivity and bulky tumors did worse, with a 5-year local control of 23% as compared to 92% for all other groups combined (p = 0.0001). Among other variables, only the length of radiation time was of borderline significance. Conclusion: Both p53 overexpression and tumor bulk are independent prognostic factors for local control in early-stage glottic cancer treated with curative radiotherapy. The precise relationship between a genetic event, the p53 mutation, and an observable phenotype expression such as tumor bulk needs to be further defined

  16. Coordination complexes of niobium and tantalum pentahalides with a bulky NHC ligand.

    Science.gov (United States)

    Bortoluzzi, Marco; Ferretti, Eleonora; Marchetti, Fabio; Pampaloni, Guido; Zacchini, Stefano

    2016-04-19

    The 1 : 1 molar reactions of niobium and tantalum pentahalides with the monodentate NHC ligand 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (Ipr), in toluene (or benzene) at ca. 80 °C, afforded the complexes NbX5(Ipr) (X = F, ; Br, ) and TaX5(Ipr) (X = F, ; Cl, ; Br, ), in generally good yields. Complexes represent uncommon cases of stable NHC adducts of metal halides with the metal in an oxidation state higher than +4, and also rare examples of Nb-NHC and Ta-NHC bonding systems. In particular, the X-ray molecular structure determined for provides the unprecedented crystallographic characterization of a tantalum compound with a monodentate NHC ligand. DFT results indicate that the metal-carbon bond in is a purely σ one. According to NMR studies ((1)H, (13)C, (93)Nb), the formation of , , , as well as the previously communicated NbCl5(Ipr), , proceeded with the intermediacy of [MX6](-) salts, presumably due to steric reasons. On the other hand, the intermediate formation of MF6(-) in the pathways to and was not observed, according to (19)F (and (93)Nb in the case of ) NMR. DFT calculations were carried out in order to shed light on structural and mechanistic aspects, and allowed to trace possible reaction routes. PMID:26982241

  17. Quantitation of DNA Adducts Induced by 1,3-Butadiene

    Science.gov (United States)

    Sangaraju, Dewakar; Villalta, Peter W.; Wickramaratne, Susith; Swenberg, James; Tretyakova, Natalia

    2014-07-01

    Human exposure to 1,3-butadiene (BD) present in automobile exhaust, cigarette smoke, and forest fires is of great concern because of its potent carcinogenicity. The adverse health effects of BD are mediated by its epoxide metabolites such as 3,4-epoxy-1-butene (EB), which covalently modify genomic DNA to form promutagenic nucleobase adducts. Because of their direct role in cancer, BD-DNA adducts can be used as mechanism-based biomarkers of BD exposure. In the present work, a mass spectrometry-based methodology was developed for accurate, sensitive, and precise quantification of EB-induced N-7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) DNA adducts in vivo. In our approach, EB-GII adducts are selectively released from DNA backbone by neutral thermal hydrolysis, followed by ultrafiltration, offline HPLC purification, and isotope dilution nanoLC/ESI+-HRMS3 analysis on an Orbitrap Velos mass spectrometer. Following method validation, EB-GII lesions were quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of EB and in liver tissues of rats exposed to sub-ppm concentrations of BD (0.5-1.5 ppm). EB-GII concentrations increased linearly from 1.15 ± 0.23 to 10.11 ± 0.45 adducts per 106 nucleotides in HT1080 cells treated with 0.5-10 μM DEB. EB-GII concentrations in DNA of laboratory rats exposed to 0.5, 1.0, and 1.5 ppm BD were 0.17 ± 0.05, 0.33 ± 0.08, and 0.50 ± 0.04 adducts per 106 nucleotides, respectively. We also used the new method to determine the in vivo half-life of EB-GII adducts in rat liver DNA (2.20 ± 0.12 d) and to detect EB-GII in human blood DNA. To our knowledge, this is the first application of nanoLC/ESI+-HRMS3 Orbitrap methodology to quantitative analysis of DNA adducts in vivo.

  18. Mutational properties of the primary aflatoxin B1-DNA adduct.

    OpenAIRE

    Bailey, E A; Iyer, R S; Stone, M. P.; Harris, T M; Essigmann, J M

    1996-01-01

    The mutagenic activity of the major DNA adduct formed by the liver carcinogen aflatoxin B1 (AFB1) was investigated in vivo. An oligonucleotide containing a single 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) adduct was inserted into the single-stranded genome of bacteriophage M13. Replication in SOS-induced Escherichia coli yielded a mutation frequency for AFB1-N7-Gua of 4%. The predominant mutation was G --> T, identical to the principal mutation in human liver tumors believ...

  19. Chemistry and Biology of Aflatoxin-DNA Adducts

    Energy Technology Data Exchange (ETDEWEB)

    Stone, Michael P.; Banerjee, Surajit; Brown, Kyle L.; Egli, Martin (Vanderbilt)

    2012-03-27

    Aspergillus flavus is a fungal contaminant of stored rice, wheat, corn, and other grainstuffs, and peanuts. This is of concern to human health because it produces the mycotoxin aflatoxin B{sub 1} (AFB{sub 1}), which is genotoxic and is implicated in the etiology of liver cancer. AFB{sub 1} is oxidized in vivo by cytochrome P450 to form aflatoxin B{sub 1} epoxide, which forms an N7-dG adduct (AFB{sub 1}-N7-dG) in DNA. The latter rearranges to a formamidopyrimidine (AFB{sub 1}-FAPY) derivative that equilibrates between {alpha} and {beta} anomers of the deoxyribose. In DNA, both the AFB{sub 1}-N7-dG and AFB{sub 1}-{beta}-FAPY adducts intercalate above the 5'-face of the damaged guanine. Each produces G {yields} T transversions in Escherichia coli, but the AFB{sub 1}-{beta}-FAPY adduct is more mutagenic. The Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) provides a model for understanding error-prone bypass of the AFB{sub 1}-N7-dG and AFB{sub 1}-{beta}-FAPY adducts. It bypasses the AFB{sub 1}-N7-dG adduct, but it conducts error-prone replication past the AFB{sub 1}-FAPY adduct, including mis-insertion of dATP, consistent with the G {yields} T mutations characteristic of AFB{sub 1} mutagenesis in E. coli. Crystallographic analyses of a series of binary and ternary complexes with the Dpo4 polymerase revealed differing orientations of the N7-C8 bond of the AFB{sub 1}-N7-dG adduct as compared to the N{sup 5}-C8 bond in the AFB{sub 1}-{beta}-FAPY adduct, and differential accommodation of the intercalated AFB{sub 1} moieties within the active site. These may modulate AFB{sub 1} lesion bypass by this polymerase.

  20. [sup 129]I Moessbauer spectroscopic study of metallocene-iodine adducts

    Energy Technology Data Exchange (ETDEWEB)

    Nakashima, Satoru (Dept. of Chemistry, Faculty of Science, Hiroshima Univ. (Japan)); Sakai, Hiroshi (Dept. of Chemistry, Faculty of Science, Hiroshima Univ. (Japan)); Watanabe, Masanobu (Dept. of Chemistry, Coll. of Arts and Sciences, Univ. of Tokyo (Japan)); Maeda, Yutaka (Research Reactor Inst., Kyoto Univ., Osaka (Japan))

    1994-05-01

    A [sup 129]I Moessbauer spectroscopic study of iodine adducts of ferrocenophane, biruthenocene, and osmocene is reported. The spectra show the existence of iodine bonded to the central metals of metallocenes in addition to triiodide anions. The valence state of iron in the ferrocenophane-iodine adduct is the same as those of ruthenium and osmium in their adducts. (orig.)

  1. A treatment planning approach to spatially fractionated megavoltage grid therapy for bulky lung cancer

    International Nuclear Information System (INIS)

    The purpose of this study was to explore the treatment planning methods of spatially fractionated megavoltage grid therapy for treating bulky lung tumors using multileaf collimator (MLC). A total of 5 patients with lung cancer who had gross tumor volumes ranging from 277 to 635 cm3 were retrospectively chosen for this study. The tumors were from 6.5 to 9.6 cm at shortest dimension. Several techniques using either electronic compensation or intensity-modulated radiation therapy (IMRT) were used to create a variety of grid therapy plans on the Eclipse treatment planning system. The dose prescription point was calculated to the volume, and a dose of 20 Gy with 6-MV/15-MV beams was used in each plan. The dose-volume histogram (DVH) curves were obtained to evaluate dosimetric characteristics. In addition, DVH curves from a commercially available cerrobend grid collimator were also used for comparison. The linear-quadratic radiobiological response model was used to assess therapeutic ratios (TRs) and equivalent uniform doses (EUD) for all generated plans. A total of 6 different grid therapy plans were created for each patient. Overall, 4 plans had different electronic compensation techniques: Ecomps-Tubes, Ecomps-Circles, Ecomps-Squares, and Ecomps-Weave; the other 2 plans used IMRT and IMRT-Weave techniques. The DVH curves and TRs demonstrated that these MLC-based grid therapy plans can achieve dosimetric properties very similar to those of the cerrobend grid collimator. However, the MLC-based plans have larger EUDs than those with the cerrobend grid collimator. In addition, the field shaping can be performed for targets of any shape in MLC-based plans. Thus, they can deliver a more conformal dose to the targets and spare normal structures better than the cerrobend grid collimator can. The plans generated by the MLC technique demonstrated the advantage over the standard cerrobend grid collimator on accommodating targets and sparing normal structures. Overall, 6

  2. A treatment planning approach to spatially fractionated megavoltage grid therapy for bulky lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Costlow, Heather N. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN (United States); Zhang, Hualin, E-mail: hzhang@nmh.org [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN (United States); Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Northwestern University, Northwestern Memorial Hospital, Chicago, IL (United States); Das, Indra J. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN (United States)

    2014-10-01

    The purpose of this study was to explore the treatment planning methods of spatially fractionated megavoltage grid therapy for treating bulky lung tumors using multileaf collimator (MLC). A total of 5 patients with lung cancer who had gross tumor volumes ranging from 277 to 635 cm{sup 3} were retrospectively chosen for this study. The tumors were from 6.5 to 9.6 cm at shortest dimension. Several techniques using either electronic compensation or intensity-modulated radiation therapy (IMRT) were used to create a variety of grid therapy plans on the Eclipse treatment planning system. The dose prescription point was calculated to the volume, and a dose of 20 Gy with 6-MV/15-MV beams was used in each plan. The dose-volume histogram (DVH) curves were obtained to evaluate dosimetric characteristics. In addition, DVH curves from a commercially available cerrobend grid collimator were also used for comparison. The linear-quadratic radiobiological response model was used to assess therapeutic ratios (TRs) and equivalent uniform doses (EUD) for all generated plans. A total of 6 different grid therapy plans were created for each patient. Overall, 4 plans had different electronic compensation techniques: Ecomps-Tubes, Ecomps-Circles, Ecomps-Squares, and Ecomps-Weave; the other 2 plans used IMRT and IMRT-Weave techniques. The DVH curves and TRs demonstrated that these MLC-based grid therapy plans can achieve dosimetric properties very similar to those of the cerrobend grid collimator. However, the MLC-based plans have larger EUDs than those with the cerrobend grid collimator. In addition, the field shaping can be performed for targets of any shape in MLC-based plans. Thus, they can deliver a more conformal dose to the targets and spare normal structures better than the cerrobend grid collimator can. The plans generated by the MLC technique demonstrated the advantage over the standard cerrobend grid collimator on accommodating targets and sparing normal structures. Overall, 6

  3. Synthesis of Borinic Acids and Borinate Adducts Using Diisopropylaminoborane.

    Science.gov (United States)

    Marciasini, Ludovic; Cacciuttolo, Bastien; Vaultier, Michel; Pucheault, Mathieu

    2015-07-17

    In situ formation of aryl Grignard under Barbier condition and diisopropylaminoborane as boron source allows a complete control of the addition onto the boron electrophile. Analytically pure borinic acid derivatives were produced at the gram scale without column chromatography and isolated as borinates adducts, with ethanolamine or 8-hydroxyquinoline, after workup. PMID:26183591

  4. Characterization of trypsin-derived peptides acrylamide-adducted hemoglobin

    International Nuclear Information System (INIS)

    Even though there are a number of sources for human exposure to acrylamide, reliable biomarkers of exposure are not available. In an effort to develop such a biomarker, the authors are characterizing peptides derived from trypsin digests of acrylamide-adducted hemoglobin. For this, radiolabeled acrylamide was incubated with this, radiolabeled acrylamide was incubated with purified human hemoglobin (Ao) and decomposition products removed by dialysis. When the adducted hemoglobin was separated by reverse-phase HPLC, radioactivity eluted with the α and β subunits, suggesting covalent binding. Digestion of individual subunits with trypsin followed by reverse phase HPLC, indicated that most of the radioactivity associated with the α subunit co-eluted with a single peptide. Similar results were observed for the β subunit except that significant amounts of radioactivity eluted with the solvent front, suggesting that radioactivity was released by trypsin digestion. Currently, these preparation are under further characterization by electrospray ionization mass spectrometry. This approach will aid in the identification of the adducted will aid in the identification of the adducted peptide and subsequent preparation of an acrylamide-specific antibody

  5. Stability, accumulation and cytotoxicity of an albumin-cisplatin adduct

    DEFF Research Database (Denmark)

    Møller, Charlotte; Tastesen, Hanne Sørup; Gammelgaard, Bente;

    2010-01-01

    The accumulation and cytotoxicity of a 10 µmol L¿¹ equimolar human serum albumin-cisplatin adduct (HSA-Pt) was investigated in suspension Ehrlich Ascites Tumor Cells (EATC) and adherent Ehrlich Lettré Ascites Cells (Lettré). HSA-Pt did not induce apoptosis nor was it taken up by the cells to any...

  6. Triphosgene mediated chlorination of Baylis-Hillman adducts

    Indian Academy of Sciences (India)

    Narender Reddy Thatikonda; Naga Sesha Sai Pavan Kumar Chebolu; Mahendar Budde; Jayathirtha Rao Vaidya

    2012-03-01

    An efficient method for the preparation of allyl chlorides from Baylis-Hillman adducts has been developed using triphosgene/pyridine system. This method is best illustrated by its advantages like operational simplicity, excellent yields, short reaction time, simple procedure and stereoselectivity.

  7. Detection of protein adduction derived from dauricine by alkaline permethylation.

    Science.gov (United States)

    Xie, Honglei; Liu, Yuyang; Peng, Ying; Zhao, Dongmei; Zheng, Jiang

    2016-06-01

    Dauricine is a bisbenzylisoquinoline alkaloid derivative and has shown multiple pharmacological properties. Despite this, our previous study demonstrated that dauricine induced severe lung toxicity in experimental animals. Metabolic activation of dauricine to the corresponding quinone methide intermediate is suggested to play an important role in dauricine-induced cytotoxicity. Protein adduction derived from the reactive intermediate is considered to initiate the process of the toxicity. In the present study, we developed an alkaline permethylation- and mass spectrometry-based approach to detect dauricine-derived protein adduction. Protein samples were permethylated in the presence of NaOH and CH3I at 80 °C, followed by LC-MS/MS analysis. A thioether product was produced in the reaction. Not only does this technique quantify dauricine-derived protein adduction but also it tells the nature of the interaction between the target proteins and the reactive intermediate of dauricine. The recovery, precision, limit of detection, limit of quantity, and method detection limit were found to be 102.8 %±1.7 %, 1.89 %, 1.32 fmol/mL, 4.93 fmol/mL and 3.37 fmol/mL respectively. The surrogate recovery and surrogate RSD values were 81.5-103.0 % and 2.59 %, respectively. This analytical method has proven sensitive, selective, reliable, and feasible to assess total protein adduction derived from dauricine, and will facilitate the mechanistic investigation of dauricine and other bisbenzylisoquinoline toxicities. Graphical Abstract Alkaline permethylation of dauricine derived protein adduct. PMID:27071763

  8. Quantification of Carnosine-Aldehyde Adducts in Human Urine.

    Science.gov (United States)

    da Silva Bispo, Vanderson; Di Mascio, Paolo; Medeiros, Marisa

    2014-10-01

    Lipid peroxidation generates several reactive carbonyl species, including 4-hydroxy-2-nonenal (HNE), acrolein (ACR), 4-hydroxy-2-hexenal (HHE) and malondialdehyde. One major pathwayof aldehydes detoxification is through conjugation with glutathione catalyzed by glutathione-S-transferases or, alternatively, by conjugation with endogenous histidine containing dipeptides, such as carnosine (CAR). In this study, on-line reverse-phase high-performance liquid chromatography (HPLC) separation with tandem mass spectrometry detection was utilized for the accurate quantification of CAR- ACR, CAR-HHE and CAR-HNE adducts in human urinary samples from non-smokers young adults. Standard adducts were prepared and isolated by HPLC. The results showed the presence of a new product from the reaction of CAR with ACR. This new adduct was completely characterized by HPLC/MS-MSn, 1H RMN, COSY and HSQC. The new HPLC/MS/MS methodology employing stable isotope-labeled internal standards (CAR-HHEd5 and CAR-HNEd11) was developed for adducts quantification. This methodology permits quantification of 10pmol CAR-HHE and 1pmol of CAR-ACR and CAR-HNE. Accurate determinations in human urine sample were performed and showed 4.65±1.71 to CAR-ACR, 5.13±1.76 to CAR-HHE and 5.99±3.19nmol/mg creatinine to CAR-HNE. Our results indicate that carnosine pathways can be an important detoxification route of a, ß -unsaturated aldehydes. Moreover, carnosine adducts may be useful as redox stress indicator. PMID:26461323

  9. 32P-postlabeling DNA adduct assay: cigarette smoke-induced dna adducts in the respiratory and nonrespiratory rat tissues. Book chapter

    International Nuclear Information System (INIS)

    An analysis of the tissue DNA adducts in rats by the sensitive (32)p-postlabeling assay showed one to eight detectable DNA adducts in lung, trachea, larynx, heart and bladder of the sham controls. Chronic exposure of animals to mainstream cigarette smoke showed a remarkable enhancement of most adducts in the lung and heart DNA. Since cigarette smoke contains several thousand chemicals and a few dozen of them are known or potential carcinogens, the difference between the DNA adducts of nasal and the other tissues may reflect the diversity of reactive constituents and their differential absorption in different tissues. In comparison to the lung DNA adducts, the adducts in nasal DNA were less hydrophobic. Identity of the predominant adducts was further investigated by comparison with several reference DNA adducts from 10 PAH and aromatic amines. Since some of these chemicals are present in cigarette smoke, the results suggest that these constituents of cigarette smoke may not be directly responsible for formation of DNA adducts in the lung and heart of the smoke-exposed animals

  10. Photochemistry of psoralen-DNA adducts, biological effects of psoralen-DNA adducts, applications of psoralen-DNA photochemistry

    International Nuclear Information System (INIS)

    This thesis consists of three main parts and totally eight chapters. In Part I, The author will present studies on the photochemistry of psoralen-DNA adducts, specifically, the wavelength dependencies for the photoreversals of thymidine-HMT (4'-hydroxymethyl-4, 5', 8-trimenthylpsoralen) monoadducts and diadduct and the same adducts incorporated in DNA helices and the wavelength dependecies for the photocrossslinking of thymidine-HMT monoadducts in double-stranded helices. In Part II, The author will report some biological effects of psoralen-DNA adducts, i.e., the effects on double-stranded DNA stability, DNA structure, and transcription by E. coli and T7 RNA polymerases. Finally, The author will focus on the applications of psoralen-DNA photochemistry to investigation of protein-DNA interaction during transcription, which includes the interaction of E. coli and T7 RNA polymerases with DNA in elongation complexes arrested at specific psoralen-DNA adduct sites as revealed by DNase I footprinting experiments. 123 refs., 52 figs., 12 tabs

  11. Photochemistry of psoralen-DNA adducts, biological effects of psoralen-DNA adducts, applications of psoralen-DNA photochemistry

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Yun-bo

    1988-03-01

    This thesis consists of three main parts and totally eight chapters. In Part I, The author will present studies on the photochemistry of psoralen-DNA adducts, specifically, the wavelength dependencies for the photoreversals of thymidine-HMT (4'-hydroxymethyl-4, 5', 8-trimenthylpsoralen) monoadducts and diadduct and the same adducts incorporated in DNA helices and the wavelength dependecies for the photocrossslinking of thymidine-HMT monoadducts in double-stranded helices. In Part II, The author will report some biological effects of psoralen-DNA adducts, i.e., the effects on double-stranded DNA stability, DNA structure, and transcription by E. coli and T7 RNA polymerases. Finally, The author will focus on the applications of psoralen-DNA photochemistry to investigation of protein-DNA interaction during transcription, which includes the interaction of E. coli and T7 RNA polymerases with DNA in elongation complexes arrested at specific psoralen-DNA adduct sites as revealed by DNase I footprinting experiments. 123 refs., 52 figs., 12 tabs.

  12. Chloroethyinitrosourea-derived ethano cytosine and adenine adducts are substrates for escherichia coli glycosylases excising analogous etheno adducts

    Energy Technology Data Exchange (ETDEWEB)

    Guliaev, Anton B.; Singer, B.; Hang, Bo

    2004-05-05

    Exocyclic ethano DNA adducts are saturated etheno ring derivatives formed mainly by therapeutic chloroethylnitrosoureas (CNUs), which are also mutagenic and carcinogenic. In this work, we report that two of the ethano adducts, 3,N{sup 4}-ethanocytosine (EC) and 1,N{sup 6}-ethanoadenine (EA), are novel substrates for the Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug) and 3-methyladenine DNA glycosylase II (AlkA), respectively. It has been shown previously that Mug excises 3,N{sup 4}-ethenocytosine ({var_epsilon}C) and AlkA releases 1,N{sup 6}-ethenoadenine ({var_epsilon}A). Using synthetic oligonucleotides containing a single ethano or etheno adduct, we found that both glycosylases had a {approx}20-fold lower excision activity toward EC or EA than that toward their structurally analogous {var_epsilon}C or {var_epsilon}A adduct. Both enzymes were capable of excising the ethano base paired with any of the four natural bases, but with varying efficiencies. The Mug activity toward EC could be stimulated by E. coli endonuclease IV and, more efficiently, by exonuclease III. Molecular dynamics (MD) simulations showed similar structural features of the etheno and ethano derivatives when present in DNA duplexes. However, also as shown by MD, the stacking interaction between the EC base and Phe 30 in the Mug active site is reduced as compared to the {var_epsilon}C base, which could account for the lower EC activity observed in this study.

  13. Eradicative brachytherapy with hyaluronate gel injection into pararectal space in treatment of bulky vaginal stump recurrence of uterine cancer

    International Nuclear Information System (INIS)

    The purpose of this study is to develop a procedure for eradicative brachytherapy that can deliver a curative boost dose to bulky (>4 cm) vaginal stump recurrence of uterine cancer without risk of damaging surrounding organs. We separated risk organs (the rectum and sigmoid) from the target during brachytherapy, with a hyaluronate gel injection into the pararectal space via the percutaneous paraperineal approach under local anesthesia. The rectum anchored to the sacrum by native ligament was expected to shift posteriorly. We encountered a patient with bulky stump recurrence of uterine cancer, approximately 8 cm in maximum diameter. She was complaining of abdominal pain and constipation due to bowel encasement. Following 50 Gy of external beam radiotherapy, we applied a single fraction of brachytherapy under gel separation and delivered 14.5 Gy (50.8 GyE: equivalent dose in 2-Gy fraction calculated with linear quadratic model at α/β=3) to the target. The gel injection procedure was completed in 30 min without complications. A total irradiation dose of 100.8 GyE was delivered to the target and the cumulative minimum dose to the most irradiated rectosigmoidal volume of 2 cc (cumulative D2cc) was calculated as 58.5 GyE with gel injection, and was estimated to be 96 GyE without. Over three years, the local stump tumor has completely disappeared, with no complications. Brachytherapy with a pararectal gel injection can be a safe and effective eradicative option for bulky vaginal stump recurrence. (author)

  14. Tuning the self-assembly of the bioactive dipeptide L-carnosine by incorporation of a bulky aromatic substituent

    OpenAIRE

    Castelletto, Valeria; Cheng, Ge; Greenland, Barny W.; Hamley, Ian W.; Harris, Peter J. F.

    2011-01-01

    The dipeptide L-carnosine has a number of important biological properties. Here, we explore the effect of attachment of a bulky hydrophobic aromatic unit, Fmoc [N-(fluorenyl-9-methoxycarbonyl)] on the self-assembly of Fmoc-L-carnosine, i.e., Fmoc-Beta-alanine-histidine (Fmoc-BetaAH). It is shown that Fmoc-BetaAH forms well-defined amyloid fibril containing Beta sheets above a critical aggregation concentration, which is determined from pyrene and ThT fluorescence experiments. Twisted fi...

  15. Seasonal variations in levels of DNA adducts and X-spots in human populations living in different parts of Poland.

    OpenAIRE

    Grzybowska, E; Hemminki, K; Choraźy, M

    1993-01-01

    White blood cell DNA adducts were measured in coke oven workers, in residents from the area next to the coke oven in Silesia, Poland (highly industrialized region), and in residents from the rural area of Poland using the 32P-postlabeling technique. This method detected aromatic adducts including adducts formed by polycyclic aromatic hydrocarbons (PAHs). Highest levels of adducts in DNA were seen in the group of coke battery workers (6.9 adducts/10(8) nucleotides). Seasonal variations in leve...

  16. A novel technique of in situ phase-shift interferometry applied for faint dissolution of bulky montmorillonite in alkaline solution

    International Nuclear Information System (INIS)

    The effect of alkaline pH on the dissolution rate of bulky aggregated montmorillonite samples at 23°C was investigated for the first time by using an enhanced phase-shift interferometry technique combined with an internal refraction interferometry method developed for this study. This technique was applied to provide a molecular resolution during the optical observation of the dissolution phenomena in real time and in situ while remaining noninvasive. A theoretical normal resolution limit of this technique was 0.78 nm in water for opaque material, but was limited to 6.6 nm for montmorillonite due to the transparency of the montmorillonite crystal. Normal dissolution velocities as low as 1 × 10-4 to 1 × 10-3 nm/s were obtained directly by using the measured temporal change in height of montmorillonite samples set in a reaction cell. The molar dissolution fluxes of montmorillonite obtained in this study gave considerably faster dissolution rates in comparison to those obtained in previous investigations by solution analysis methods. The pH dependence of montmorillonite dissolution rate determined in this study was qualitatively in good agreement with those reported in the previous investigations. The dissolution rates to be used in safety assessments of geological repositories for radioactive wastes should be obtained for bulky samples. This goal has been difficult to achieve using conventional powder experiment technique and solution analysis method, but has been shown to be feasible using the enhanced phase-shift interferometry. (author)

  17. Protein tyrosine adduct in humans self-poisoned by chlorpyrifos

    International Nuclear Information System (INIS)

    Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos. - Highlights: • Chlorpyrifos-poisoned patients have adducts on protein tyrosine. • Diethoxyphosphate-tyrosine does not lose an alkyl group. • Proteins in addition to AChE and BChE are modified by organophosphates

  18. SEM-EDX STUDIES OF CHITOSAN DERIVATIVES-METAL ADDUCTS

    OpenAIRE

    Galo Cárdenas; Edelio Taboada; Armando Bravo; S. Patricia Miranda

    2003-01-01

    Chitosan was obtained from shrimps shells (pleuroncodes monodon) using chemical methods. A series of chitosan (QS)charged with solution of copper, cobalt, nickel and mercury ions were prepared at room temperature using the batch method. N-3,5-diethylamino benzoyl chitosan (QDAB); N,O-dimercapto succinate chitosan (QNOT) and 4-aminobenzoate chitosan (QAB) derivatives were prepared. The chitosan metal adducts with Cu, Co, Ni and Hg ions and derivatives maximum loading is discussed. Chitosan and...

  19. Tunable degradation of maleimide-thiol adducts in reducing environments

    OpenAIRE

    Baldwin, Aaron D.; Kiick, Kristi L.

    2011-01-01

    Addition chemistries are widely used in preparing biological conjugates, and in particular, maleimide-thiol adducts have been widely employed. Here we show that the resulting succinimide thioether formed by a Michael type addition of a thiol to N-ethylmaleimide (NEM), generally accepted as stable, can in fact undergo retro and exchange reactions in the presence of other thiol compounds at physiological pH and temperature, offering a novel strategy for controlled release. Model studies (1H NMR...

  20. Protein modification by acrolein: Formation and stability of cysteine adducts

    OpenAIRE

    Cai, Jian; Bhatnagar, Aruni; Pierce, William M.

    2009-01-01

    The toxicity of the ubiquitous pollutant and endogenous metabolite, acrolein, is due in part to covalent protein modifications. Acrolein reacts readily with protein nucleophiles via Michael addition and Schiff base formation. Potential acrolein targets in protein include the nucleophilic side chains of cysteine, histidine, and lysine residues as well as the free amino terminus of proteins. Although cysteine is the most acrolein-reactive residue, cysteine-acrolein adducts are difficult to iden...

  1. PHOSPHATO AND PHOSPHONATO ADDUCTS: SYNTHESIS AND SPECTROSCOPIC STUDY

    Directory of Open Access Journals (Sweden)

    Mouhamadou Birame Diop

    2014-05-01

    Full Text Available Two new adducts have been synthesized and studied by infrared and NMR spectroscopy. The suggested structures are discrete or of infinite chain type with a phosphate behaving as a bidentate ligand, a phosphonate acting as a monodentate ligand, the environments around the tin centre being tetrahedral or trigonal bipyramidal. In all the studied compounds, supramolecular architectures are obtained when hydrogen bonds are considered.

  2. Protein tyrosine adduct in humans self-poisoned by chlorpyrifos

    Energy Technology Data Exchange (ETDEWEB)

    Li, Bin, E-mail: binli@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States); Eyer, Peter, E-mail: peter.eyer@lrz.uni-muenchen.de [Walther-Straub-Institut Für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 München (Germany); Eddleston, Michael, E-mail: M.Eddleston@ed.ac.uk [Clinical Pharmacology Unit, University of Edinburgh, Edinburgh (United Kingdom); Jiang, Wei, E-mail: wjiang@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States); Schopfer, Lawrence M., E-mail: lmschopf@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States); Lockridge, Oksana, E-mail: olockrid@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States)

    2013-06-15

    Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos. - Highlights: • Chlorpyrifos-poisoned patients have adducts on protein tyrosine. • Diethoxyphosphate-tyrosine does not lose an alkyl group. • Proteins in addition to AChE and BChE are modified by organophosphates.

  3. Ion Pairs or Neutral Molecule Adducts? Cooperativity in Hydrogen Bonding

    Science.gov (United States)

    DeKock, Roger L.; Schipper, Laura A.; Dykhouse, Stephanie C.; Heeringa, Lee P.; Brandsen, Benjamin M.

    2009-01-01

    We performed theoretical studies on the systems NH[subscript 3] times HF times mH[subscript 2]O, NH[subscript 3] times HCl times mH[subscript 2]O, with m = 0, 1, 2, and 6. The molecules with m = 0 form hydrogen-bonded adducts with little tendency to form an ion-pair structure. The molecule NH[subscript 3] times HCl times H[subscript 2]O cannot be…

  4. Formation and persistence of arylamine DNA adducts in vivo.

    OpenAIRE

    Beland, F A; Kadlubar, F F

    1985-01-01

    Aromatic amines are urinary bladder carcinogens in man and induce tumors at a number of sites in experimental animals including the liver, mammary gland, intestine, and bladder. In this review, the particular pathways involved in the metabolic activation of aromatic amines are considered as well as the specific DNA adducts formed in target and nontarget tissue. Particular emphasis is placed on the following compounds: 1-naphthylamine, 2-naphthylamine, 4-aminobiphenyl, 4-acetylaminobiphenyl, 4...

  5. High resolution mass spectrometry based profiling of diet-related deoxyribonucleic acid adducts.

    Science.gov (United States)

    Hemeryck, Lieselot Y; Decloedt, Anneleen I; Vanden Bussche, Julie; Geboes, Karen P; Vanhaecke, Lynn

    2015-09-10

    Exposure of DNA to endo- and exogenous DNA binding chemicals can result in the formation of DNA adducts and is believed to be the first step in chemically induced carcinogenesis. DNA adductomics is a relatively new field of research which studies the formation of known and unknown DNA adducts in DNA due to exposure to genotoxic chemicals. In this study, a new UHPLC-HRMS(/MS)-based DNA adduct detection method was developed and validated. Four targeted DNA adducts, which all have been linked to dietary genotoxicity, were included in the described method; O(6)-methylguanine (O(6)-MeG), O(6)-carboxymethylguanine (O(6)-CMG), pyrimidopurinone (M1G) and methylhydroxypropanoguanine (CroG). As a supplementary tool for DNA adductomics, a DNA adduct database, which currently contains 123 different diet-related DNA adducts, was constructed. By means of the newly developed method and database, all 4 targeted DNA adducts and 32 untargeted DNA adducts could be detected in different DNA samples. The obtained results clearly demonstrate the merit of the described method for both targeted and untargeted DNA adduct detection in vitro and in vivo, whilst the diet-related DNA adduct database can distinctly facilitate data interpretation. PMID:26388482

  6. Formation and persistence of DNA adducts of anticancer drug ellipticine in rats

    International Nuclear Information System (INIS)

    Ellipticine is an antineoplastic agent, whose mode of antitumor and/or toxic side effects is based on DNA intercalation, inhibition of topoisomerase II and formation of DNA adducts mediated by cytochromes P450 and peroxidases. We investigated the formation and persistence of DNA adducts generated in rat, the animal model mimicking the bioactivation of ellipticine in human. Using 32P-postlabeling, ellipticine-DNA adducts were found in liver, kidney, lung, spleen, heart and brain of female and male rats exposed to ellipticine (4, 40 and 80 mg/kg body weight, i.p.). The two major adducts were identical to the deoxyguanosine adducts generated in DNA by 13-hydroxy- and 12-hydroxyellipticine in vitro as confirmed by HPLC of the isolated adducts. At four post-treatment times (2 days, 2, 10 and 32 weeks) DNA adducts in rats treated with 80 mg/kg of ellipticine were analyzed in each tissue to study their long-term persistence. In all organs maximal adduct levels were found 2 days after administration. At all time points highest total adduct levels were in liver (402 adducts/108 nucleotides after 2 days and 3.6 adducts/108 nucleotides after 32 weeks), kidney and lung followed by spleen, heart and brain. Total adduct levels decreased over time to 0.8-8.3% of the initial levels till the latest time point and showed a biphasic profile, a rapid loss during the first 2 weeks was followed by a much slower decline till 32 weeks. These results, the first characterization of persistence of ellipticine-DNA adducts in vivo, are necessary to evaluate genotoxic side effects of ellipticine

  7. Decay kinetics of nicotine/NNK-DNA adducts in vivo studied by accelerator mass spectrometry

    International Nuclear Information System (INIS)

    The decay kinetics of nicotine-DNA adducts and NNK-DNA adducts in mice liver after single dosing was studied by accelerator mass spectrometry (AMS). The decay is characterized by a two-stage process. The half-lives of nicotine-DNA adducts are 1.3 d (4-24 h) and 7.0 d (1-21 d), while for NNK-DNA adducts are 0.7 d (4-24 h) and 18.0 d (1-21 d). The relatively faster decay of nicotine-DNA adducts suggests that the genotoxicity of nicotine is weaker than that of NNK. The in vitro study shows that the metabolization of nicotine is necessary for the final formation of nicotine-DNA adducts, and nicotine Δ1'(5') iminium ion is a probable metabolite species that binds to DNA molecule covalently

  8. Fast repair of oxidizing OH adducts of DNA by hydroxycinnamic acid derivatives. A pulse radiolytic study

    International Nuclear Information System (INIS)

    Using pulse radiolytic techniques, it has been demonstrated that the interactions of oxidizing OH adducts of DNA (ssDNA and dsDNA), polyA and polyG with hydroxycinnamic acid derivatives proceed via an electron transfer process (k=5-30x108 dm3 mol-1 s-1). In addition, the rates for fast repair of OH adducts of dAMP, polyA and DNA (ssDNA and dsDNA) are slower than the corresponding rates for the rest OH adducts of DNA constituents. The slower rates for repair of oxidizing OH adducts of dAMP may be the rate determining step during the interaction of hydroxycinnamic acid derivatives with OH adducts of DNA containing the varieties of OH adducts of DNA constituents

  9. Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry.

    Science.gov (United States)

    Guo, Jingshu; Turesky, Robert J

    2016-01-01

    Humans are continuously exposed to hazardous chemicals in the environment. These chemicals or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. The identification of DNA adducts is required for understanding exposure and the etiological role of a genotoxic chemical in cancer risk. The analytical chemist is confronted with a great challenge because the levels of DNA adducts generally occur at spectrometry has emerged as an important technique to screen for DNA adducts because of the high level sensitivity and selectivity, particularly when employing multi-stage scanning (MS(n) ). The product ion spectra provide rich structural information and corroborate the adduct identities even at trace levels in human tissues. Ion trap technology represents a significant advance in measuring DNA adducts in humans. © 2016 by John Wiley & Sons, Inc. PMID:27584705

  10. Detection of Adriamycin–DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations

    OpenAIRE

    Coldwell, Kate E.; Cutts, Suzanne M.; Ognibene, Ted J.; Henderson, Paul T; Phillips, Don R.

    2008-01-01

    Limited sensitivity of existing assays has prevented investigation of whether Adriamycin–DNA adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin–DNA adducts/104 bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin–DNA adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We...

  11. Structure of adducts of isoindolo[2,1-a]benzimidazole derivatives with maleimides

    Science.gov (United States)

    Korolev, Oleksandr; Yegorova, Tatyana; Levkov, Igor; Malytskyy, Volodymyr; Shishkin, Oleg; Zubatyuk, Roman; Palamarchuk, Genadiy; Vedrenne, Marc; Baltas, Michel; Voitenko, Zoia

    2015-03-01

    The selectivity of formation and some mechanistic insights during the synthesis of substituted isoindolo[2,1-a]benzimidazoles are discussed. Furthermore, the reactions of the obtained products with maleimides were carried out. Two types rearrangement adducts together with intermediate Michael type adducts were isolated. The influence of the reaction conditions and reagents ratio is discussed. Specific spectral criteria for the identification of the Michael type adducts are indicated.

  12. Knee adduction moment and medial contact force - facts about their correlation during gait

    OpenAIRE

    Kutzner, Ines; Trepczynski, Adam; Heller, Markus O.; Bergmann, Georg

    2013-01-01

    The external knee adduction moment is considered a surrogate measure for the medial tibiofemoral contact force and is commonly used to quantify the load reducing effect of orthopedic interventions. However, only limited and controversial data exist about the correlation between adduction moment and medial force. The objective of this study was to examine whether the adduction moment is indeed a strong predictor for the medial force by determining their correlation during gait. Instrumented kn...

  13. Structural aspects of adducts of N-phthaloylglycine and its derivatives

    Science.gov (United States)

    Barooah, Nilotpal; Sarma, Rupam J.; Batsanov, Andrei S.; Baruah, Jubaraj B.

    2006-06-01

    N-phthaloylglycine forms 2:1 adduct with 1,3-dihydroxybenzene and 1:2 adduct with 2-aminopyrimidine. Whereas N-phthaloylglycine form salts with 2,6-diaminopyridine and with 8-hydroxyquinoline. The 1:1 adduct of N, N'-bis(glycinyl)pyromellitic diimide with dimethylsulphoxide, 2-aminopyrimidine and 4,4'-dihydroxybiphenyl are prepared and characterised. The reaction of N, N'-bis(glycinyl)pyromellitic diimide with 2,6-diaminopyridine gives corresponding salt.

  14. Metabolism of the Antibacterial Triclocarban by Human Epidermal Keratinocytes to Yield Protein Adducts

    OpenAIRE

    Schebb, Nils Helge; Buchholz, Bruce A.; Hammock, Bruce D.; Rice, Robert H.

    2012-01-01

    Previous studies of triclocarban suggest that its biotransformation could yield reactive metabolites that form protein adducts. Since the skin is the major route of triclocarban exposure, present work examined this possibility in cultured human keratinocytes. The results provide evidence for considerable biotransformation and protein adduct formation when cytochrome P450 activity is induced in the cells by TCDD, a model Ah receptor ligand. Since detecting low adduct levels in cells and tissue...

  15. Benzene hemoglobin adducts in mice and rats: Characterization of formation and physiological modeling

    International Nuclear Information System (INIS)

    Benzene is a myelotoxin and a human leukemogen. Humans are exposed to this compound, both occupationally and environmentally. This study was conducted to determine whether formation of benzene-derived adducts with blood hemoglobin (Hb) can be used as a biomarker of exposure to benzene. B6C3F1 mice and F344/N rats were given 0.1 to 10,000 mumol [14C]benzene/kg body wt, orally. Twenty-four hours later, animals were euthanized, and globin was isolated from blood samples. The globin was analyzed by liquid scintillation spectrometry for the presence of [14C]benzene-derived adducts. Hb adduct formation was linear with respect to dose for amounts of up to 500 mumol [14C]benzene/kg body wt, for both rodent species. Within this linear dose-response range, mice formed adducts from [14C]benzene approximately 3.5 times less efficiently [0.022 +/- 0.010 (pmol adducts/mg globin)/(mumol/kg body wt dose)] than did rats [0.076 +/- 0.014 (pmol adducts)/(mumol/kg body wt dose)]. Benzene-derived Hb adducts also accumulated linearly when mice and rats were given up to three daily doses of 500 mumol [14C]benzene/kg body wt. These data were used to develop a physiological model for benzene-derived Hb adduct formation. Both first-order and saturable pathways for adduct formation were incorporated. The results showed that the model simulated the levels of Hb adducts in both mice and rats after oral exposures to benzene and predicted the levels of Hb adducts present after inhalation exposure. These studies suggest that Hb adducts might be useful biomarkers for human exposures to benzene

  16. Biomarkers of genotoxicity of air pollution (the AULIS project): bulky DNA adducts in subjects with moderate to low exposures to airborne polycyclic aromatic hydrocarbons and their relationship to environmental tobycco smoke and other parameters

    Czech Academy of Sciences Publication Activity Database

    Georgiadis, P.; Topinka, Jan; Stoikidou, M.; Kaila, S.; Gioka, M.; Katsouyanni, K.; Šrám, Radim; Autrup, H.; Kyrtopoulos, S. A.

    2001-01-01

    Roč. 22, č. 9 (2001), s. 1447-1457. ISSN 0143-3334 R&D Projects: GA MŽP SI/340/2/00 Grant ostatní: EU(XC) ENV4V-CT96-0203; EU(XC) IC20CT960063 Institutional research plan: CEZ:AV0Z5039906 Keywords : biomarkers * air pollution Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.543, year: 2001

  17. Biomarkers of genotoxicity of air pollution (the AULIS project): bulky DNA adducts in subjects with moderate to low exposures to airborne polycyclic aromatic hydrocarbons and their relationship to environmental tobacco smoke and other parameters

    DEFF Research Database (Denmark)

    Georgiadis, P.; Topinka, J.; Stoikidou, M.;

    2001-01-01

    tobacco smoke (ETS), namely (i) declared times of exposure to ETS during the 24 h prior to blood donation, (ii) plasma cotinine levels and (iii) chrysene/benzo[g,h,i]perylene ratios in the profile of personal PAH exposure. Furthermore, among the Halkida campus area subjects (but not the remaining subjects...

  18. Synthesis and characterization of novel polyamide-ethers based on bis-imidazole containing bulky aryl pendant groups

    Directory of Open Access Journals (Sweden)

    Seyed Mahdi Saadati

    2013-01-01

    Full Text Available A series of novel polyamide-ethers (PAEs based on bis-imidazole containing bulky aryl pendant groups was prepared by direct polycondensation of a diamine, 4-(1-(4-(4-(2-(4-aminophenyl-4,5-diphenyl-1H-imidazol-1-ylphenoxyphenyl-4,5-diphenyl-1H-imidazol-2-ylbenzenamine (DABI, and various dicarboxylic acids. All the resulting polyamide-ethers were amorphous with inherent viscosities ranged from 0.52 to 0.61 dL/g and were readily soluble in many organic solvents which could be solution-cast into transparent and tough films. The glass transition temperatures (Tg of these polymers were affected considerably by their chemical structure and ranged from 230 to 310 ºC. They had useful levels of thermal stability associated with relatively high temperatures of 10% weight loss (T10 in the range of 329-399 ºC in air atmosphere.

  19. Synthesis and Characterization of the Adducts of Bis(O-ethyldithiocarbonatocopper(II with Substituted Pyridines

    Directory of Open Access Journals (Sweden)

    Gurpreet Kour

    2013-01-01

    Full Text Available Monomeric five coordinated adducts of bis(O-ethyldithiocarbonatocopper(II of general formula [Cu(C2H5OCS22(L], [L = 2-, 3-, 4-methylpyridines and 2-, 3-, 4-ethylpyridines] have been synthesized and characterized by elemental analysis, i.r. and electronic spectroscopy, magnetic and conductivity measurements. Analytical results show that the adducts have 1 : 1 stoichiometry. The adducts were found to be paramagnetic and their magnetic moments at room temperature lie within the 1.81–1.94 B.M. range and this indicates the presence of one unpaired electron. All the adducts have distorted square pyramidal geometry.

  20. Glutathione transferase A4-4 resists adduction by 4-hydroxynonenal.

    Science.gov (United States)

    Shireman, Laura M; Kripps, Kimberly A; Balogh, Larissa M; Conner, Kip P; Whittington, Dale; Atkins, William M

    2010-12-15

    4-Hydroxy-2-trans-nonenal (HNE) is a lipid peroxidation product that contributes to the pathophysiology of several diseases with components of oxidative stress. The electrophilic nature of HNE results in covalent adduct formation with proteins, fatty acids and DNA. However, it remains unclear whether enzymes that metabolize HNE avoid inactivation by it. Glutathione transferase A4-4 (GST A4-4) plays a significant role in the elimination of HNE by conjugating it with glutathione (GSH), with catalytic activity toward HNE that is dramatically higher than the homologous GST A1-1 or distantly related GSTs. To determine whether enzymes that metabolize HNE resist its covalent adduction, the rates of adduction of these GST isoforms were compared and the functional effects of adduction on catalytic properties were determined. Although GST A4-4 and GST A1-1 have striking structural similarity, GST A4-4 was insensitive to adduction by HNE under conditions that yield modest adduction of GST A1-1 and extensive adduction of GST P1-1. Furthermore, adduction of GST P1-1 by HNE eliminated its activity toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB) and toward HNE itself. HNE effects on GST A4-4 and A1-1 were less significant. The results indicate that enzymes that metabolize HNE may have evolved structurally to resist covalent adduction by it. PMID:20836986

  1. Glutathione transferase A4-4 resists adduction by 4-hydroxynonenal☆

    Science.gov (United States)

    Shireman, Laura M.; Kripps, Kimberly A.; Balogh, Larissa M.; Conner, Kip P.; Whittington, Dale; Atkins, William M.

    2010-01-01

    4-Hydroxy-2-trans-nonenal (HNE) is a lipid peroxidation product that contributes to the pathophysiology of several diseases with components of oxidative stress. The electrophilic nature of HNE results in covalent adduct formation with proteins, fatty acids and DNA. However, it remains unclear whether enzymes that metabolize HNE avoid inactivation by it. Glutathione transferase A4-4 (GST A4-4) plays a significant role in the elimination of HNE by conjugating it with glutathione (GSH), with catalytic activity toward HNE that is dramatically higher than the homologous GST A1-1 or distantly related GSTs. To determine whether enzymes that metabolize HNE resist its covalent adduction, the rates of adduction of these GST isoforms were compared and the functional effects of adduction on catalytic properties were determined. Although GST A4-4 and GST A1-1 have striking structural similarity, GST A4-4 was insensitive to adduction by HNE under conditions that yield modest adduction of GST A1-1 and extensive adduction of GST P1-1. Furthermore, adduction of GST P1-1 by HNE eliminated its activity toward the substrates 1-chloro- 2,4-dinitrobenzene (CDNB) and toward HNE itself. HNE effects on GST A4-4 and A1-1 were less significant. The results indicate that enzymes that metabolize HNE may have evolved structurally to resist covalent adduction by it. PMID:20836986

  2. Phosphoryl chloride-methanol adducts: Matrix isolation infrared and DFT studies

    Science.gov (United States)

    Ramanathan, N.; Sankaran, K.

    2013-12-01

    The adducts of phosphoryl chloride (POCl3) and methanol (CH3OH) were studied using matrix isolation infrared spectroscopy and DFT calculations. The 1:1 POCl3:CH3OH binary adduct was generated in a nitrogen matrix at low temperatures and studied using infrared spectroscopy. Formation of the adduct was evidenced by the shifts in the vibrational frequencies of the modes involving POCl3 and CH3OH sub-molecules. The structures, vibrational frequencies and stabilization energies of the adducts were computed at B3LYP/aug-cc-pVDZ level of theory. Our computations located two minima for POCl3:CH3OH adducts on the potential energy surface. However, only one adduct was experimentally identified in the matrix at low temperatures, which was the structure corresponding to the global minimum. The computed vibrational frequencies of the adduct agreed well with the observed experimental frequencies. Atoms In Molecules (AIM) analysis was performed to understand the nature of the interactions in these adducts. Natural Bond Orbital (NBO) analysis was performed to understand the effect of charge-transfer interactions on the stability of adducts.

  3. Temporal and spatial features of the formation of DNA adducts in sulfur mustard-exposed skin

    International Nuclear Information System (INIS)

    Sulfur mustard (SM) is a chemical warfare agent that targets skin where it induces large blisters. DNA alkylation is a critical step to explain SM-induced cutaneous symptoms. We determined the kinetics of formation of main SM–DNA adducts and compare it with the development of the SM-induced pathogenesis in skin. SKH-1 mice were exposed to 2, 6 and 60 mg/kg of SM and treated skin was biopsied between 6 h and 21 days. Formation of SM DNA adducts was dose-dependent with a maximum immediately after exposure. However, adducts were persistent and still detectable 21 days post-exposure. The time-dependent formation of DNA adducts was also found to be correlated with the appearance of apoptotic cells. This temporal correlation suggests that these two early events are responsible for the severity of the damage to the skin. Besides, SM–DNA adducts were also detected in areas located next to contaminated zone, thus suggesting that SM diffuses in skin. Altogether, this work provides for the first time a clear picture of SM-induced genotoxicity using DNA adducts as a marker. - Highlights: • Sulfur mustard adducts are formed in DNA after skin exposure. • DNA damage formation is an early event in the pathological process of skin burn. • The amount of SM–DNA adducts is maximal at the earliest time point investigated. • Adducts are still detected 3 weeks after exposure. • Sulfur mustard diffuses in skin especially when large doses are applied

  4. Environmental air pollution and DNA adducts in Copenhagen bus drivers - effect of GSTM1 and NAT2 genotypes on adduct level

    DEFF Research Database (Denmark)

    Nielsen, Per Sabro; de Pater, Nettie; Okkels, Henrik; Autrup, Herman

    1996-01-01

    rural controls (0.074 fmol/microg DNA, n = 60, P < 0.001). No significant influence on adduct levels was demonstrated from potential confounders, including smoking and diet. The effect of the metabolizing enzymes, GSTM1 and NAT2, on adduct levels was investigated. No statistically significant effects...... levels of exposure to urban air pollution and indicated that these adducts might be helpful as a means of classifying better different exposure groups for epidemiological studies. Furthermore, it demonstrated the ability of 32P-postlabelling to discern small differences in low exposure to ambient air...

  5. Group 13 Superacid Adducts of [PCl2N]3.

    Science.gov (United States)

    Tun, Zin-Min; Heston, Amy J; Panzner, Matthew J; Scionti, Vincenzo; Medvetz, Doug A; Wright, Brian D; Johnson, Nicholas A; Li, Linlin; Wesdemiotis, Chrys; Rinaldi, Peter L; Youngs, Wiley J; Tessier, Claire A

    2016-04-01

    Irrespective of the order of the addition of reagents, the reactions of [PCl2N]3 with MX3 (MX3 = AlCl3, AlBr3, GaCl3) in the presence of water or gaseous HX give the air- and light-sensitive superacid adducts [PCl2N]3·HMX4. The reactions are quantitative when HX is used. These reactions illustrate a Lewis acid/Brønsted acid dichotomy in which Lewis acid chemistry can become Brønsted acid chemistry in the presence of adventitious water or HX. The crystal structures of all three [PCl2N]3·HMX4 adducts show that protonation weakens the two P-N bonds that flank the protonated nitrogen atom. Variable-temperature NMR studies indicate that exchange in solution occurs in [PCl2N]3·HMX4, even at lower temperatures than those for [PCl2N]3·MX3. The fragility of [PCl2N]3·HMX4 at or near room temperature and in the presence of light suggests that such adducts are not involved directly as intermediates in the high-temperature ring-opening polymerization (ROP) of [PCl2N]3 to give [PCl2N]n. Attempts to catalyze or initiate the ROP of [PCl2N]3 with the addition of [PCl2N]3·HMX4 at room temperature or at 70 °C were not successful. PMID:26974866

  6. Metabolites and DNA adduct formation from flavoenzyme-activated porfiromycin.

    Science.gov (United States)

    Pan, S S; Iracki, T

    1988-08-01

    Porfiromycin was reductively metabolized by NADPH cytochrome P-450 reductase and xanthine oxidase under anaerobic conditions. The production of metabolites varied with the pH and the contents of the reaction buffer. In Tris buffer, two major metabolites were produced at pH 7.5 and above, whereas one major metabolite was produced at pH 6.5. The three major metabolites were separated and isolated by HPLC. Identification by californium-252 plasma desorption mass spectrometry showed that the two major metabolites from pH 7.5 were (trans) and (cis)-forms of 7-amino-1-hydroxyl-2-methylaminomitosene and the major metabolite from pH 6.5 was 7-amino-2-methylaminomitosene. All three major metabolites showed substitutions at the C-1 position. DNA was alkylated readily by enzyme-activated porfiromycin. Digestion of porfiromycin-alkylated DNA by DNase, snake venom phosphodiesterase, and alkaline phosphatase resulted in an insoluble nuclease-resistant fraction and a soluble fraction. The nuclease-resistant fraction reflected a high content of cross-linked adducts. Upon HPLC analysis, the solubilized fraction contained two monofunctionally linked porfiromycin adducts and a possibly cross-linked dinucleotide. The major adduct was isolated by HPLC and identified by NMR, as N2-(2'-deoxyguanosyl)-7-amino-2-methylaminomitosene. The N2 position of deoxyguanosine appeared as the major monofunctional alkylating site for DNA alkylation by porfiromycin. Thus, mitomycin C and porfiromycin (which differs from mitomycin C only by the addition of a methyl group to the aziridine nitrogen) share the same enzymatic activating mechanism that leads to the formation of the same types of metabolites and the same specificity of DNA alkylation. PMID:3412325

  7. EMG evaluation of hip adduction exercises for soccer players

    DEFF Research Database (Denmark)

    Serner, Andreas; Jakobsen, Markus Due; Andersen, Lars Louis;

    2014-01-01

    INTRODUCTION: Exercise programmes are used in the prevention and treatment of adductor-related groin injuries in soccer; however, there is a lack of knowledge concerning the intensity of frequently used exercises. OBJECTIVE: Primarily to investigate muscle activity of adductor longus during six...... traditional and two new hip adduction exercises. Additionally, to analyse muscle activation of gluteals and abdominals. MATERIALS AND METHODS: 40 healthy male elite soccer players, training >5 h a week, participated in the study. Muscle activity using surface electromyography (sEMG) was measured bilaterally...

  8. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

    OpenAIRE

    Judge Bryan S; James Laura P; Green Jody L; Heard Kennon J; Zolot Liza; Rhyee Sean; Dart Richard C

    2011-01-01

    Abstract Background Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from ...

  9. Effect of the diaminocyclohexane carrier ligand on platinum adduct formation, repair, and lethality

    International Nuclear Information System (INIS)

    Platinum compounds with the diaminocyclohexane (dach) carrier ligand are of particular interest because cell lines that have developed resistance to platinum compounds in general often retain sensitivity to dach-platinum compounds, suggesting that the dach carrier ligand affects the formation, repair, or lethality of platinum-DNA adducts. The effect of the dach ligand on platinum adduct formation was assessed by using the (HaeIII-HindIII)146 fragment of pBR322 treated to give equal amounts of dach- or ethylene-diamine-platinum adducts. The sites of adduct formation were mapped by digestion with Escherichia coli ABC excinuclease. There were no significant effects of the dach carrier ligand on the types or sites of platinum adduct formation. The effect of the dach ligand on platinum adduct repair was determined by using synthetic oligomers designed to have single, specific platinum adducts. These data suggest that if the carrier ligand has any effect on the repair of platinum adducts, it is more likely to exert that effect on the repair of platinum monoadducts or GNG diadducts rather than on the more abundant AG or GG diadducts. [14C]Thiourea incorporation was used to quantitate the rate of monoadduct to diadduct conversion. Finally, the effect of the dach ligand on platinum adduct lethality was assessed by determining the effect of dach- and en-platinum adducts on the transformation efficiency of pBR322 into a repair-deficient (recA- uvrA-) strain of E. coli. These data suggest that the dach carrier ligand can significantly affect the ability of platinum-DNA adducts to block essential processes such as replication and transcription

  10. NMR studies of the exocyclic 1,N6-ethenodeoxyadenosine adduct (εdA) opposite thymidine in a DNA duplex. Nonplanar alignment of εdA(anti) and dT(anti) at the lesion site

    International Nuclear Information System (INIS)

    Two-dimensional proton NMR studies are reported on the complementary d(C-A-T-G-T-G-T-A-C)·d(G-T-A-C-εA-C-A-T-G) nonanucleotide duplex (designated εdA·dT 9-mer duplex) containing 1,N6-ethenodeoxyadenosine (εdA), a carcinogen-DNA adduct, positioned opposite thymidine in the center of the helix. The authors NMR studies have focused on the conformation of the εdA·dT 9-mer duplex at neutral pH with emphasis on defining the alignment at the dT5·εdA14 lesion site. The through-space NOE distance connectivities establish that both dT5 and εdA14 adopt anti glycosidic torsion angles, are directed into the interior of the helix, and stack with flanking Watson-Crick dG4·dC15 and dG6·dC13 pairs. Furthermore, the d(G4-T5-G6)·d(C13-εA14-C15) trinucleotide segment centered about the dT5·εdA14 lesion site adopts a right-handed helical conformation in solution. Energy minimization computations were undertaken starting from six different alignments of dT5(anti) and εdA14(anti) at the lesion site and were guided by distance constraints defined by lower and upper bounds estimated from NOESY data sets on the εdA·dT 9-mer duplex. The NMR data are consistent with a nonplanar alignment of εdA14(anti) and dT5(anti) with dT5 displaced toward the flanking dG4·dC15 base pair within the d(G4-T5-G6)·d(C13-εA14-C15) segment of the εdA·dT 9-mer duplex

  11. Effect of a bulky lateral substitution by chlorine atom and methoxy group on self-assembling properties of lactic acid derivatives

    International Nuclear Information System (INIS)

    Several chiral liquid crystalline materials derived from the lactic acid have been studied with the aim to establish the effect of bulky lateral substituents on their self-assembling properties. A chlorine atom and methoxy group have been used as lateral substituents in ortho position to ether group position on phenyl ring far from the chiral centre. All the studied materials possess tilted ferroelectric smectic C* phase in a broad temperature range. In dependence on the molecular structure namely type of lateral substituent and length of the chiral chain, the cholesteric mesophase, orthogonal paraelectric smectic A* and crystal mesophases have been detected. Lateral chlorine substitution results in decrease of both the clearing point and crystallisation temperature as well as in a distinct increase of spontaneous polarization. Bulky methoxy substitution slightly suppresses the spontaneous polarisation but strongly increases the melting point that results in monotropic peculiarity of the SmC* phase. Mesomorphic, spontaneous, structural and dielectric properties of the substituted compounds were established and compared to those of the non-substituted ones in order to contribute to better understanding of the structure–property relationship for such chiral self-assembling materials. - Highlights: • Chiral liquid crystalline materials derived from the lactic acid have been studied. • Effect of bulky lateral substituents on self-assembling properties has been established. • Bulky methoxy substitution suppresses spontaneous polarisation but increases the melting point. • The compounds might have a strong potential for many advanced electro-optic applications

  12. Effect of a bulky lateral substitution by chlorine atom and methoxy group on self-assembling properties of lactic acid derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Stojanović, Maja, E-mail: maja.stojanovic@df.uns.ac.rs [Department of Physics, Faculty of Sciences, University of Novi Sad, Trg D.Obradovića 4, 21000 Novi Sad (Serbia); Bubnov, Alexej [Institute of Physics, Academy of Sciences of the Czech Republic, Na Slovance 2, 182 21 Prague (Czech Republic); Obadović, Dušanka Ž. [Department of Physics, Faculty of Sciences, University of Novi Sad, Trg D.Obradovića 4, 21000 Novi Sad (Serbia); Hamplová, Věra [Institute of Physics, Academy of Sciences of the Czech Republic, Na Slovance 2, 182 21 Prague (Czech Republic); Cvetinov, Miroslav [Department of Physics, Faculty of Sciences, University of Novi Sad, Trg D.Obradovića 4, 21000 Novi Sad (Serbia); Kašpar, Miroslav [Institute of Physics, Academy of Sciences of the Czech Republic, Na Slovance 2, 182 21 Prague (Czech Republic)

    2014-07-01

    Several chiral liquid crystalline materials derived from the lactic acid have been studied with the aim to establish the effect of bulky lateral substituents on their self-assembling properties. A chlorine atom and methoxy group have been used as lateral substituents in ortho position to ether group position on phenyl ring far from the chiral centre. All the studied materials possess tilted ferroelectric smectic C* phase in a broad temperature range. In dependence on the molecular structure namely type of lateral substituent and length of the chiral chain, the cholesteric mesophase, orthogonal paraelectric smectic A* and crystal mesophases have been detected. Lateral chlorine substitution results in decrease of both the clearing point and crystallisation temperature as well as in a distinct increase of spontaneous polarization. Bulky methoxy substitution slightly suppresses the spontaneous polarisation but strongly increases the melting point that results in monotropic peculiarity of the SmC* phase. Mesomorphic, spontaneous, structural and dielectric properties of the substituted compounds were established and compared to those of the non-substituted ones in order to contribute to better understanding of the structure–property relationship for such chiral self-assembling materials. - Highlights: • Chiral liquid crystalline materials derived from the lactic acid have been studied. • Effect of bulky lateral substituents on self-assembling properties has been established. • Bulky methoxy substitution suppresses spontaneous polarisation but increases the melting point. • The compounds might have a strong potential for many advanced electro-optic applications.

  13. Ultrasensitive isolation, identification and quantification of DNA-protein adducts by ELISA-based RADAR assay.

    Science.gov (United States)

    Kiianitsa, Kostantin; Maizels, Nancy

    2014-07-01

    Enzymes that form transient DNA-protein covalent complexes are targets for several potent classes of drugs used to treat infectious disease and cancer, making it important to establish robust and rapid procedures for analysis of these complexes. We report a method for isolation of DNA-protein adducts and their identification and quantification, using techniques compatible with high-throughput screening. This method is based on the RADAR assay for DNA adducts that we previously developed (Kiianitsa and Maizels (2013) A rapid and sensitive assay for DNA-protein covalent complexes in living cells. Nucleic Acids Res., 41:e104), but incorporates three key new steps of broad applicability. (i) Silica-assisted ethanol/isopropanol precipitation ensures reproducible and efficient recovery of DNA and DNA-protein adducts at low centrifugal forces, enabling cell culture and DNA precipitation to be carried out in a single microtiter plate. (ii) Rigorous purification of DNA-protein adducts by a procedure that eliminates free proteins and free nucleic acids, generating samples suitable for detection of novel protein adducts (e.g. by mass spectroscopy). (iii) Identification and quantification of DNA-protein adducts by direct ELISA assay. The ELISA-based RADAR assay can detect Top1-DNA and Top2a-DNA adducts in human cells, and gyrase-DNA adducts in Escherichia coli. This approach will be useful for discovery and characterization of new drugs to treat infectious disease and cancer, and for development of companion diagnostics assays for individualized medicine. PMID:24914050

  14. Yield of photo-adduct formation of LOV domains from Chlamydomonas reinhardtii by picosecond laser excitation

    International Nuclear Information System (INIS)

    The photo-excitation of flavin mononucleotide (FMN) in the wild-type light, oxygen and voltage sensitive (LOV) domains of the blue-light photoreceptors phototropin causes the formation of an intermediate flavin-C(4a)-cysteinyl adduct. The adduct formation due to picosecond laser pulse exaction (wavelength 400nm) is studied on wild-type LOV1 and LOV2 domains of the phototropin phot from Chlamydomonas reinhardtii. The efficiency of adduct formation is probed by detection of the fluorescence signals caused by time-separated picosecond excitation pulses since FMN is fluorescent and the formed adduct is non-fluorescent. Quantum yields of adduct formation of φAd∼0.06 are determined for excitation with intense single-pulses of energy densities, wL, comparable to or larger than the saturation energy density, wsat,S0, of ground-state population depletion. Under repetitive picosecond pulse excitation conditions the efficiency of adduct formation rises with decreasing picosecond pulse energy density and approaches for wLsat,S0 the continuous blue-light exposure quantum yields of adduct formation in the range from φAd=0.5-0.9. Picosecond laser pulse induced energy deposition in the LOV domains causing protein conformational changes is discussed as main origin of the intensity dependent reduction of the efficiency of adduct-formation

  15. High-performance liquid chromatography for analysis of 32P-Postlabeled DNA adducts

    OpenAIRE

    Zeisig, Magnus

    1996-01-01

    High-Performance Liquid Chromatography for Analysis of 32P-Postlabeled DNA Adducts Magnus Zeisig Center for Nutrition and Toxicology, Department of Bioscience at Novum, Karolinska Institutet, Novum, S-141 57 Huddinge, SwedenThe formation of DNA adducts, i.e. the covalent binding of chemicals and chemical groups to DNA,isbelieved to be an important step in chemical carciwg...

  16. DNA adducts in marine mussel Mytilus galloprovincialis living in polluted and unpolluted environments

    International Nuclear Information System (INIS)

    A generally applicable 32-P post-labelling assay was used to examine for the presence of DNA adducts in mussels experimentally exposed to known carcinogens and in mussels collected from sites impacted by wastewaters. Mussels exposed to seawater artificially polluted with 2-aminofluorene showed exclusively an adduct which was identified as dG-C8-2-aminofluorene. Under the same experimental conditions, Diesel-2 oil did not induce any detectable adducts. When mussel digestive gland DNA was collected and analyzed from one unpolluted site, two moderately impacted sites, and one site heavily impacted by cannery wastewaters, mussel DNA from the unpolluted and only one moderately polluted site showed the presence of 6 to 10 adducts. This indicates they were not related to the pollution. This was further supported by the absence of dose-related adducts. Clear evidence for the presence of pollution-related DNA adducts was, however, found in juvenile mussels collected from an oil refinery site. One major and three minor adducts were detected in these mussels with no adducts detected in juvenile mussels from an unpolluted site. Results indicate that while mussels are capable of metabolizing 2-aminofluorene to a DNA binding species, the environmental pollutants may be metabolized only selectively. Further, the mussel digestive gland DNA also contained DNA modifications which are unrelated to pollutants and their presence appeared to be sex and season dependent

  17. Liquid chromatography-thermospray mass spectrometry of DNA adducts formed with mitomycin C, porfiromycin and thiotepa.

    Science.gov (United States)

    Musser, S M; Pan, S S; Callery, P S

    1989-07-14

    High-performance liquid chromatography (HPLC) and thermospray mass spectrometry were combined for the analysis of DNA adducts formed from the interaction of the anticancer drugs mitomycin C, porfiromycin and thiotepa with calf thymus DNA. The adducts formed from reaction of mitomycin C and porfiromycin with DNA were separated from unmodified nucleosides by HPLC on a C18 column and identified by thermospray mass spectrometry. Thiotepa DNA adducts readily depurinated from DNA and were chromatographed and identified by thermospray liquid chromatography-mass spectrometry as the modified bases without the ribose moiety attached. The utility of thermospray mass spectrometry for the identification of microgram quantities of nucleoside adducts and depurinated base adducts of these anticancer drugs was demonstrated. PMID:2504760

  18. DNA adducts in marine mussel and fresh water fishes living in polluted and unpolluted environments

    International Nuclear Information System (INIS)

    32P-postlabeling analysis of DNA adducts in the digestive gland of marine mussel Mytilus galloprovincialis from polluted and unpolluted sites near Rovinj, Northern Adriatic, revealed that majority of adducts are caused by natural environmental factors rather than by man-made chemicals. The only pollutant-specific adducts were observed in a mussel exposed to seawater experimentally polluted with aminofluorene, and in a population of mussel living at a site heavily polluted with a waste waters of an oil refinery. Fresh water fish species Leuciscus cephalus, Barbus barbus, Abramis brama and Rutilus pigus virgo living in a polluted Sava River, Yugoslavia, or in its unpolluted tributary Korana River, have induced in their livers qualitatively identical and quantitatively similar DNA adducts. These DNA adducts had a species-specific patterns and their appearance was seasonally-dependent

  19. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention.

    Science.gov (United States)

    Cavalieri, Ercole L; Rogan, Eleanor G

    2016-12-01

    Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens. PMID:26979321

  20. Line narrowing spectroscopic studies of DNA-carcinogen adducts and DNA-dye complexes

    International Nuclear Information System (INIS)

    Laser-induced fluorescence line narrowing and non-line narrowing spectroscopic methods were applied to conformational studies of stable DNA adducts of the 7β, 8α-dihydoxy-9α, l0α-epoxy-7,8,9, 10-tetrahydrobenzo[α]pyrene (anti-BPDE). Stereochemically distinct (+)-trans-, (-)-trans-, (+)-cis- and (-)-cis adducts of anti-BPDE bound to exocyclic amino group of the central guanine in an 11-mer oligonucleotide, exist in a mixture of conformations in frozen aqueous buffer matrices. The (+)-trans adduct adopts primarily an external conformation with a smaller fraction ( ∼ 25 %) exists in a partially base-stacked conformation. Both cis adducts were found to be intercalated with significant π-π stacking interactions between the pyrenyl residues and the bases. Conformations of the trans-adduct of (+)-anti -BPDE in 11-mer oligonucleotides were studied as a function of flanking bases. In single stranded form the adduct at G2 or G3 (5 ft-flanking, base guanine) adopts a conformation with strong, interaction with the bases. In contrast, the adduct with a 5ft-flanking, thymine exists in a primarily helixexternal conformation. Similar differences were observed in the double stranded oligonucleotides. The nature of the 3ft-flanking base has little influence on the conformational equilibrium of the (+)-trans-anti BPDE-dG adduct. The formation and repair of BPDE-N2-dG in DNA isolated from the skin of mice treated topically with benzo[α]pyrene (BP) was studied. Low-temperature fluorescence spectroscopy of the intact DNA identified the major adduct as (+)-trans-anti-BPDE-N-dG, and the minor adduct fraction consisted mainly of (+)-cis-anti-BPDE-N2-dG

  1. Line narrowing spectroscopic studies of DNA-carcinogen adducts and DNA-dye complexes

    Energy Technology Data Exchange (ETDEWEB)

    Suh, Myungkoo

    1995-12-06

    Laser-induced fluorescence line narrowing and non-line narrowing spectroscopic methods were applied to conformational studies of stable DNA adducts of the 7{beta}, 8{alpha}-dihydoxy-9{alpha}, l0{alpha}-epoxy-7,8,9, 10-tetrahydrobenzo[{alpha}]pyrene (anti-BPDE). Stereochemically distinct (+)-trans-, ({minus})-trans-, (+)-cis- and ({minus})-cis adducts of anti-BPDE bound to exocyclic amino group of the central guanine in an 11-mer oligonucleotide, exist in a mixture of conformations in frozen aqueous buffer matrices. The (+)-trans adduct adopts primarily an external conformation with a smaller fraction ( {approximately} 25 %) exists in a partially base-stacked conformation. Both cis adducts were found to be intercalated with significant {pi}-{pi} stacking interactions between the pyrenyl residues and the bases. Conformations of the trans-adduct of (+)-anti -BPDE in 11-mer oligonucleotides were studied as a function of flanking bases. In single stranded form the adduct at G{sub 2} or G{sub 3} (5 ft-flanking, base guanine) adopts a conformation with strong, interaction with the bases. In contrast, the adduct with a 5ft-flanking, thymine exists in a primarily helixexternal conformation. Similar differences were observed in the double stranded oligonucleotides. The nature of the 3ft-flanking base has little influence on the conformational equilibrium of the (+)-trans-anti BPDE-dG adduct. The formation and repair of BPDE-N{sup 2}-dG in DNA isolated from the skin of mice treated topically with benzo[{alpha}]pyrene (BP) was studied. Low-temperature fluorescence spectroscopy of the intact DNA identified the major adduct as (+)-trans-anti-BPDE-N-dG, and the minor adduct fraction consisted mainly of (+)-cis-anti-BPDE-N{sup 2}-dG.

  2. Exposure of bus and taxi drivers to urban air pollutants as measured by DNA and protein adducts

    DEFF Research Database (Denmark)

    Hemminki, K.; Zhang, L.F.; Krüger, J.;

    1994-01-01

    Urinary 1-hydroxypyrene, lymphocyte DNA adducts, serum protein-bound PAH and hemoglobin-bound alkene adducts were analysed from 4 groups of non-smoking men: urban and suburban bus drivers, taxi drivers and suburban controls. The only differences between the groups were in DNA adducts between subu...

  3. The formation of covalent adducts between benzo[a]pyrenediol epoxide and RNA: Structural analysis by mass spectrometry

    International Nuclear Information System (INIS)

    Racemic 7-r,8-t-dihydroxy-9-t,10-t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene was reacted with yeast RNA. Modified nucleosides were isolated and resolved by high-performance liquid chromatography; nine adduct peaks were collected for analysis. The bases in these adducts were identified by comparing their retention time with those of adducts from poly(G), poly(A), and poly(C). These samples gave two major and two minor Guo adducts, four major Ado adducts, and at least four Cyd adducts. The relative efficiencies of adduct formation with the polyribionucleotides were poly(G) > yeast RNA > poly(A) > poly(C). Fluorescence measurements show that emission from Guo adducts is strongly quenched relative to that from Ado adducts. Liquid secondary ion mass spectrometry (LSIMS) of underivatized samples and electron-impact mass spectrometry (EIMS) of permethyl derivatives were used to confirm the base identities and establish the alkylation sites of the RNA adducts. Unique nitrogen-containing hydrocarbon fragments that were observed with all samples by EIMS establish that in each adduct analyzed the C-10 position of the hydrocarbon is linked to the exocyclic amino group of the base. This suggested that the multiple adducts formed with each base are diastereomers derived from cis/trans epoxide ring opening of the (+) and (-) enantiomers of the carcinogen. Major fragmentation pathways resulted in formation of nucleoside, base, ribose, hydrocarbon, and base-hydrocarbon ions

  4. Leading research on supermetals. Part 1. Bulky material (iron system); Supermetal no sendo kenkyu. 1. Ogata sozai (tetsukei)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-03-01

    For further improvement of iron system materials, supermetals with ultimate characteristics were researched. Since their strength and toughness have been improved with grain refinement by thermomechanical treatment, improvement of single-phase steel is nearly completed, and the study on ultra-fine multi-phase steel is indispensable. Bulky materials are also restrained from grain refinement because of the capability of existing processing facilities. Making a breakthrough in such restraint requires a challenge to high-speed rolling, repeated shear deformation and ultra-high strain rate process beyond conventional technologies. Further improvement of microstructure and dynamic characteristics requires other energies such as magnetism as well as mechanical energy. {gamma}-{alpha} phase transition important for structure control of steel materials is dependent on magnetism. The study on structure control and characteristics improvement under ferromagnetic field is essential in the future. Material improvement such as reduction of impurities and circulating elements, environmental measures, and mechanical alloying remain as issues to be studied. 224 refs., 176 figs., 18 tabs.

  5. Total digestibility and in situ degradability of bulky diets with the inclusion of ionophores or probiotics for cattle and buffaloes

    Directory of Open Access Journals (Sweden)

    Lúcia Maria Zeoula

    2014-09-01

    Full Text Available The effects of ionophores (monensin and probiotic (Saccharomyces cerevisiae + selenium + chromium in diets with 80% forage were evaluated on the digestibility of nutrients. Three buffaloes, Murrah (Bubalus bubalis and three cattle, Holstein (Bos taurus, with an average weight of 520 ± 30 kg and 480 ± 182 kg, respectively, with rumen cannula, over experimental design with two 3 x 3 Latin squares in a 3 x 2 factorial arrangement, with the absence or presence of additives: ionophore or probiotic and two species, were used. The internal flow indicator of fecal dry matter (DM was the acid insoluble ash. DM, crude protein (CP and neutral detergent fiber (NDF ruminal degradability of Tifton 85 hay was conducted for cattle and buffaloes. A diet containing probiotics had higher dry matter and organic matter digestibility in buffalo and cattle, indicating a good performance in bulky diets. The potential and effective dry matter degradability in diet with probiotic in buffaloes, were smaller than diet with ionophore, suggesting that there was a better digestion of nutrients in the intestine of these animals. The potential and effective degradability of neutral detergent fiber and crude protein in the diet containing ionophores were superior than diet containing probiotic. Buffaloes showed higher capacity of dry matter and fiber digestion than cattle.

  6. Tuning the self-assembly of the bioactive dipeptide L-carnosine by incorporation of a bulky aromatic substituent.

    Science.gov (United States)

    Castelletto, V; Cheng, G; Greenland, B W; Hamley, I W; Harris, P J F

    2011-03-15

    The dipeptide L-carnosine has a number of important biological properties. Here, we explore the effect of attachment of a bulky hydrophobic aromatic unit, Fmoc [N-(fluorenyl-9-methoxycarbonyl)] on the self-assembly of Fmoc-L-carnosine, i.e., Fmoc-β-alanine-histidine (Fmoc-βAH). It is shown that Fmoc-βAH forms well-defined amyloid fibrils containing β sheets above a critical aggregation concentration, which is determined from pyrene and ThT fluorescence experiments. Twisted fibrils were imaged by cryogenic transmission electron microscopy. The zinc-binding properties of Fmoc-βAH were investigated by FTIR and Raman spectroscopy since the formation of metal ion complexes with the histidine residue in carnosine is well-known, and important to its biological roles. Observed changes in the spectra may reflect differences in the packing of the Fmoc-dipeptides due to electrostatic interactions. Cryo-TEM shows that this leads to changes in the fibril morphology. Hydrogelation is also induced by addition of an appropriate concentration of zinc ions. Our work shows that the Fmoc motif can be employed to drive the self-assembly of carnosine into amyloid fibrils. PMID:21338121

  7. Structural phase transitions and adduct release in calcium borohydride

    Energy Technology Data Exchange (ETDEWEB)

    Paolone, A.; Palumbo, O.; Rispoli, P.; Miriametro, A.; Cantelli, R.; Luedtke, A.; Rönnebro, E.; Chandra, D.

    2011-09-01

    Ca(BH4)2 compounds were investigated above room temperature by anelastic spectroscopy (AS) and concomitant measurements of thermogravimetry and mass spectrometry (TGA/MS). Both AS and TGA/MS indicate that even after a thermal treatment at 125 °C for 20 h, a non-negligible residual of THF adduct is still present in the sample, which can be removed on a subsequent thermal treatment at temperatures lower than 250 °C. Above 250 °C dehydrogenation takes place. Moreover, AS sensitively detects the occurrence of the α → α’ structural phase transition around 180 °C, and the α’ → β transformation, which is completed around 330 °C. Finally, we also show that both transitions are irreversible and are not accompanied by a latent heat.

  8. SEM-EDX STUDIES OF CHITOSAN DERIVATIVES-METAL ADDUCTS

    Directory of Open Access Journals (Sweden)

    Galo Cárdenas

    2003-12-01

    Full Text Available Chitosan was obtained from shrimps shells (pleuroncodes monodon using chemical methods. A series of chitosan (QScharged with solution of copper, cobalt, nickel and mercury ions were prepared at room temperature using the batch method. N-3,5-diethylamino benzoyl chitosan (QDAB; N,O-dimercapto succinate chitosan (QNOT and 4-aminobenzoate chitosan (QAB derivatives were prepared. The chitosan metal adducts with Cu, Co, Ni and Hg ions and derivatives maximum loading is discussed. Chitosan and derivatives containing copper were analyzed by SEM to find out the morphology of the polymers. Chitosan-Cu and derivatives charged, QDAB-Ni and QDAB-Hg were analyzed by EDX to verify the presence of the metal in the polymeric chain

  9. Characterization of DNA adducts with fourier transform mass spectrometry

    International Nuclear Information System (INIS)

    The sensitive detection and unambiguous structural characterization of modified nucleic acid constituents is vital for understanding the nature of DNA modification induced by carcinogenic agents. Fourier transform mass spectrometry (FTMS) combined with matrix-assisted laser desorption provides a powerful technique for examining picomole quantities of modified nucleosides, nucleotides, and oligonucleotides. The structures of these modified biomolecules can be probed in detail with a variety of gas phase processes, including collision-induced dissociation, ion-molecule reactions such as deuterium exchange, and selective cationization reactions. Each of these processes provides a wealth of structural information which can be used to not only identify the adduct present, but also determine its exact site of attachment to the nucleic acid constituent, thereby providing isomeric differentiation. This FTMS technique has been applied to the examination of DNA damage induced by high energy (x-rays) as well as low energy radiation (far ultraviolet)

  10. Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics.

    Science.gov (United States)

    Sparrow, Janet R

    2016-04-26

    Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation. PMID:27071115

  11. Use of the /sup 32/P-postlabeling method to detect DNA adducts of 2-amino-3-methylimidazolo(4,5-f)quinoline (IQ) in monkeys fed IQ: identification of the N-(deoxyguanosin-8-yl)-IQ adduct

    Energy Technology Data Exchange (ETDEWEB)

    Snyderwine, E.G.; Yamashita, K.; Adamson, R.H.; Sato, S.; Nagao, M.; Sugimura, T.; Thorgeirsson, S.S.

    1988-10-01

    Eight DNA adducts of 2-amino-3-methylimidazolo(4,5-f)-quinoline (IQ) were found by the standard /sup 32/P-postlabeling method in livers from male Cynomolgus monkeys fed IQ (5 days/week, 3 weeks, 20 mg/kg, nasal-gastric intubation). The IQ-DNA adduct fingerprints observed in monkeys were identical to those observed in rats that received IQ (0.03%) in the diet for 2 weeks. The C8-guanine-IQ adduct was identified by comigration with the synthetic 3',5'-bisphosphate derivative of N(-deoxyguanosin-8-yl)-IQ. DNA modified in vitro with N-hydroxy-IQ showed seven adducts, including the C8-guanine-IQ adduct, that were identical to those found in monkeys and rats. Thus it appears that N-hydroxy-IQ, the reactive metabolite of IQ, was responsible for all adducts found in vivo, except one. In order to detect adducts in other organs that were present at lower levels, the intensification (ATP-deficient) method for /sup 32/P-postlabeling was used. Five of the adducts detected under standard conditions, including the C8-guanine-IQ adduct, were also detected under intensification conditions. The total level of DNA-IQ adducts was highest in the liver, followed by the kidney, colon and stomach, and bladder. The adduct patterns were identical in all organs examined. The results indicate that IQ is potentially genotoxic in primates and therefore a likely human carcinogen.

  12. Synthesis and mutagenesis of the butadiene-derived N3 2'-deoxyuridine adducts.

    Science.gov (United States)

    Fernandes, Priscilla H; Hackfeld, Linda C; Kozekov, Ivan D; Hodge, Richard P; Lloyd, R Stephen

    2006-07-01

    1,3-Butadiene is a known carcinogen and mutagen that acts through a variety of metabolic intermediates that react with DNA, forming stable and unstable lesions on dG, dA, dC, and dT. The N3 2'-deoxyuridine adducts are a highly stable, stereoisomeric mixture of adducts derived from the reaction of cytosine with the monoepoxide metabolite of butadiene, followed by spontaneous deamination. In this study, the phosphoramidites and subsequent oligodeoxynucleotides containing the N3 2'-deoxyuridine adducts have been constructed and characterized. Using a single-stranded shuttle vector DNA, the mutagenic potential of these adducts has been tested following replication in mammalian cells. Replication past the N3 2'-deoxyuridine adducts was found to be highly mutagenic with an overall mutation yield of approximately 97%. The major mutations that were observed were C to T transitions and C to A transversions. In vitro, these adducts posed a complete block to both the Klenow fragment of Escherichia coli polymerase I and polymerase epsilon, while these lesions significantly blocked polymerase delta. These data suggested a possible involvement of bypass polymerases in the in vivo replication of these lesions. Overall, these findings indicate that the N3 2'-deoxyuridine adducts are highly mutagenic lesions that may contribute to butadiene-mediated carcinogenesis. PMID:16841966

  13. Inhibition of nitrobenzene-induced DNA and hemoglobin adductions by dietary constituents

    Energy Technology Data Exchange (ETDEWEB)

    Li Hongli; Cheng Yan; Wang Haifang; Sun Hongfang; Liu Yuanfang E-mail: yliu@pku.edu.cn; Liu Kexin; Peng Shixiang

    2003-03-01

    Nitrobenzene (NB), a widely used industrial chemical, is a likely human carcinogen. Many dietary constituents can suppress the DNA-adduction, acting as the inhibitors of cancer. In this study, we investigated the inhibitory effects of vitamin C (VC), vitamin E (VE), tea polyphenols (TP), garlic squeeze, curcumin, and grapestone extract on NB-DNA and NB-hemoglobin (Hb) adductions in mice using an ultrasensitive method of accelerator mass spectrometry (AMS) with {sup 14}C-labelled nitrobenzene. All of these dietary constituents showed their inhibitory effects on DNA or Hb adduction. VC, VE, TP and grapestone extract could efficaciously inhibit the adductions by 33-50%, and all of these six agents could inhibit Hb adduction by 30-64%. We also investigated resveratrol, curcumin, VC and VE as inhibitors of NB-DNA adduction in vitro using liquid scintillation counting technique. These agents in the presence of NADPH and S9 components also pronouncedly blocked DNA adduction in a dose-dependent profile. Our study suggests that these seven constituents may interrupt the process of NB-induced chemical carcinogenesis.

  14. Seasonal and intertidal impact on DNA adduct levels in gills of blue mussels (Mytilus edulis L.)

    International Nuclear Information System (INIS)

    The aim of this study was to elucidate possible seasonal variation in DNA adduct levels in blue mussels (Mytilus edulis), and to investigate the impact of intertidal exposure on the DNA adduct levels, i.e. to explore if DNA adduct levels in mussels in the intertidal zone differ from those in the subtidal zone. Blue mussels were deployed separately in the intertidal and subtidal zone at a contaminated and a reference site in Iceland, and sampled regularly during one year. Gill DNA adduct levels were found to be higher in mussels in the intertidal zone compared to the subtidal zone at the contaminated site, the difference being largest in winter. Total PAH tissue levels were also higher in mussels in the intertidal zone. Seasonal variation was observed in both DNA adduct and PAH tissue levels in mussels at the contaminated site, with lower levels from the time of transplantation in summer to autumn, maximum levels in winter, which decreased to lower levels again in spring and summer the following year. DNA adducts and PAH levels were low or below the detection limits in mussels at the reference site at all times, both in the intertidal and subtidal zone. - Gill DNA adduct and total PAH tissue levels were higher in mussels in the intertidal than subtidal zone, and higher in winter than summer

  15. Seasonal and intertidal impact on DNA adduct levels in gills of blue mussels (Mytilus edulis L.)

    Energy Technology Data Exchange (ETDEWEB)

    Skarpheoinsdottir, Halldora [Institute of Applied Environmental Research, Laboratory for Aquatic Ecotoxicology, Stockholm University, 106 91 Stockholm (Sweden)]. E-mail: halldora@itm.su.se; Ericson, Gunilla [Institute of Applied Environmental Research, Laboratory for Aquatic Ecotoxicology, Stockholm University, 106 91 Stockholm (Sweden); Halldorsson, Halldor P. [Institute of Biology, University of Iceland, Askja, Sturlugata 7, 101 Reykjavik (Iceland); University of Iceland, Sandgeroei Marine Centre, Garoevegur 1, 245 Sandgeroei (Iceland); Svavarsson, Joerundur [Institute of Biology, University of Iceland, Askja, Sturlugata 7, 101 Reykjavik (Iceland); University of Iceland, Sandgeroei Marine Centre, Garoevegur 1, 245 Sandgeroei (Iceland)

    2005-07-15

    The aim of this study was to elucidate possible seasonal variation in DNA adduct levels in blue mussels (Mytilus edulis), and to investigate the impact of intertidal exposure on the DNA adduct levels, i.e. to explore if DNA adduct levels in mussels in the intertidal zone differ from those in the subtidal zone. Blue mussels were deployed separately in the intertidal and subtidal zone at a contaminated and a reference site in Iceland, and sampled regularly during one year. Gill DNA adduct levels were found to be higher in mussels in the intertidal zone compared to the subtidal zone at the contaminated site, the difference being largest in winter. Total PAH tissue levels were also higher in mussels in the intertidal zone. Seasonal variation was observed in both DNA adduct and PAH tissue levels in mussels at the contaminated site, with lower levels from the time of transplantation in summer to autumn, maximum levels in winter, which decreased to lower levels again in spring and summer the following year. DNA adducts and PAH levels were low or below the detection limits in mussels at the reference site at all times, both in the intertidal and subtidal zone. - Gill DNA adduct and total PAH tissue levels were higher in mussels in the intertidal than subtidal zone, and higher in winter than summer.

  16. 32P analysis of DNA adducts in tissues of benzene-treated rats

    International Nuclear Information System (INIS)

    Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, liver, and mammary gland of Sprague-Dawley rats following chronic, high-dose administration of benzene. The carcinogenic activity of benzene is thought to be caused by activation to toxic metabolites that can interact with DNA, forming covalent adducts. A nuclease P1-enhanced 32P-postlabeling assay, having a sensitivity limit of 1 adduct in 10(9-10) DNA nucleotides, was found suitable for measuring aromatic DNA adducts derived in vitro from catechol, benzenetriol (BT), phenol, hydroquinone (HQ), and benzoquinone (BQ), potential metabolites of benzene. When DNA specimens isolated from tissues of female Sprague-Dawley rats at 24 hr after an oral gavage dose of 200 to 500 mg/kg, 5 days/week, in olive oil (3 mL/kg) for 1 day, 1 week, 5 weeks, and 10 weeks were analyzed by the 32P-postlabeling procedure, no aromatic adducts were detected unequivocally with DNA samples of liver, kidney, bone marrow, and mammary gland. With Zymbal gland DNA, three weak spots at levels totaling four lesions per 10(9) DNA nucleotides were seen only after 10 weeks of treatment, and these adducts did not correspond chromatographically to major adducts in vitro from the above specified compounds. Consequently, this finding requires confirmatory experiments. This distinct adduct pattern may relate to tumor induction in this organ following benzene administration. Our results also indicate that DNA adducts derived from catechol, BT, phenol, HQ, and BQ are either not formed in vivo with benzene or formed at levels below the detection limit of 1 adduct per 10(9-10) DNA nucleotides

  17. Determinants of 4-aminobiphenyl-DNA adducts in bladder cancer biopsies.

    Science.gov (United States)

    Airoldi, Luisa; Orsi, Federica; Magagnotti, Cinzia; Coda, Renato; Randone, Donato; Casetta, Giovanni; Peluso, Marco; Hautefeuille, Agnes; Malaveille, Christian; Vineis, Paolo

    2002-05-01

    Exposure to 4-aminobiphenyl (4-ABP) is an important determinant of urinary bladder cancer in humans. We have analyzed by gas chromatography-mass spectrometry the DNA adducts of 4-ABP in 75 bladder cancer biopsies. The purpose was to understand whether smoking, N-acetyltransferase 2 (NAT2) polymorphism, diet or tumor grade were determinants of 4-ABP-DNA levels. 4-ABP-DNA adducts were above the detection limit of 0.1 fmol/microg DNA for 37/75 patients. Overall the level of adducts was 2.7 +/- 0.7 (mean +/- SE) fmol/microg DNA (86 +/- 22 adducts/10(8) normal nucleotides, mean +/- SE). A strong association with grade was observed. In the group of patients with detectable 4-ABP-DNA adducts the odds ratio for having a tumor grade of 2 or 3 was respectively 4.3 (95% CI 0.8-21.9) and 6 (1.3-27.5), compared with grade 1. A non-statistically significant association was found between adduct levels and the deduced slow acetylator phenotype in grades 2 and 3. The intake of fruit and vegetables produced a lower frequency of detectable adducts, though the association was not statistically significant. Detectable 4-ABP-DNA adducts were clearly associated with current smoking in higher tumor grades (grade 3 versus grades 1 + 2, odds ratios 10.4; 95% CI 1.7-63.1). Overall, our findings indicate that higher levels of DNA adducts characterize more invasive tumors (higher tumor grades). This seems to be facilitated by smoking and contrasted by the intake of fruit and vegetables. PMID:12016161

  18. Polycyclic aromatic hydrocarbon-DNA adducts and survival among women with breast cancer

    International Nuclear Information System (INIS)

    Polycyclic aromatic hydrocarbons (PAH) are mammary carcinogens in animal studies, and a few epidemiologic studies have suggested a link between elevated levels of PAH-DNA adducts and breast cancer incidence. An association between PAH-DNA adducts and survival among breast cancer cases has not been previously reported. We conducted a survival analysis among women with newly diagnosed invasive breast cancer between 1996 and 1997, enrolled in the Long Island Breast Cancer Study Project. DNA was isolated from blood samples that were obtained from cases shortly after diagnosis and assayed for PAH-DNA adducts using ELISA. Among the 722 cases with PAH-DNA adduct measurements, 97 deaths (13.4%) from all causes and 54 deaths (7.5%) due to breast cancer were reported to National Death Index (NDI) by December 31, 2002. Using Cox proportional hazards models and controlling for age at diagnosis, we did not find evidence that all-cause mortality (hazard ratio (HR)=0.88; 95% confidence interval (CI): 0.57-1.37), or breast cancer mortality (HR=1.20; 95% CI: 0.63-2.28) was strongly associated with detectable PAH-DNA adduct levels compared with non-detectable adducts; additionally, no dose-response association was observed. Among a subgroup with treatment data (n=520), adducts were associated with over a two-fold higher mortality among those receiving radiation, but mortality for adducts was reduced among hormone therapy users. Results from this large population-based study do not provide strong support for an association between detectable PAH-DNA adducts and survival among women with breast cancer, except perhaps among those receiving radiation treatment

  19. Inhaled cigarette smoke induces the formation of DNA adducts in lungs of rats

    International Nuclear Information System (INIS)

    Cigarette smoking causes a variety of adverse human health effects, including lung cancer. The molecular events associated with smoke-induced carcinogenesis are thought to be related in part to the genotoxic activities of the chemicals associated with smoke. The purpose of this investigation was to determine the molecular dosimetry of compounds in cigarette smoke in lungs of rats exposed by inhalation. These studies investigated the effects of exposure mode, sex, and time (adduct persistence) on the level of DNA adducts. Male and female F344/N rats were exposed 6 hr/day, 5 days/week for 22 days to cigarette smoke by nose-only intermittent (NOI), nose-only continuous (NOC), or whole-body continuous (WBC) exposures. Separate groups of rats were sham-exposed nose-only (NOS) or whole-body (WBS) to filtered air. All smoke exposure modes yielded daily smoke exposure concentration X time products of 600 mg particulate.hr/m3 for the first week and 1200 mg particulate.hour/m3 thereafter. Groups of rats were killed at 18 hr and 3 weeks after the 22-day exposure period and DNA adducts in lung tissues were quantified by the 32P-postlabeling method. There were significant (p less than 0.05) increases in levels of clearly resolved lung DNA adducts in male and female rats exposed to smoke compared to sham-exposed rats. There were no significant effects of exposure mode or sex on lung DNA adducts. Mean levels (+/- SE) of clearly resolved lung DNA adducts for both sexes combined in NOI, NOC, WBC, NOS, and WBS groups were 50 +/- 4, 52 +/- 6, 52 +/- 7, 21 +/- 6, and 22 +/- 4 adducts per 10(9) bases, respectively. Levels of clearly resolved DNA adducts were significantly less in lungs of rats killed 3 weeks after exposure and had declined to near control levels, suggesting that smoke-induced adducts are repaired by lung DNA repair enzymes

  20. DNA-nicotine adduction of lung and liver of mice exposed to passive smoking studied by AMS

    International Nuclear Information System (INIS)

    The author presents the measurement of adduction of mice lung or liver DNA with nicotine by accelerator mass spectrometry (AMS). Mice were exposed in a toxicity infecting chamber filled up with cigarette smoke for a period of time of simulate the exposure of mice to passive smoking. The dose of nicotine inhaled by mice was determined. The results of AMS showed, when the dose of inhaled nicotine ranged from 33 μg/kg to 330 μg/kg, the adducts number of lung DNA was 103-104 adducts/1012 nucleotides, and the adducts increased linearly with increasing dose of nicotine; the adducts number of liver DNA reached to 104-105 adducts/1012 nucleotides, when the dose of nicotine ranged from 99 μg/kg to 330 μg/kg, and the adducts increased vigorously as dose of nicotine increased. Comparing the DNA adducts levels of the same nicotine dose, liver DNA adducts were more than lung DNA adducts. This study also suggested that the other components of cigarette smoke have synergic effect on the formation of nicotine derived DNA adducts

  1. Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53

    Science.gov (United States)

    Denissenko, Mikhail F.; Pao, Annie; Tang, Moon-Shong; Pfeifer, Gerd P.

    1996-10-01

    Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.

  2. Moessbauer studies of mercury(II) salt adducts of (2)ferrocenophane derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Masanobu; Ichikawa, Hajime; Motoyama, Izumi; Sano, Hirotoshi (Tokyo Metropolitan Univ. (Japan). Faculty of Science)

    1983-11-01

    Various adducts of mercuric salts with (2)ferrocenophane and 1,1,2,2-tetramethyl(2)ferrocenophane, were prepared by treating HgX/sub 2/ (X=Cl/sup -/, I/sup -/, CN/sup -/) with the (2)ferrocenophane derivatives in ether. The adducts were studied by Moessbauer spectroscopy and other physicochemical measurements. Anomalously large quadrupole splitting values of the adducts (about 3.10-3.30 mms/sup -1/ at 78 K) suggest the presence of a strong direct interaction between the Fe and Hg atoms.

  3. Base-Displaced Intercalated Structure of the N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone DNA Adduct.

    Science.gov (United States)

    Politica, Dustin A; Malik, Chanchal K; Basu, Ashis K; Stone, Michael P

    2015-12-21

    3-Nitrobenzanthrone (3-NBA), an environmental mutagen found in diesel exhaust and a suspected carcinogen, undergoes metabolic reduction followed by reaction with DNA to form aminobenzanthrone (ABA) adducts, with the major alkylation product being N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (C8-dG-ABA). Site-specific synthesis of the C8-dG-ABA adduct in the oligodeoxynucleotide 5'-d(GTGCXTGTTTGT)-3':5'-d(ACAAACACGCAC)-3'; X = C8-dG-ABA adduct, including codons 272-275 of the p53 gene, has allowed for investigation into the structural and thermodynamic properties of this adduct. The conformation of the C8-dG-ABA adduct was determined using NMR spectroscopy and was refined using molecular dynamics (MD) calculations restrained by experimentally determined interproton distance restraints obtained from NOE experiments. The refined structure revealed that the C8-dG-ABA adduct formed a base-displaced intercalated conformation. The adducted guanine was shifted into the syn conformation about the glycosidic bond. The 5'- and 3'-neighboring base pairs remained intact. While this facilitated π-stacking interactions between the ABA moiety and neighboring bases, the thermal melting temperature (Tm) of the adduct-containing duplex showed a decrease of 11 °C as compared to the corresponding unmodified oligodeoxynucleotide duplex. Overall, in this sequence, the base-displaced intercalated conformation of the C8-dG-ABA lesion bears similarity to structures of other arylamine C8-dG adducts. However, in this sequence, the base-displaced intercalated conformation for the C8-dG-ABA adduct differs from the conformation of the N(2)-dG-ABA adduct reported by de los Santos and co-workers, in which it is oriented in the minor groove toward the 5' end of the duplex, with the modified guanine remaining in the anti conformation about the glyosidic torsion angle, and the complementary base remaining within the duplex. The results are discussed in relationship to differences between the C8-d

  4. NEW THIO S2- ADDUCTS WITH ANTIMONY (III AND V HALIDE: SYNTHESIS AND INFRARED STUDY

    Directory of Open Access Journals (Sweden)

    HASSAN ALLOUCH

    2013-12-01

    Full Text Available Five new S2- adducts with SbIII and SbV halides have been synthesized and studied by infrared. Discrete structures have been suggested, the environment around the antimony being tetrahedral, trigonal bipyramidal or octahedral.

  5. Methods for synthesizing alane without the formation of adducts and free of halides

    Science.gov (United States)

    Zidan, Ragaiy; Knight, Douglas A; Dinh, Long V

    2013-02-19

    A process is provided to synthesize an alane without the formation of alane adducts as a precursor. The resulting product is a crystallized .alpha.-alane and is a highly stable product and is free of halides.

  6. 4-Aminobiphenyl-DNA adducts and p53 mutations in bladder cancer.

    Science.gov (United States)

    Martone, T; Airoldi, L; Magagnotti, C; Coda, R; Randone, D; Malaveille, C; Avanzi, G; Merletti, F; Hautefeuille, A; Vineis, P

    1998-02-01

    Epidemiologic studies have suggested that smokers of air-cured tobacco (rich in arylamines) are at higher risk of bladder cancer than smokers of flue-cured tobacco. The risk has been shown to be modulated by the N-acetyltransferase genotype. We analyzed the biopsies of 45 patients with bladder cancer. p53 mutations were sought by direct sequencing, and 4-aminobiphenyl-DNA adducts were measured by negative ion gas chromatography-mass spectrometry. 4-Aminobiphenyl-DNA adducts were higher in smokers of air-cured tobacco and in current smokers, but no relationship with the number of cigarettes smoked was found. Adducts were higher in more advanced histologic grades of tumors. No pattern was evident for p53 mutations. Seven of 9 mutations occurred in grade 3 tumors. No association was found between 4-ABP adducts and GSTM1 or NAT2 genetic polymorphisms. PMID:9466649

  7. Recent progress in quantitative analysis of DNA adducts of nephrotoxin aristolochic acid

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Aristolochic acid (AA), a mixture of structure-related nitrophenanthrene carboxylic acid derivatives derived from Aristolochia spp, is associated with nephrotoxin and carcinogen. AA-DNA adducts induced by reductive metabolic activation of AA were detected in tissues of animals and in patients exposed to AA. The DNA adducts were generally used as biomarkers in toxicological study of AA. In this short review, quantitative analysis of AA-DNA adducts in various in vitro and in vivo systems by using 32P-postlabelling assay, HPLC-UV, HPLC-radiation monitor, HPLC-FLD, HPLC-ESI/MS and UPLC-MS/MS methods is discussed. The distribution of AA-DNA adducts in various tissues is also summarized.

  8. Fast repair activities of quercetin and rutin toward dGMP hydroxyl radical adducts

    International Nuclear Information System (INIS)

    The repair activities and mechanisms of both quercetin and rutin towards the oxidizing deoxyguanosine monophosphate (d GMP) hydroxyl radical adduct were investigated with pulse radiolytic technique. On pulse irradiation of nitrous oxide saturated 2 mm d GMP aqueous solution containing 0.1 mm quercetin, the transient absorption spectrum of the d GMP hydroxyl radical adduct decays with the formation of phenoxyl radical of quercetin within tens of microseconds. It indicates that there is a repair reaction between d GMP hydroxyl radical adduct and quercetin. The repair activity of rutin towards hydroxyl radical adducts of d GMP was also observed. The rate constants of the repair reactions were calculated to be 3.05x108 and 1.31x108 M-1 s-1for quercetin and rutin, respectively. This result together with our previous studies demonstrated that non-enzymatic, fast repair is a universal repair mechanism of phenolic antioxidants.

  9. Development of methods to measure hemoglobin adducts by gel electrophoresis - Preliminary results

    International Nuclear Information System (INIS)

    Chemical adducts formed on blood hemoglobin may be a useful biomarker for assessing human exposures to these compounds. This paper reports preliminary results in the development of methods to measure such adducts that may be generally applicable for a wide variety of chemicals. Male F344/N rats were intraperitoneally injected with 14C-BaP dissolved in corn oil. Twenty-four hours later, the rats were sacrificed. Blood samples were collected and globin was isolated. Globin protein was then cleaved into peptide fragments using cyanogen bromide and the fragments separated using 2-dimensional gel electrophoresis. The results showed that the adducted 14C-globin fragments migrated to different areas of the gel than did unadducted fragments. Further research is being conducted to develop methods that will allow quantitation of separated adducted globin fragments from human blood samples without the use of a radiolabel. (author)

  10. Ultrasensitive isolation, identification and quantification of DNA–protein adducts by ELISA-based RADAR assay

    OpenAIRE

    Kiianitsa, Kostantin; Maizels, Nancy

    2014-01-01

    Enzymes that form transient DNA–protein covalent complexes are targets for several potent classes of drugs used to treat infectious disease and cancer, making it important to establish robust and rapid procedures for analysis of these complexes. We report a method for isolation of DNA–protein adducts and their identification and quantification, using techniques compatible with high-throughput screening. This method is based on the RADAR assay for DNA adducts that we previously developed (Kiia...

  11. DNA adducts in target and nontarget tissues of 3,2'-dimethyl-4-aminobiphenyl in rats.

    OpenAIRE

    Shirai, T; Tada, M; Kojima, M; Hasegawa, R.; Masui, T.; Ito, N.

    1994-01-01

    3,2'-Dimethyl-4-aminobiphenyl (DMAB) is a potent carcinogenic aromatic amine which demonstrates multiorgan tropism in rats. Using polyclonal antibodies against DMAB-DNA adducts, an immunohistochemical procedure as well as an ELISA were applied to investigate the relationship between DMAB-DNA adduct formation and tumorigenicity. Dose-related nuclear staining was observed 24 hr after application of the carcinogen but specificity in terms of sites of tumor development was lacking. No observable ...

  12. NMR solution structures of adducts derived from the binding of polycyclic aromatic diol epoxides to DNA

    Energy Technology Data Exchange (ETDEWEB)

    Cosman, M.; Patel, D.J. [Memorial Sloan Kettering Cancer Center, New York, NY (United States). Cellular Biochemistry and Biophysics Program; Hingerty, B.E. [Oak Ridge National Lab., TN (United States). Health and Safety Research Div.; Amin, S. [American Health Foundation, Valhalla, NY (United States); Broyde, S.; Geacintov, N.E. [New York Univ., NY (United States)

    1995-12-31

    Site-specifically modified oligonucleotides were derived from the reactions of stereoisomeric polycyclic aromatic diol epoxide metabolite model compounds with oligonucleotides of defined base composition and sequence. The NMR solution structures of ten different adducts studied so far are briefly described, and it is shown that stereochemical factors and the nature of the oligonucleotide context of the complementary strands, exert a powerful influence on the conformational features of these adducts.

  13. Comparison of DNA adducts from exposure to complex mixtures in various human tissues and experimental systems

    OpenAIRE

    Lewtas, Joellen; Mumford, Judy; Everson, Richard B; Hulka, Barbara; Wilcosky, Tim; Kozumbo, Walter; Thompson, Claudia; George, Michael; Dobiáš, Lubomir; Šrám, Radim; Li, Xueming; Gallagher, Jane

    1993-01-01

    DNA adducts derived from complex mixtures of polycyclic aromatic compounds emitted from tobacco smoke are compared to industrial pollution sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and urban air pollution. Exposures to coke oven emissions and smoky coal, both potent rodent skin tumor initiators and lung carcinogens in humans, result in high levels of DNA adducts compared to tobacco smoke in the in vitro calf thymus DNA model system, in cultured lymphocytes, and in ...

  14. DNA adducts as a measure of lung cancer risk in humans exposed to polycyclic aromatic hydrocarbons.

    OpenAIRE

    Kriek, E; van Schooten, F.J.; Hillebrand, M J; van Leeuwen, F E; Den Engelse, L; De Looff, A J; Dijkmans, A P

    1993-01-01

    Workers in the coking, foundry, and aluminum industry can be exposed to high concentrations of polycyclic aromatic hydrocarbons (PAHs) and are at increased risk for lung cancer, as are cigarette smokers. In recent years several studies on workers in the foundry and coking industries have been reported. In these studies, white blood cell(WBC) DNA was used for analysis of PAH-DNA adducts. Theoretically, DNA adduct formation is a more relevant biological parameter for assessing exposure risk tha...

  15. Albumin Adducts of Electrophilic Benzene Metabolites in Benzene-Exposed and Control Workers

    OpenAIRE

    Lin, Yu-Sheng; Vermeulen, Roel; Tsai, Chin H.; Waidyanatha, Suramya; Lan, Qing; Rothman, Nathaniel; Smith, Martyn T.; Zhang, Luoping; Shen, Min; Li, Guilan; Yin, Songnian; Kim, Sungkyoon; Rappaport, Stephen M.

    2006-01-01

    Background Metabolism of benzene produces reactive electrophiles, including benzene oxide (BO), 1,4-benzoquinone (1,4-BQ), and 1,2-benzoquinone (1,2-BQ), that are capable of reacting with blood proteins to produce adducts. Objectives The main purpose of this study was to characterize relationships between levels of albumin adducts of these electrophiles in blood and the corresponding benzene exposures in benzene-exposed and control workers, after adjusting for important covariates. Because se...

  16. Adducts of Amine with Dimeric Rhodium(II) Tetracarboxylates - Formation of Nitrogenous Chiral Center

    International Nuclear Information System (INIS)

    Rhodium(II) tetracarboksylates Rh2(RCO2)4 (1a) are able to produce various complexes with organic ligands, like the 1:1 and 2:1 adducts containing axially bonded ligands (1b), or the compounds with rearranged dirhodium core (1c). The solution of dirhodium(II) tetracarboxylate and a ligand usually contains a mixture of adducts, due to ligand exchange and different equilibriums between species. However, application of nuclear magnetic resonance measurements at reduced temperature allows often observing the signals of all species in the solution. Ligands containing nitrogen atom were the subject of our previous investigation. It was found that dirhodium salts are able to form both 1:1 and 2:1 adducts with an amine, depending on reagents ratio. The present investigations are devoted to the amines with general formula NRR'R', is the amines having potential nitrogenous chiral center. An amine with three various substituents NRR'R' is formally a chiral molecule, but in the solution the molecule forms racemic mixture due to fast pyramidal inversion at the nitrogen atom. However, dirhodium(II) tetracarboxylates bonding the amine acts as an agent freezing pyramidal inversion at nitrogen atom, and results in formation of a new, nitrogenous chiral center in the adduct. Thus, the chiral dirhodium salt (4R)-Rh2[(CF3)(OCH3)(Ph)CO2]4 forms with benzyl-ethyl-methylamine five adducts: (4R)/(S), (4R)/(R) (1:1 adducts) and (R)/(4R)/(R), (R)/(4R)/(S), (S)/(4R)/(S) (2:1 adducts). All these diastereoisomers were detected by means of low temperature NMR (253 K). Similar effect was observed for the adducts with methyl-(1-phenylethyl)- amine, PhCH(NHCH3)CH3, having both nitrogenous and carbon chiral centers. (author)

  17. Formation and characterization of covalent guanosine adducts with electrochemistry—liquid chromatography–mass spectrometry ☆

    OpenAIRE

    Plattner, Sabine; Erb, Robert; Pitterl, Florian; Brouwer, Hendrik-Jan; Oberacher, Herbert

    2012-01-01

    Chemicals can interact with the genetic material giving rise to the formation of covalent adducts. These alterations can lead to adverse consequences, including cancer, reproductive impairment, development anomalies, or genetic diseases. In search for an assay allowing identification of hazardous compounds that might form covalent adducts with nucleic acids, electrochemistry (EC)/liquid chromatography (LC)/mass spectrometry (MS) is presented. EC/LC/MS is a purely instrumental approach. EC is ...

  18. Supercritical fluid extraction (SFE) of actinide complexes. Communication 1. SFE of uranyl trifluoroacetylacetonate adduct with pyridine

    International Nuclear Information System (INIS)

    Comparison of some methods of ascertaining the solubility of metal complexes in supercritical carbon dioxide (SC-CO2) was made. It is shown that solubility of uranyl trifluoroacetylacetonate adduct with pyridine exceeds 100 g/l (36 mg of uranium per ml) of SC-CO2 under the pressure of 300 atm and temperature of 60 deg C. Partial degrading of the uranyl trifluoroacetylacetonate adduct with pyridine is pointed out

  19. Surgical treatment of thumb adduction contracture in children with infantile cerebral palsy

    OpenAIRE

    Vladimir Alexandrovich Novikov; Valery Vladimirovich Umnov

    2015-01-01

    The purpose of the work is to evaluate the effectiveness of different methods of surgical treatment of thumb adduction contracture in children with infantile cerebral palsy.Materials and methods.The present study is based on diagnostic results of children with infantile cerebral palsy with affected upper limb. The main criterion for selection of patients was the presence of thumb adduction contracture, the absence of significant positive outcome in a patient after conservative treatment, the ...

  20. Haemoglobin adducts formed by aromatic amines in smokers: sources of inter-individual variability.

    OpenAIRE

    Ronco, G.; Vineis, P; Bryant, M S; Skipper, P. L.; Tannenbaum, S R

    1990-01-01

    In a previous study we found that aromatic amines, particularly 4-aminobiphenyl, formed haemoglobin adducts at higher concentrations in the blood of smokers compared to non-smokers. We re-analyse here data on haemoglobin adducts of 14 aromatic amines in order to ascertain if the inter-individual variability left unexplained by tobacco smoking could be attributed to differences in individual metabolic patterns. For this purpose we computed residuals from analysis of variance in order to adjust...

  1. Hemoglobin adducts of aromatic amines: associations with smoking status and type of tobacco.

    OpenAIRE

    Bryant, M S; Vineis, P; Skipper, P. L.; Tannenbaum, S R

    1988-01-01

    Hemoglobin adducts of 15 aromatic amines were determined in nonsmokers and smokers of blond- or black-tobacco cigarettes living in Turin, Italy. The subjects were all males age 55 or less and were representative of the population previously examined in a case/control study of bladder cancer. 4-Aminobiphenyl adduct levels were found to be significantly different in the three groups, and the differences were approximately proportional to the relative risk of each group. Adjustment for age and c...

  2. Effects of Metal Ion Adduction on the Gas-Phase Conformations of Protein Ions

    OpenAIRE

    Flick, Tawnya G.; Merenbloom, Samuel I.; Williams, Evan R.

    2013-01-01

    Changes in protein ion conformation as a result of nonspecific adduction of metal ions to the protein during electrospray ionization (ESI) from aqueous solutions were investigated using traveling wave ion mobility spectrometry (TWIMS). For all proteins examined, protein cations (and in most cases anions) with nonspecific metal ion adducts are more compact than the fully protonated (or deprotonated) ions with the same charge state. Compaction of protein cations upon nonspecific metal ion bindi...

  3. Structural Elucidation of a Carnosine-Acrolein Adduct and its Quantification in Human Urine Samples.

    Science.gov (United States)

    Bispo, Vanderson S; de Arruda Campos, Ivan P; Di Mascio, Paolo; Medeiros, Marisa H G

    2016-01-01

    Aldehydes accumulate in inflammation, during myocardial infarction and have been associated with pain symptoms. One pathway of aldehyde detoxification is the conjugation with carnosine. A 3-methylpyridinium carnosine adduct from the reaction of carnosine and acrolein was characterized using extensive spectroscopic measurements. The adduct with urinary concentrations of 1.82 ± 0.68 nmol/mg of creatinine is one of the most abundant acrolein metabolites in urine and opens promising therapeutic strategies for carnosine. PMID:26783107

  4. Structural Elucidation of a Carnosine-Acrolein Adduct and its Quantification in Human Urine Samples

    OpenAIRE

    Vanderson S. Bispo; Ivan P. de Arruda Campos; Paolo Di Mascio; Medeiros, Marisa H. G.

    2016-01-01

    Aldehydes accumulate in inflammation, during myocardial infarction and have been associated with pain symptoms. One pathway of aldehyde detoxification is the conjugation with carnosine. A 3-methylpyridinium carnosine adduct from the reaction of carnosine and acrolein was characterized using extensive spectroscopic measurements. The adduct with urinary concentrations of 1.82 ± 0.68 nmol/mg of creatinine is one of the most abundant acrolein metabolites in urine and opens promising therapeutic s...

  5. Detection of benzo[a]pyrene diol epoxide-DNA adducts in peripheral blood lymphocytes and antibodies to the adducts in serum from coke oven workers.

    OpenAIRE

    Harris, C. C.; Vahakangas, K.; Newman, M J; Trivers, G E; Shamsuddin, A; Sinopoli, N; Mann, D L; Wright, W. E.

    1985-01-01

    Coke oven workers are exposed to high levels of carcinogenic polycyclic aromatic hydrocarbons, including benzo[a]pyrene (B[a]P), and are at increased risk of lung cancer. Since B[a]P is enzymatically activated to 7 beta,8 alpha-dihydroxy(9 alpha, 10 alpha)epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE) that forms adducts with DNA, the presence of these adducts was measured in DNA from peripheral blood lymphocytes by synchronous fluorescence spectrophotometry and enzyme radioimmunoassay. App...

  6. Implications of acetaldehyde-derived DNA adducts for understanding alcohol-related carcinogenesis.

    Science.gov (United States)

    Balbo, Silvia; Brooks, Philip J

    2015-01-01

    Among various potential mechanisms that could explain alcohol carcinogenicity, the metabolism of ethanol to acetaldehyde represents an obvious possible mechanism, at least in some tissues. The fundamental principle of genotoxic carcinogenesis is the formation of mutagenic DNA adducts in proliferating cells. If not repaired, these adducts can result in mutations during DNA replication, which are passed on to cells during mitosis. Consistent with a genotoxic mechanism, acetaldehyde does react with DNA to form a variety of different types of DNA adducts. In this chapter we will focus more specifically on N2-ethylidene-deoxyguanosine (N2-ethylidene-dG), the major DNA adduct formed from the reaction of acetaldehyde with DNA and specifically highlight recent data on the measurement of this DNA adduct in the human body after alcohol exposure. Because results are of particular biological relevance for alcohol-related cancer of the upper aerodigestive tract (UADT), we will also discuss the histology and cytology of the UADT, with the goal of placing the adduct data in the relevant cellular context for mechanistic interpretation. Furthermore, we will discuss the sources and concentrations of acetaldehyde and ethanol in different cell types during alcohol consumption in humans. Finally, in the last part of the chapter, we will critically evaluate the concept of carcinogenic levels of acetaldehyde, which has been raised in the literature, and discuss how data from acetaldehyde genotoxicity are and can be utilized in physiologically based models to evaluate exposure risk. PMID:25427902

  7. Sperm DNA adducts impair fertilization during ICSI but not during IVF.

    Directory of Open Access Journals (Sweden)

    Piotr Widłak

    2008-04-01

    Full Text Available Many studies emphasize the influence of the status of spermatozoal nucleus on fertilization, mainly with regard to DNA fragmentation. This study was undertaken to analyze the influence of DNA adducts content in spermatozoa on fertilization during assisted reproduction. Ovarian hyperstimulation, oocyte retrieval and laboratory work-up in 61 IVF (in vitro fertilization and 118 ICSI (intracytoplasmic sperm injection first cycles were performed according to the same protocol. Semen analysis was made according to WHO Manual (1999. DNA adducts assay in spermatozoa was performed by 32Ppostlabeling method. In total 331 fertilizable oocytes were obtained during IVF and 659 during ICSI. Both groups differed significantly by sperm count, motility and morphology but not by the concentration of DNA adducts in spermatozoa (0.0306 +/- 0.0217 in IVF versus 0.0373 +/- 0.0321 in ICSI. The fertilization rate during IVF was significantly influenced by sperm count (p=0.0002 and motility (p=0.0037 but not by DNA adducts concentration (p=0.30528, whereas during ICSI was positively influenced by sperm motility (p=0.04669 and negatively by DNA adducts concentration (p=0.00796. DNA adducts concentration in spermatozoa significantly negatively influences fertilization rate during ICSI, but not during IVF.

  8. Scavenging of Toxic Acrolein by Resveratrol and Hesperetin and Identification of Adducts.

    Science.gov (United States)

    Wang, Weixin; Qi, Yajing; Rocca, James R; Sarnoski, Paul J; Jia, Aiqun; Gu, Liwei

    2015-11-01

    The objective of this study was to investigate the ability of resveratrol and hesperetin to scavenge acrolein at pH 7.4 and 37 °C. About 6.4 or 5.2% of acrolein remained after reaction with resveratrol or hesperetin for 12 h at equimolar concentrations. An acrolein-resveratrol adduct and two acrolein-hesperetin adducts were isolated. Their structures were elucidated using mass and NMR spectroscopy. Acrolein reacted with resveratrol at the C-2 and C-3 positions through nucleophilic addition and formed an additional heterocyclic ring. Two similar monoacrolein-conjugated adducts were identified for hesperetin. Spectroscopic data suggested each acrolein-hesperetin adduct was a mixture of four stereoisomers due to the existence of two chiral carbon atoms. Yield of adducts was low at pH 5.4 but increased at pH 7.4 and 8.4. Higher pH also promoted the formation of diacrolein adducts. Results suggest that resveratrol and hesperetin exert health benefits in part through neutralizing toxic acrolein in vivo. PMID:26457480

  9. Abacavir forms novel cross-linking abacavir protein adducts in patients.

    Science.gov (United States)

    Meng, Xiaoli; Lawrenson, Alexandre S; Berry, Neil G; Maggs, James L; French, Neil S; Back, David J; Khoo, Saye H; Naisbitt, Dean J; Park, B Kevin

    2014-04-21

    Abacavir (ABC), a nucleoside-analogue reverse transcriptase inhibitor, is associated with severe hypersensitivity reactions that are thought to involve the activation of CD8+ T cells in a HLA-B*57:01-restricted manner. Recent studies have claimed that noncovalent interactions of ABC with HLA-B*57:01 are responsible for the immunological reactions associated with ABC. However, the formation of hemoglobin-ABC aldehyde (ABCA) adducts in patients exposed to ABC suggests that protein conjugation might represent a pathway for antigen formation. To further characterize protein conjugation reactions, we used mass spectrometric methods to define ABCA modifications in patients receiving ABC therapy. ABCA formed a novel intramolecular cross-linking adduct on human serum albumin (HSA) in patients and in vitro via Michael addition, followed by nucleophilic adduction of the aldehyde with a neighboring protein nucleophile. Adducts were detected on Lys159, Lys190, His146, and Cys34 residues in the subdomain IB of HSA. Only a cysteine adduct and a putative cross-linking adduct were detected on glutathione S-transferase Pi (GSTP). These findings reveal that ABC forms novel types of antigens in all patients taking the drug. It is therefore vital that the immunological consequences of such pathways of haptenation are explored in the in vitro models that have been used by various groups to define new mechanisms of drug hypersensitivity exemplified by ABC. PMID:24571427

  10. Novel pyrano and vinylphenol adducts of deoxyanthocyanidins in sorghum sourdough.

    Science.gov (United States)

    Bai, Yunpeng; Findlay, Brandon; Maldonado, Alma Fernanda Sanchez; Schieber, Andreas; Vederas, John C; Gänzle, Michael G

    2014-11-26

    This study determined the fate of deoxyanthocyanidins in sorghum sourdoughs. Sourdoughs prepared from the red sorghum variety Town were fermented with the caffeic acid-decarboxylating strains Lactobacillus plantarum FUA3171 and the decarboxylase negative L. casei FUA3166. Deoxyanthocyanidins were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Apigeninidin and methoxyapigeninidin were the major deoxyanthocyanidins prior to fermentation. During fermentation, novel deoxyanthocyanidins were formed. Purification by preparative LC, followed by NMR analysis and high-resolution MS identified two of the compounds as 6-deoxyanthocyanidin-vinylphenol and pyrano-3-deoxyanthocyanidin. To identify pathways for their formation, sorghum was fermented with single strains, L. plantarum or L. casei. 6-Deoxyanthocyanidin-vinylphenol and pyrano-3-deoxyanthocyanidin were formed only during fermentation with L. plantarum FUA3171, indicating a role of vinylphenol in their formation. Chemical synthesis confirmed that 6-deoxyanthocyanidin-vinylphenol and pyrano-3-deoxyanthocyanidin are formed from apigeninidin with vinylphenol but not with p-coumaric acid as reactants. In conclusion, the products of microbial decarboxylation of hydroxycinnamic acids convert apigeninidin and methoxyapigeninidin to pyrano-3-deoxyanthocyanidins and vinylphenol adducts. PMID:25370078

  11. Diazoalkane addition reaction on the fullerene dimer C120O and characterization of the resulting mono-adduct.

    Directory of Open Access Journals (Sweden)

    Uwe Ritter

    2008-06-01

    Full Text Available A mono-adduct of the fullerene dimer C120O was prepared via a diazoalkane addition reaction to obtain rod-like analogue of[60]PCBM opening the possibility to make photovoltaic and photosensitive layers of supra-molecular and anisotropic order.The mono-adduct was obtained as a mixture containing five isomers. The structure of the mono-adduct was verified bymass-, IR-, and 1H-NMR-spectroscopies. The mono-adduct is readily soluble in common fullerene solvents and shows abroader and stronger optical absorption than [60]PCBM. The mono-adduct features a similar acceptor strength as [60]PCBMand [70]PCBM, is stable in air below 150 °C and in nitrogen below 500 °C. The mono-adduct is expected to be a valuablematerial for photovoltaic and photosensitive applications.

  12. Simultaneous detection of multiple DNA adducts in human lung samples by isotope-dilution UPLC-MS/MS.

    Science.gov (United States)

    Monien, Bernhard H; Schumacher, Fabian; Herrmann, Kristin; Glatt, Hansruedi; Turesky, Robert J; Chesné, Christophe

    2015-01-01

    Recent studies have demonstrated that various DNA adducts can be detected in human tissues and fluids using liquid chromatography connected to tandem mass spectrometry (LC-MS/MS). However, the utility of a single DNA adduct as a biomarker in risk assessment is debatable because humans are exposed to many genotoxicants. We established a method to measure DNA adducts derived from 16 ubiquitous genotoxicants and developed an analytical technique for their simultaneous quantification by ultra performance liquid chromatography (UPLC)-MS/MS. Methods for the enrichment of the analytes from DNA hydrolysates and chromatographic separation preceding mass spectrometric analysis were optimized, and the resultant technique was used for the simultaneous analysis of the 16 DNA adducts in human lung biopsy specimens. Eleven adducts (formed by benzo[a]pyrene, 1-methylpyrene, 4-aminobiphenyl, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 1-methoxy-3-indolylmethylglucosinolate, 5-hydroxymethylfurfural, and malondialdehyde) were not detected in any tissue sample (limits of detection: 0.02-7.1 adducts/10(8) nucleosides). 3,N(4)-etheno-2'-deoxycytidine and 1,N(6)-etheno-2'-deoxyadenosine, formed from 2,3-epoxyaldehydes of endogenous lipid peroxidation products, were present in all subjects (16.9-115.3 and 27.2-179/10(8) nucleosides, respectively). The same was true for N(2)-(trans-methylisoeugenol-3'-yl)-2'-deoxyguanosine, the major adduct of methyleugenol (1.7-23.7/10(8) nucleosides). A minor adduct of methyleugenol and two adducts of furfuryl alcohol were detected in several pulmonary specimens. Taken together, we developed a targeted approach for the simultaneous mass spectrometric analyses of 16 DNA adducts, which can be easily extended by adducts formed from other mutagens. The method allowed one to detect adducts of furfuryl alcohol and methyleugenol in samples of human lung. PMID:25423194

  13. Simultaneous Detection of Multiple DNA Adducts in Human Lung Samples by Isotope-Dilution UPLC-MS/MS

    OpenAIRE

    Monien, Bernhard H.; Schumacher, Fabian; Herrmann, Kristin; Glatt, Hansruedi; Turesky, Robert J.; Chesné, Christophe

    2014-01-01

    Recent studies have demonstrated that various DNA adducts can be detected in human tissues and fluids using liquid chromatography connected to tandem mass spectrometry (LC-MS/MS). However, the utility of a single DNA adduct as a biomarker in risk assessment is debatable because humans are exposed to many genotoxicants. We established a method to measure DNA adducts derived from 16 ubiquitous genotoxicants and developed an analytical technique for their simultaneous quantification by ultra per...

  14. Transplatin-conjugated triplex-forming oligonucleotides form adducts with both strands of DNA.

    Science.gov (United States)

    Campbell, Meghan A; Miller, Paul S

    2009-12-01

    Triplex-forming oligonucleotides (TFOs) can bind to polypurine x polypyrimidine tracts in DNA and, as a consequence, perturb the normal functioning of a targeted gene. The effectiveness of such antigene TFOs can potentially be enhanced by covalent attachment of the TFO to its DNA target. Here, we report that attachment of N-7-platinated guanine nucleosides to the 3'- and/or 5'-ends of oligopyrimidine TFOs enables these TFOs to form highly stable adducts with target DNA deoxyguanosines or deoxyadenosines that are adjacent to the TFO binding site. Such adduct formation stably anchors the TFO to its target. Depending on the sequences adjacent to the TFO binding site, adduct formation can occur on either strand of the DNA. Adduct formation by 3',5'-bis-platinated TFOs can result in the formation of an interstrand cross-link between both strands of the DNA duplex. Formation of the adducts, which could be reversed by treatment with sodium cyanide, was dependent upon the ability of the TFO to bind to DNA and appeared to occur at a rate slower than that at which the TFO bound to the DNA duplex. The extent of adduct formation at 37 degrees C by platinated deoxyribo-TFOs diminished as the pH was increased from 6.5 to 7.4. In contrast, high levels (approximately 86%) of adduct formation by platinated 2'-O-methylribo-TFOs were observed at both pH 6.5 and pH 7.4. Platinated 2'-O-methylribo-TFOs were also shown to bind to plasmid DNA and inhibit transcription in vitro, and to inhibit plasmid replication in E. coli cells. These results suggest that platinum-conjugated TFOs may be good candidates for use as antigene agents. PMID:19950917

  15. Silver adducts of four-branched histidine rich peptides exhibit synergistic antifungal activity.

    Science.gov (United States)

    Leng, Qixin; Woodle, Martin C; Liu, Yijia; Mixson, A James

    2016-09-01

    Previously, a four branched histidine-lysine rich peptide, H3K4b, was shown to demonstrate selective antifungal activity with minimal antibacterial activity. Due to the potential breakdown from proteases, H3K4b was further evaluated in the current study by varying the D- and l-amino acid content in its branches. Whereas analogues of H3K4b that selectively replaced l-amino acids (H3k4b, h3K4b) had improved antifungal activity, the all d-amino acid analogue, h3k4b, had reduced activity, suggesting that partial breakdown of the peptide may be necessary. Moreover, because histidines form coordination bonds with the silver ion, we examined whether silver adducts can be formed with these branched histidine-lysine peptides, which may improve antifungal activity. For Candida albicans, the silver adduct of h3K4b or H3k4b reduced the MIC compared to peptide and silver ions alone by 4- and 5-fold, respectively. For Aspergillus fumigatus, the silver adducts showed even greater enhancement of activity. Although the silver adducts of H3k4b or h3K4b showed synergistic activity, the silver adduct with the all l-amino acid H3K4b surprisingly showed the greatest synergistic and growth inhibition of A. fumigatus: the silver adduct of H3K4b reduced the MIC compared to the peptide and silver ions alone by 30- and 26-fold, respectively. Consistent with these antifungal efficacy results, marked increases in free oxygen radicals were produced with the H3K4b and silver combination. These studies suggest that there is a balance between stability and breakdown for optimal antifungal activity of the peptide alone and for the peptide-silver adduct. PMID:27387239

  16. Formation of 1,4-dioxo-2-butene-derived adducts of 2'-deoxyadenosine and 2'-deoxycytidine in oxidized DNA.

    Science.gov (United States)

    Chen, Bingzi; Vu, Choua C; Byrns, Michael C; Dedon, Peter C; Peterson, Lisa A

    2006-08-01

    Oxidation of deoxyribose in DNA produces a variety of electrophilic residues that are capable of reacting with nucleobases to form adducts such as M(1)dG, the pyrimidopurinone adduct of dG. We now report that deoxyribose oxidation in DNA leads to the formation of oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA. We previously demonstrated that these adducts arise in reactions of nucleosides and DNA with trans-1,4-dioxo-2-butene, the beta-elimination product of the 2-phosphoryl-1,4-dioxobutane residue arising from 5'-oxidation of deoxyribose in DNA, and with cis-1,4-dioxo-2-butene, a metabolite of furan. Treatment of DNA with enediyne antibiotics capable of oxidizing the 5'-position of deoxyribose (calicheamicin and neocarzinostatin) led to a concentration-dependent formation of oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA, while the antibiotic bleomycin, which is capable of performing only 4-oxidation of deoxyribose, did not give rise to the adducts. The nonspecific DNA oxidant, gamma-radiation, also produced the adducts that represented approximately 0.1% of the 2-phosphoryl-1,4-dioxobutane residues formed during the irradiation. These results suggest that the oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA could represent endogenous DNA lesions arising from oxidative stresses that also give rise to other DNA adducts. PMID:16918236

  17. Formation of metal-ion adducts and evidence for surface-catalyzed ionization in electrospray analysis of pharmaceuticals and pesticides

    Science.gov (United States)

    Thurman, E.M.; Ferrer, I.

    2002-01-01

    The formation of metal ion adducts in liquid chromatography/mass spectrometry positive-ion electrospray analysis of pharmaceuticals and pesticides was investigated. The evidence of surface-catalyzed ionization in the electrospray analysis was also studied. Both positive and negative ion mass spectrometry were used for the analysis of the products. It was found that the sodium adducts formed in the analysis included single, double, and triple sodium adducts. Adduction was found to occur by attachment of the metal ion to carboxyl, carbonyl and aromatic pi electrons of the molecule.

  18. DNA isolation and sample preparation for quantification of adduct levels by accelerator mass spectrometry.

    Science.gov (United States)

    Dingley, Karen H; Ubick, Esther A; Vogel, John S; Ognibene, Ted J; Malfatti, Michael A; Kulp, Kristen; Haack, Kurt W

    2014-01-01

    Accelerator mass spectrometry (AMS) is a highly sensitive technique used for the quantification of adducts following exposure to carbon-14- or tritium-labeled chemicals, with detection limits in the range of one adduct per 10(11)-10(12) nucleotides. The protocol described in this chapter provides an optimal method for isolating and preparing DNA samples to measure isotope-labeled DNA adducts by AMS. When preparing samples, special precautions must be taken to avoid cross-contamination of isotope among samples and produce a sample that is compatible with AMS. The DNA isolation method described is based upon digestion of tissue with proteinase K, followed by extraction of DNA using Qiagen isolation columns. The extracted DNA is precipitated with isopropanol, washed repeatedly with 70 % ethanol to remove salt, and then dissolved in water. DNA samples are then converted to graphite or titanium hydride and the isotope content measured by AMS to quantify adduct levels. This method has been used to reliably generate good yields of uncontaminated, pure DNA from animal and human tissues for analysis of adduct levels. PMID:24623226

  19. Induction of stable protein-deoxyribonucleic acid adducts in Chinese hamster cell chromatin by ultraviolet light

    International Nuclear Information System (INIS)

    Ultraviolet (uv)-light-mediated formation of protein-DNA adducts in Chinese hamster cell chromatin was investigated in an attempt to compare chromatin alterations induced in vitro with those observed in vivo. Three independent methods of analysis indicated stable protein-DNA associations: a membrane filter assay which retained DNA on the filter in the presence of high salt-detergent; a Sepharose 4B column assay in which protein eluted coincident with DNA; and a CsCl density gradient equilibrium assay which showed both protein and DNA banding at densities other than their respective native densities. Treatment of the irradiated chromatin with DNase provided further evidence that protein--DNA and not protein-protein adducts were being observed in the column assay. There is a fluence-dependent response of protein-DNA adduct formation when the chromatin is irradiated at low ionic strength and is linear for protein over the range studied. When the chromatin is exposed to differing conditions of pH, ionic strength, or divalent metal ion concentration, the quantity of adduct formed upon uv irradiation varies. Susceptibility to adduct formation can be partially explained in terms of the condensation state of the chromatin and other factors such as rearrangement, denaturation, and dissociation of the chromatin components. Besides providing information on the biological significance of these types of uv-induced lesions, this technique may be useful as a probe of chromatin structure

  20. Inhibition of nicotine-DNA adduct formation by polyphenolic compounds in vitro

    Institute of Scientific and Technical Information of China (English)

    CHENG Yan; WANG Hai-Fang; SUN Hong-Fang; LI Hong-Li

    2004-01-01

    Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco products, has proven to be a potential genotoxic compound. Some polyphenolic compounds can suppress the DNA adduction, and hence act as the potential inhibitors of carcinogenesis. In this study, the inhibitory effects of three polyphenolic compounds, curcumin (diferuloylmethane), resveratrol (trans-3, 5, 4-trihydroxystilbene) and tea polyphenols, on the nicotine-DNA adduction have been investigated in vitro using radiolabelled nicotine and liquid scintillation counting (LSC) technique. Also, the inhibition mechanism of these chemopreventive agents in regard to the activity of the biotransformation enzymes, including cytochrome P450 (CYP450), cytochrome b5 (CYb5) and glutathione S-transferase (GST), has been studied. The results demonstrated that these three polyphenols induced marked dose-dependent decrease in nicotine-DNA adducts as compared with the controls. The elimination rate of adducts reached above 46% at the highest dose for all the three agents with 51.6% for resveratrol. Correspondingly, three polyphenols all suppressed CYP450 and CYb5, whereas curcumin and resveratrol induced GST. We may arrive at a point that the three polyphenols are beneficial to prevent the nicotine adduct formation, and thus may be used to block the potential carcinogenesis induced by nicotine.

  1. Characterization of model peptide adducts with reactive metabolites of naphthalene by mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Nathalie T Pham

    Full Text Available Naphthalene is a volatile polycyclic aromatic hydrocarbon generated during combustion and is a ubiquitous chemical in the environment. Short term exposures of rodents to air concentrations less than the current OSHA standard yielded necrotic lesions in the airways and nasal epithelium of the mouse, and in the nasal epithelium of the rat. The cytotoxic effects of naphthalene have been correlated with the formation of covalent protein adducts after the generation of reactive metabolites, but there is little information about the specific sites of adduction or on the amino acid targets of these metabolites. To better understand the chemical species produced when naphthalene metabolites react with proteins and peptides, we studied the formation and structure of the resulting adducts from the incubation of model peptides with naphthalene epoxide, naphthalene diol epoxide, 1,2-naphthoquinone, and 1,4-naphthoquinone using high resolution mass spectrometry. Identification of the binding sites, relative rates of depletion of the unadducted peptide, and selectivity of binding to amino acid residues were determined. Adduction occurred on the cysteine, lysine, and histidine residues, and on the N-terminus. Monoadduct formation occurred in 39 of the 48 reactions. In reactions with the naphthoquinones, diadducts were observed, and in one case, a triadduct was detected. The results from this model peptide study will assist in data interpretation from ongoing work to detect peptide adducts in vivo as markers of biologic effect.

  2. Serine Protease Catalysis: A Computational Study of Tetrahedral Intermediates and Inhibitory Adducts.

    Science.gov (United States)

    Ngo, Phong D; Mansoorabadi, Steven O; Frey, Perry A

    2016-08-01

    Peptide boronic acids and peptidyl trifluoromethyl ketones (TFKs) inhibit serine proteases by forming monoanionic, tetrahedral adducts to serine in the active sites. Investigators regard these adducts as analogs of monoanionic, tetrahedral intermediates. Density functional theory (DFT) calculations and fractional charge analysis show that tetrahedral adducts of model peptidyl TFKs are structurally and electrostatically very similar to corresponding tetrahedral intermediates. In contrast, the DFT calculations show the structures and electrostatic properties of analogous peptide boronate adducts to be significantly different. The peptide boronates display highly electrostatically positive boron, with correspondingly negative ligands in the tetrahedra. In addition, the computed boron-oxygen and boron-carbon bond lengths in peptide boronates (which are identical or very similar to the corresponding bonds in a peptide boronate adduct of α-lytic protease determined by X-ray crystallography at subangstrom resolution) are significantly longer than the corresponding bond lengths in model tetrahedral intermediates. Since protease-peptidyl TFKs incorporate low-barrier hydrogen bonds (LBHBs) between an active site histidine and aspartate, while the protease-peptide boronates do not, these data complement the spectroscopic and chemical evidence for the participation of LBHBs in catalysis by serine proteases. Moreover, while the potency of these classes of inhibitors can be correlated to the structures of the peptide moieties, the present results indicate that the strength of their bonds to serine contribute significantly to their inhibitory properties. PMID:27387593

  3. Inhibition of nicotine-DNA adduct formation by polyphenolic compounds in vitro

    International Nuclear Information System (INIS)

    Nicotine[3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco products, has proven to be a potential genotoxic compound. Some polyphenolic compounds can suppress the DNA adduction, and hence act as the potential inhibitors of carcinogenesis. In this study, the inhibitory effects of three polyphenolic compounds, curcumin (diferuloylmethane), resveratrol (trans-3, 5, 4-trihydroxystilbene) and tea polyphenols, on the nicotine-DNA adduction have been investigated in vitro using radiolabelled nicotine and liquid scintillation counting (LSC) technique. Also, the inhibition mechanism of these chemopreventive agents in regard to the activity of the biotransformation enzymes, including cytochrome P450 (CYP450), cytochrome b5 (CYb5) and glutathione S-transferase (GST), has been studied. The results demonstrated that these three polyphenols induced marked dose-dependent decrease in nicotine-DNA adducts as compared with the controls. The elimination rate of adducts reached above 46% at the highest dose for all the three agents with 51.6% for resveratrol. Correspondingly, three polyphenols all suppressed CYP450 and CYb5, whereas curcumin and resveratrol induced GST. The authors may arrive at a point that the three polyphenols are beneficial to prevent the nicotine adduct formation, and thus may be used to block the potential carcinogenesis induced by nicotine. (authors)

  4. Targeted mutations induced by a single acetylaminofluorene DNA adduct in mammalian cells and bacteria

    International Nuclear Information System (INIS)

    Mutagenic specificity of 2-acetylaminofluorene (AAF) has been established in mammalian cells and several strains of bacteria by using a shuttle plasmid vector containing a single N-(deoxyguanosin-8-yl)acetylaminofluorene (C8-dG-AAF) adduct. The nucleotide sequence of the gene conferring tetracycline resistance was modified by conservative codon replacement so as to accommodate the sequence d(CCTTCGCTAC) flanked by two restriction sites, Bsm I and Xho I. The corresponding synthetic oligodeoxynucleotide underwent reaction with 2-(N-acetoxy-N-acetylamino)-fluorene (AAAF), forming a single dG-AAF adduct. This modified oligodeoxynucleotide was hybridized to its complementary strand and ligated between the Bsm I and Xho I sites of the vector. Plasmids containing the C8-dG-AAF adduct were used to transfect simian virus 40-transformed simian kidney (COS-1) cells and to transform several AB strains of Escherichia coli. Colonies containing mutant plasmides were detected by hybridization to 32P-labeled oligodeoxynucleotides. Presence of the single DNA adduct increased the mutation frequency by 8-fold in both COS cells and E. coli. Over 80% of mutations detected in both systems were targeted and represented G x C → C x G or G x C → T x A transversions or single nucleotide deletions. The authors conclude that modification of a deoxyguanosine residue with AAF preferentially induces mutations targeted at this site when a plasmid containing a single C8-dG-AAF adduct is introduced into mammalian cells or bacteria

  5. Consolidation Radiotherapy in Stage IE- IIE, Non-Bulky Primary Gastric Diffuse Large B-Cell Lymphoma with Post-Chemotherapy Complete Remission.

    Directory of Open Access Journals (Sweden)

    Qiwen Li

    Full Text Available To investigate the effects of consolidation radiation in patients with stage IE-IIE, non-bulky primary gastric diffuse large B-cell lymphoma (DLBCL.A cohort consisted of 71 consecutive patients with stage IE-IIE, non-bulky primary gastric DLBCL was retrospectively analyzed. All of them had been in complete remission after receiving at least four cycles of chemotherapy, containing rituximab or not. Consolidation radiation was delivered thereafter in 28 patients while other 43 received clinical observation only. Locoregional relapse-free survival (LRFS, disease-free survival (DFS, overall survival (OS and distant metastasis-free survival (DMFS were compared between patients with or without radiotherapy.The 10-year LRFS, DFS, OS and DMFS were 100% and 81.4% (p = 0.028, 91.7% and 77.1% (p = 0.14, 91.7% and 77.8% (p = 0.67, 91.7% and 78.0% (p = 0.42 for patients with or without radiotherapy.Radiotherapy is associated with improved locoregional control of patients with early stage primary gastric DLBCL, who have achieved complete remission following at least four cycles of chemotherapy.

  6. Development of sandwich ELISAs for the detection of aromatic diisocyanate adducts.

    Science.gov (United States)

    Lemons, Angela R; Bledsoe, Toni A; Siegel, Paul D; Beezhold, Donald H; Green, Brett J

    2013-11-29

    Diisocyanates (dNCOs) are highly reactive low molecular weight chemicals commonly used in the manufacturing industry. Occupational exposures to dNCOs have been shown to elicit allergic sensitization and occupational asthma. Among the most commonly used dNCOs in industry are the aromatic dNCOs, toluene diisocyanate (TDI) and methylene diphenyl diisocyanate (MDI). This study aimed to develop enzyme linked immunosorbent assays (ELISA) utilizing aromatic dNCO-specific monoclonal antibodies (mAbs) for the detection of aromatic dNCO adducts. Two sandwich ELISAs were developed. The first sandwich ELISA utilized mAb 60G2 along with an anti-human serum albumin (HSA) polyclonal antibody. This assay detected MDI-, 2,4- and 2,6-TDI-HSA adducts with limits of detection (LOD) of 2.67, characterization of aromatic dNCO adducts as well as in biomonitoring occupational and environmental dNCO exposures. PMID:24012971

  7. Atomic-Resolution Structure of an N(5) Flavin Adduct in D-Arginine Dehydrogenase

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Guoxing; Yuan, Hongling; Wang, Siming; Gadda, Giovanni; Weber, Irene T. (GSU)

    2011-09-06

    D-Arginine dehydrogenase (DADH) catalyzes the flavin-dependent oxidative deamination of D-arginine and other D-amino acids to the corresponding imino acids. The 1.07 {angstrom} atomic-resolution structure of DADH crystallized with D-leucine unexpectedly revealed a covalent N(5) flavin adduct, instead of the expected iminoleucine product in the active site. This acyl adduct has been successfully reproduced by photoreduction of DADH in the presence of 4-methyl-2-oxopentanoic acid (ketoleucine). The iminoleucine may be released readily because of weak interactions in the binding site, in contrast to iminoarginine, converted to ketoleucine, which reacts with activated FAD to form the covalently linked acyl adduct.

  8. Atomic-resolution structure of an N5 flavin adduct in D-arginine dehydrogenase.

    Science.gov (United States)

    Fu, Guoxing; Yuan, Hongling; Wang, Siming; Gadda, Giovanni; Weber, Irene T

    2011-07-26

    D-Arginine dehydrogenase (DADH) catalyzes the flavin-dependent oxidative deamination of D-arginine and other D-amino acids to the corresponding imino acids. The 1.07 Å atomic-resolution structure of DADH crystallized with D-leucine unexpectedly revealed a covalent N(5) flavin adduct, instead of the expected iminoleucine product in the active site. This acyl adduct has been successfully reproduced by photoreduction of DADH in the presence of 4-methyl-2-oxopentanoic acid (ketoleucine). The iminoleucine may be released readily because of weak interactions in the binding site, in contrast to iminoarginine, converted to ketoleucine, which reacts with activated FAD to form the covalently linked acyl adduct. PMID:21707047

  9. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

    Directory of Open Access Journals (Sweden)

    Judge Bryan S

    2011-03-01

    Full Text Available Abstract Background Acetaminophen-cysteine adducts (APAP-CYS are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Methods Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated. Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. Results Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20 nmol/ml, Trial 2- 0.1 (0.09 nmol/ml and Trial 3- 0.3 (0.12 nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml. No subject had detectable APAP

  10. GSTM1 and XRCC3 Polymorphisms: Effects on Levels of Aflatoxin B1-DNA Adducts

    Institute of Scientific and Technical Information of China (English)

    Xi-dai Long; Yun Ma; Zhou-lin Deng

    2009-01-01

    Objective: Aflatoxin B1 (AFB1), which can cause the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen-metabolizing or repairing genotypes may experience an increased risk of genotoxicity. This study was designed to investigate whether the polymorphisms of two genes, the metabolic gene Glutathione S-transferase M1 (GSTM1) and DNA repair gene x-ray repair cross-complementing group 3 (XRCC3), can affect the levels of AFB1-DNA adducts in Guangxi Population (n= 966) from an AFB1-exposure area.Methods: AFB1-DNA adducts were measured by ELISA, and GSTM1 and XRCC3 codon 241 genotypes were identified by PCR-RFLP.Results: The GSTM1-null genotype [adjusted odds ratio (OR) = 2.09; 95% confidence interval (CI) = 1.61(2.71] and XRCC3 genotypes with 241 Met alleles [i.e., XRCC3-TM and -MM, adjusted ORs (95% CI) were 1.43 (1.08(1.89) and 2.42 (1.13(5.22), respectively] were significantly associated with higher levels of AFB1-DNA adducts. Compared with those individuals who did not express any putative risk genotypes as reference (OR = 1), individuals featuring all of the putative risk genotypes did experience a significantly higher DNA-adduct levels (adjusted ORs were 2.87 for GSTM1-null and XRCC3-TM; 5.83 for GSTM1-null and XRCC3-MM). Additionally, there was a positive joint effect between XRCC3 genotypes and long-term AFB1 exposure in the formation of AFB1-DNA adducts.Conclusion: These results suggest that individuals with susceptible genotypes GSTM1-null, XRCC3-TM, or XRCC3-MM may experience an increased risk of DNA damage elicited by AFB1 exposure.

  11. Formation of melamium adducts by pyrolysis of thiourea or melamine/NH4 Cl mixtures.

    Science.gov (United States)

    Braml, Nicole E; Sattler, Andreas; Schnick, Wolfgang

    2012-02-01

    Pyrolysis of prominent precursor compounds for the synthesis of carbon nitride type materials (e.g., melamine, thiourea) have been studied in detail. Molecular adducts containing monoprotonated melamium C(6)N(11)H(10)(+) and melaminium HC(3)N(3)(NH(2))(3)(+) ions, respectively, have been identified as intermediates. The adduct C(6)N(11)H(10)Cl·0.5NH(4)Cl was obtained by the reaction of melamine C(3)N(3)(NH(2))(3) with NH(4)Cl at 450 °C. During the pyrolysis of thiourea, guanidinium thiocyanate was initially formed and subsequently the melamium thiocyanate melamine adduct C(6)N(11)H(10)SCN·2C(3)N(3)(NH(2))(3) was isolated at 300 °C. A second melaminium thiocyanate melamine adduct with the formula HC(3)N(3)(NH(2))(3)SCN·2C(3)N(3)(NH(2))(3) represents an intermediary reaction product that is best accessible at low pressures. The crystal structures of the compounds were solved by single-crystal XRD. Unequivocal proton localization at the C(6)N(11)H(10)(+) ion was established. A typical intramolecular and interannular hydrogen bridge and other characteristic hydrogen-bonding motifs were identified. Additionally, the adducts were investigated by solid-state NMR spectroscopy. Our study provides detailed insight into the thermal condensation of thiourea by identifying and characterizing key intermediates involved in the condensation process leading to carbon nitride type materials. Furthermore, factors promoting the formation of melamium adduct phases over melem are discussed. PMID:22223531

  12. Few constraints limit the design of quinone methide-oligonucleotide self-adducts for directing DNA alkylation†

    OpenAIRE

    Rossiter, Clifford S.; Modica, Emilia; Kumar, Dalip; Rokita, Steven E

    2010-01-01

    Nucleotide sequences minimally containing adenosine, cytosine or guanosine are sufficient to form intrastrand oligonucleotide quinone methide self-adducts reversibly for subsequent alkylation of complementary DNA. The general lack of sequence restrictions should now allow for alkylation of most any target of interest although reaction is most efficient when the self-adducts contain guanine residues and do not form hairpin structures.

  13. DNA adducts in marine mussel Mytilus galloprovincialis living in polluted and unpolluted environments. Chapter 12. Book chapter

    International Nuclear Information System (INIS)

    A generally applicable (32)P-postlabeling assay was used to examine the presence of DNA adducts in mussels experimentally exposed to known carcinogens and in mussels collected from sites impacted by wastewaters. Mussels exposed to seawater artificially polluted with 2-aminofluorene showed exclusively one adduct which was identified to be dG-C8-2-aminofluorene. Under the same experimental conditions, Diesel-2 oil did not induce any detectable adducts. When mussel digestive gland DNA was collected and analyzed from one unpolluted site, two moderately impacted sites, and one site heavily impacted by cannery wastewaters, mussel DNA from the unpolluted and only one moderately polluted site showed the presence of 6 to 10 adducts. This indicates they were not related to the pollution. This was further supported by the absence of dose-related adducts. Clear evidence for the presence of pollution-related DNA adducts was, however, found in juvenile mussels collected from an oil refinery site. One major and three minor adducts were detected in these mussels with no adducts detected in juvenile mussels from an unpolluted site

  14. Glutathionetransferase activity and PAN-DNA adducts in human placenta as a risk factor for newborn in radioactively contaminated regions

    International Nuclear Information System (INIS)

    It was shown that the higher is the contamination of area the more decreased is GST activity and the more abundant are PAH adducts in placental DNA. Placental glutathionetransferase activity and level of PAH-DNA adducts content in placental tissue are the integral indices of environmental pollution, efficiency of maternal and placental detoxification and a prognostic factor for newborn

  15. NanoLC/ESI+ HRMS3 quantitation of DNA adducts induced by 1,3-butadiene.

    Science.gov (United States)

    Sangaraju, Dewakar; Villalta, Peter W; Wickramaratne, Susith; Swenberg, James; Tretyakova, Natalia

    2014-07-01

    Human exposure to 1,3-butadiene (BD) present in automobile exhaust, cigarette smoke, and forest fires is of great concern because of its potent carcinogenicity. The adverse health effects of BD are mediated by its epoxide metabolites such as 3,4-epoxy-1-butene (EB), which covalently modify genomic DNA to form promutagenic nucleobase adducts. Because of their direct role in cancer, BD-DNA adducts can be used as mechanism-based biomarkers of BD exposure. In the present work, a mass spectrometry-based methodology was developed for accurate, sensitive, and precise quantification of EB-induced N-7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) DNA adducts in vivo. In our approach, EB-GII adducts are selectively released from DNA backbone by neutral thermal hydrolysis, followed by ultrafiltration, offline HPLC purification, and isotope dilution nanoLC/ESI(+)-HRMS(3) analysis on an Orbitrap Velos mass spectrometer. Following method validation, EB-GII lesions were quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of EB and in liver tissues of rats exposed to sub-ppm concentrations of BD (0.5-1.5 ppm). EB-GII concentrations increased linearly from 1.15 ± 0.23 to 10.11 ± 0.45 adducts per 10(8) nucleotides in HT1080 cells treated with 0.5-10 μM EB. EB-GII concentrations in DNA of laboratory rats exposed to 0.5, 1.0, and 1.5 ppm BD were 0.17 ± 0.05, 0.33 ± 0.08, and 0.50 ± 0.04 adducts per 10(8) nucleotides, respectively [corrected]. We also used the new method to determine the in vivo half-life of EB-GII adducts in rat liver DNA (2.20 ± 0.12 d) and to detect EB-GII in human blood DNA. To our knowledge, this is the first application of nanoLC/ESI(+)-HRMS(3) Orbitrap methodology to quantitative analysis of DNA adducts in vivo. PMID:24867429

  16. Grilled Meat Consumption and PhIP-DNA Adducts in Prostate Carcinogenesis

    OpenAIRE

    Tang, Deliang; Liu, Jason J; Rundle, Andrew; Neslund-Dudas, Christine; Savera, Adnan T.; Bock, Cathryn H.; Nock, Nora L.; Yang, James J.; Rybicki, Benjamin A

    2007-01-01

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the major heterocyclic amine generated from cooking meats at high temperatures, and dietary exposures have been shown to induce prostate cancer in rats. PhIP derives its carcinogenic potential through the formation of PhIP-DNA adducts. The purpose of this study was to examine whether self-reported consumption and preparation doneness of grilled meats were associated with PhIP-DNA adduct levels in prostate epithelial cells. The study po...

  17. Quantitative strategies to determine cisplatin adducts with DNA nucleotides in drosofila larvae and tumoral cell cultures

    International Nuclear Information System (INIS)

    Full text: The antitumoral effect of cisplatin [cis-diamminodichloroplatinum(II)] in mammals is related to its binding to DNA components. A novel sensitive and selective method is proposed to quantify cisplatin-DNA adducts induced in vivo in somatic cells of Drosophila melanogaster at biologically relevant concentrations. The method uses HPLC-ICPMS in combination with species-specific isotope dilution analysis (cisplatin enriched in 194Pt). For the first time, a cisplatin-DNA adduct is quantified by this approach. The obtained results show the great potential of this system to advance our molecular understanding of the biological effects of cisplatin. (author)

  18. White blood cell DNA adducts and fruit and vegetable consumption in bladder cancer.

    Science.gov (United States)

    Peluso, M; Airoldi, L; Magagnotti, C; Fiorini, L; Munnia, A; Hautefeuille, A; Malaveille, C; Vineis, P

    2000-02-01

    The 'Mediterranean diet', a diet rich in cereals, fruit and vegetables, has been associated with lowering the risk of a variety of cancers of the digestive tract and the bladder. In a previous study, we showed that the high phenolic content these dietary components produce in the urine could be associated with higher antimutagenic properties of the urine and lower arylamine-DNA adducts in exfoliated bladder cells. We have conducted a case-control study on 162 bladder cancer patients and 104 hospital controls. Total aromatic DNA adducts were measured in white blood cells (WBC) of all subjects by (32)P-post-labelling. Genetically based metabolic polymorphisms were analysed by PCR-RFLP (NAT2, GSTM1, GSTT1, GSTP1, COMT and NQO1). All subjects were interviewed about their tobacco use, dietary habits and other risk factors. The odds ratio (OR) for the risk of bladder cancer according to the presence/absence of WBC DNA adducts (detection limit 0.1 RALx10(8)) was 3.7 [95% confidence interval (CI) 2.2-6.3] and a dose-response relationship with levels of adducts was apparent. The association between case/control status and the presence of WBC DNA adducts was significantly stronger in the subjects who consumed fewer portions of fruit or vegetables per day (OR 7.80, 95% CI 3.0-20.30 for 0-1 portions of vegetables) than in the heavy consumers (OR 4.98 for consumers of 2 portions daily, OR 1.97 for consumers of > or =3 portions; similar but lower estimates were found for the intake of fruit). No association was noticed between tobacco smoking and WBC DNA adducts. Only NAT-2, among the several genotypes considered, was associated in a statistically significant way with the risk of bladder cancer (OR 1.72, 95% CI 1.03-2.87) and with the levels of WBC DNA adducts. Our report suggests that fruit and vegetables could protect against bladder cancer by inhibiting the formation of DNA adducts. PMID:10657956

  19. Effect of external electric field on Cyclodextrin-Alcohol adducts: A DFT study

    Indian Academy of Sciences (India)

    Kundan Baruah; Pradip Kr Bhattacharyya

    2015-06-01

    Effect of external electric fields on the interaction energy between cyclodextrin and alcohol was analyzed in the light of density functional theory (DFT) and density functional reactivity theory (DFRT). Stability of the cyclodextrin-alcohol adducts was measured in terms of DFT based reactivity descriptor, global hardness, electrophilicity, and energy of the HOMO. Stability of adducts was observed to be sensitive towards the strength as well as direction of the applied external electric field. In addition, reactivity pattern follows the maximum hardness and minimum electrophilicity principles.

  20. Dosimetry by means of DNA and hemoglobin adducts in propylene oxide-exposed rats

    International Nuclear Information System (INIS)

    The main purpose of the study was to establish the relation between exposure dose of propylene oxide (PO) and dose in various tissues of male F344 rats exposed to the compound by inhalation. The animals were exposed to 0, 5, 25, 50, 300, or 500 ppm PO in the air for 3 days (6 h/day) or 4 weeks (6 h/day, 5 days/week). Blood, nasal respiratory epithelium, lung, and liver were collected. 2-Hydroxypropylvaline (HPVal) in hemoglobin was quantified using the N-alkyl Edman method and gas chromatography/tandem mass spectrometry. 7-(2-Hydroxypropyl)guanine (7-HPG) in DNA was quantified using 32P postlabeling. The levels of 7-HPG in DNA of nasal respiratory epithelium and lung increased linearly with concentration as measured both after 3 days and 4 weeks of exposure. Similarly, 7-HPG in liver DNA and HPVal in hemoglobin showed a linear increase with PO concentration in the 3-day exposure group, whereas a deviation from linearity was observed above 300 ppm in the 4-week exposure group. The new results confirm previous observations of a dose difference between tissues with the highest dose present in the nasal respiratory epithelium. The measured adduct levels were used for calculation of adduct increments and corresponding tissue doses per unit of external exposure dose. For this purpose, the buildup of adducts was modeled considering the different kinetics of formation and elimination of adducts with DNA and hemoglobin, respectively, and also considering the increasing body weight of the animals. The half-life of 7-HPG in vivo, as well as tissue doses, could be solved from DNA adduct data at the 3rd and 26th days. Within the range of concentrations where the dose-response curves for adduct formation are linear, the relationship between exposure dose and resulting tissue doses could be based equally well on adduct data from the short-term exposure as on adduct data from the prolonged exposure

  1. Polycyclic Aromatic Hydrocarbon–DNA Adducts and Breast Cancer: A Pooled Analysis

    OpenAIRE

    Gammon, Marilie D.; Sagiv, Sharon K.; Eng, Sybil M.; Shantakumar, Sumitra; Gaudet, Mia M.; Teitelbaum, Susan L; Britton, Julie A.; Terry, Mary Beth; WANG, LIAN WEN; Wang, Qiao; STELLMAN, STEVE D.; Beyea, Jan; Hatch, Maureen; Kabat, Geoffrey C; Wolff, Mary S.

    2004-01-01

    Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer in several small studies. The authors’ pooled analysis included 873 cases and 941 controls from a population-based case-control study. Competitive enzyme-linked immunosorbent assay in peripheral mononuclear cells was conducted in 2 rounds, and results were pooled on the basis of round-specific quantiles. The odds ratio for breast cancer was elevated in relation to detectable PAH-DNA adducts (1.29 as comp...

  2. Adduct formation in LC-ESI-MS of nonylphenol ethoxylates: mass spectrometrical, theoretical and quantitative analytical aspects

    International Nuclear Information System (INIS)

    The analysis of nonylphenol ethoxylate (A9PEOn) surfactants with LC-ESI-MS was investigated in a detailed study of the formation of different types of adducts. Part of the observations was explained by calculating their relative stabilities using molecular dynamics techniques. Strong differences in adduct formation behaviour were found for different oligomers. Beside the common sodium adducts, surfactant dimer adducts [2 x A9PEO1,2 + Na]+, adducts including a solvent molecule [A9PEO1,2 + MeOH + Na]+ and doubly charged adducts [A9PEO>11 + 2 x Na]2+ were found. Molecular dynamics calculations showed that the A9PEOn molecule wraps itself around the complexing sodium ion in a way that negative electronic charges on oxygen have optimum electrostatic interaction with this ion. van der Waals interactions between alkyl chains are of less importance for the stability of these adducts. Both [2 x A9PEO2,5 + Na]+ dimer and [A9PEO2,5 + Na]+ monomer adducts turned out to be stable from an energetic point of view with adducts of A9PEO5 being more stable than adducts of A9PEO2. Only for the monomer adduct the latter is in accordance with experimental observations. Consequences of the formation of several adducts per A9PEOn oligomer for the quantitative analysis of environmental samples were evaluated. In clean samples, it was found that the presence of short-chain A9PEO1,2 can cause an overestimation of long-chain A9PEO>2. In real environmental extracts, other processes like matrix effects have a stronger influence on the quantitative result, and therefore no significant influence of adduct formation processes could be observed. However, inclusion of [A9PEO1,2 + MeOH + Na]+ adduct signals does improve the detection limits of the two short-chain oligomers. Correct quantitative results are obtained when A9PEO1 and A9PEO2 are quantified separately, and longer oligomers with a molar calibration followed by correction of the average molar weight of the A9PEO>2 in the sample

  3. Comparative synchronous fluorescence spectrophotometry and 32P-postlabeling analysis of PAH-DNA adducts in human lung and the relationship to TP53 mutations

    DEFF Research Database (Denmark)

    Andreassen, Åshild; Kure, Elin H.; Nielsen, Per Sabro; Autrup, Herman; Haugen, Aage

    )-DNA adducts detected by SFS and the BPDE co-migrating spot detected by 32P-postlabeling. We have also analyzed the relationship between adduct levels and TP53 mutations. By postlabeling diagonal radioactive zone (DRZ) adducts were detected in 37 of 39 (95%) lung tissues from lung cancer patients and the...... levels in lung tissue and TP53 mutations....

  4. Clinical Analysis of stereotactic body radiation therapy using extracranial gamma knife for patients with mainly bulky inoperable early stage non-small cell lung carcinoma

    Directory of Open Access Journals (Sweden)

    Tang Hanjun

    2011-07-01

    Full Text Available Abstract Purpose To evaluate the clinical efficacy and toxicity of stereotactic body radiation therapy (SBRT using extracranial gamma knife in patients with mainly bulky inoperable early stage non-small cell lung carcinoma (NSCLC. Materials and methods A total of 43 medically inoperable patients with mainly bulky Stage I/II NSCLC received SBRT using gamma knife were reviewed. The fraction dose and the total dose were determined by the radiation oncologist according to patients' general status, tumor location, tumor size and the relationship between tumor and nearby organ at risk (OAR. The total dose of 34~47.5 Gy was prescribed in 4~12 fractions, 3.5~10 Gy per fraction, one fraction per day or every other day. The therapeutic efficacy and toxicity were evaluated. Results The median follow-up was 22 months (range, 3-102 months. The local tumor response rate was 95.35%, with CR 18.60% (8/43 and PR 76.74% (33/43, respectively. The local control rates at 1, 2, 3, 5 years were 77.54%, 53.02%, 39.77%, and 15.46%, respectively, while the 1- and 2-year local control rates were 75% and 60% for tumor ≤3 cm; 84% and 71% for tumor sized 3~5 cm; 55% and 14.6% for tumor sized 5~7 cm; and 45%, 21% in those with tumor size of >7 cm. The overall survival rate at 1, 2, 3, 5 years were 92.04%, 78.04%, 62.76%, 42.61%, respectively. The toxicity of stereotactic radiation therapy was grade 1-2. Clinical stages were significantly important factor in local control of lung tumors (P = 0.000. Both clinical stages (P = 0.015 and chemotherapy (P = 0.042 were significantly important factors in overall survival of lung tumors. Conclusion SBRT is an effective and safe therapy for medically inoperable patients with early stage NSCLC. Clinical stage was the significant prognostic factors for both local tumor control and overall survival. The toxicity is mild. The overall local control for bulky tumors is poor. Tumor size is a poor prognostic factor, and the patients for

  5. Clinical Analysis of stereotactic body radiation therapy using extracranial gamma knife for patients with mainly bulky inoperable early stage non-small cell lung carcinoma

    International Nuclear Information System (INIS)

    To evaluate the clinical efficacy and toxicity of stereotactic body radiation therapy (SBRT) using extracranial gamma knife in patients with mainly bulky inoperable early stage non-small cell lung carcinoma (NSCLC). A total of 43 medically inoperable patients with mainly bulky Stage I/II NSCLC received SBRT using gamma knife were reviewed. The fraction dose and the total dose were determined by the radiation oncologist according to patients' general status, tumor location, tumor size and the relationship between tumor and nearby organ at risk (OAR). The total dose of 34~47.5 Gy was prescribed in 4~12 fractions, 3.5~10 Gy per fraction, one fraction per day or every other day. The therapeutic efficacy and toxicity were evaluated. The median follow-up was 22 months (range, 3-102 months). The local tumor response rate was 95.35%, with CR 18.60% (8/43) and PR 76.74% (33/43), respectively. The local control rates at 1, 2, 3, 5 years were 77.54%, 53.02%, 39.77%, and 15.46%, respectively, while the 1- and 2-year local control rates were 75% and 60% for tumor ≤3 cm; 84% and 71% for tumor sized 3~5 cm; 55% and 14.6% for tumor sized 5~7 cm; and 45%, 21% in those with tumor size of >7 cm. The overall survival rate at 1, 2, 3, 5 years were 92.04%, 78.04%, 62.76%, 42.61%, respectively. The toxicity of stereotactic radiation therapy was grade 1-2. Clinical stages were significantly important factor in local control of lung tumors (P = 0.000). Both clinical stages (P = 0.015) and chemotherapy (P = 0.042) were significantly important factors in overall survival of lung tumors. SBRT is an effective and safe therapy for medically inoperable patients with early stage NSCLC. Clinical stage was the significant prognostic factors for both local tumor control and overall survival. The toxicity is mild. The overall local control for bulky tumors is poor. Tumor size is a poor prognostic factor, and the patients for adjuvant chemotherapy need to be carefully selected

  6. Group 1 and group 2 metal complexes supported by a bidentate bulky iminopyrrolyl ligand: synthesis, structural diversity, and ε-caprolactone polymerization study.

    Science.gov (United States)

    Kottalanka, Ravi K; Harinath, A; Rej, Supriya; Panda, Tarun K

    2015-12-14

    We report here a series of alkali and alkaline earth metal complexes, each with a bulky iminopyrrolyl ligand [2-(Ph3CN=CH)C4H3NH] (1-H) moiety in their coordination sphere, synthesized using either alkane elimination or silylamine elimination methods or the salt metathesis route. The lithium salt of molecular composition [Li(2-(Ph3CN=CH)C4H3N)(THF)2] (2) was prepared using the alkane elimination method, and the silylamine elimination method was used to synthesize the dimeric sodium and tetra-nuclear potassium salts of composition [(2-(Ph3CN=CH)C4H3N)Na(THF)]2 (3) and [(2-(Ph3CN=CH)C4H3N)K(THF)0.5]4 (4) respectively. The magnesium complex of composition [(THF)2Mg(CH2Ph){2-(Ph3CN=CH)C4H3N}] (5) was synthesized through the alkane elimination method, in which [Mg(CH2Ph)2(OEt2)2] was treated with the bulky iminopyrrole ligand 1-H in 1 : 1 molar ratio, whereas the bis(iminopyrrolyl)magnesium complex [(THF)2Mg{2-(Ph3CN=CH)C4H3N}2] (6) was isolated using the salt metathesis route. The heavier alkaline earth metal complexes of the general formula {(THF)nM(2-(Ph3CN=CH)C4H3N)2} [M = Ca (7), Sr (8), and n = 2; M = Ba (9), n = 3] were prepared in pure form using two synthetic methods: in the first method, the bulky iminopyrrole ligand 1-H was directly treated with the alkaline earth metal precursor [M{N(SiMe3)2}2(THF)n] (where M = Ca, Sr and Ba) in 2 : 1 molar ratio in THF solvent at ambient temperature. The complexes 7-9 were also obtained using the salt metathesis reaction, which involves the treatment of the potassium salt (4) with the corresponding metal diiodides MI2 (M = Ca, Sr and Ba) in 2 : 1 molar ratio in THF solvent. The molecular structures of all the metal complexes (1-H, 2-9) in the solid state were established through single-crystal X-ray diffraction analysis. The complexes 5-9 were tested as catalysts for the ring-opening polymerization of ε-caprolactone. High activity was observed in the heavier alkaline earth metal complexes 7-9, with a very

  7. Conformational, IR spectroscopic and electronic properties of conium alkaloids and their adducts with C60 fullerene

    Science.gov (United States)

    Zabolotnyi, M. A.; Prylutskyy, Yu I.; Poluyan, N. A.; Evstigneev, M. P.; Dovbeshko, G. I.

    2016-08-01

    Conformational, IR spectroscopic and electronic properties of the components of Conium alkaloids (Conium maculatum) in aqueous environment were determined by model calculations and experiment. With the help of FT-IR spectroscopy the possibility of formation of an adduct between γ-coniceine alkaloid and C60 fullerene was demonstrated, which is important for further application of conium analogues in biomedical purposes.

  8. Situational restriction of elevation in adduction relieved by faden on the medial rectus

    Directory of Open Access Journals (Sweden)

    R Muralidhar

    2016-01-01

    Full Text Available We describe a patient with situational restriction of elevation in adduction in his left eye. Clinical examination pointed to instability of the left medial rectus pulley. This was corrected by Faden on the medial rectus. The importance of this relatively new concept in identifying and treating orbital pulley instability is discussed.

  9. Two food-borne heterocyclic amines: Metabolism and DNA adduct formation of amino-alpha-carbolines

    DEFF Research Database (Denmark)

    Frederiksen, Hanne

    2005-01-01

    -adducts have also been studied. Characteristic for the amino-a-carbolines are that relatively large amounts of these compounds in rat and human hepatic microsomes are activated to potent carcinogenic compounds compared with other heterocyclic amines, but further in vivo studies of the amino-a-carbolines are...

  10. Cisplatin-DNA adduct formation in rat spermatozoa and its effect on fetal development

    NARCIS (Netherlands)

    Hooser, S.T.; Dijk-Knijnenburg, C.M. van; Waalkens-Berendsen, I.D.H.; Smits-van Prooije, A.E.; Snoeij, N.J.; Baan, R.A.; Fichtinger-Schepman, M.J.

    2000-01-01

    Exposure of males to some genotoxic chemicals causes DNA damage in spermatozoa resulting in embryotoxicity and developmental defects in their offspring. This study demonstrates that cisplatin-DNA adducts could be measured in spermatozoa following treatment with the antineoplastic drug, cisplatin. Th

  11. DNA adducts and atherosclerotic: A study of accidental and sudden death males in the Czech Republic

    Czech Academy of Sciences Publication Activity Database

    Binková, Blanka; Šmerhovský, Zdeněk; Strejc, P.; Boubelík, O.; Stávková, Zdena; Chvátalová, Irena; Šrám, Radim

    č. 501 (2002), s. 115-128. ISSN 0027-5107 R&D Projects: GA MŽP SI/340/1/97 Institutional research plan: CEZ:AV0Z5039906 Keywords : atherosclerosis * DNA-adducts * GSTM1 and CYP1A1 polymorphism Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.158, year: 2002

  12. The knee adduction moment measured with an instrumented force shoe in patients with knee osteoarthritis

    NARCIS (Netherlands)

    Noort, van den Josien C.; Esch, van der Martin; Steultjens, Martijn P.M.; Dekker, Joost; Schepers, H. Martin; Veltink, Peter H.; Harlaar, Jaap

    2012-01-01

    The external knee adduction moment (KAdM) during gait is an important parameter in patients with knee osteoarthritis (OA). KAdM measurement is currently restricted to instruments only available in gait laboratories. However, ambulatory movement analysis technology, including instrumented force shoes

  13. DNA adducts induced by in vitro activation of extracts of diesel and biodiesel exhaust particles

    Science.gov (United States)

    AbstractContext: Biodiesel and biodiesel-blend fuels offer a renewable alternative to petroleum diesel, but few data are available concerning the carcinogenic potential of biodiesel exhausts. Objectives: We compared the formation of covalent DNA adducts by the in vitro metabol...

  14. Eccentric hip adduction and abduction strength in elite soccer players and matched controls

    DEFF Research Database (Denmark)

    Thorborg, Kristian; Couppé, C; Petersen, J;

    2011-01-01

    Eccentric hip adduction and abduction strength plays an important role in the treatment and prevention of groin injuries in soccer players. Lower extremity strength deficits of less than 10% on the injured side, compared to the uninjured side, have been suggested as the clinical milestone before ...

  15. Adducts compounds of lanthanides (III) trifluoreacetates and yttrium and the N,N - dimenthylformamide

    International Nuclear Information System (INIS)

    Some studies on lanthanides, f transition elements, and yttrium are presented. Adducts of lanthanides trifluoroacetates and N,N -dimethylformamide are described. The characterization of complexes from elementar analysis, conductance measurements, X-ray patterns, vibrational, electronics and fluorescence spectra are analysed. (M.J.C.)

  16. Simulation of Solid-Liquid Equilibrium in a Ternary System with Adduct Compounds

    Czech Academy of Sciences Publication Activity Database

    Malijevská, I.; Sedláková, Zuzana

    Kuala Lumpur : -, 2007, s. 150-151. [Asian Chemical Congress (12ACC) 2007 /12./. Kuala Lumpur (MY), 23.08.2007-25.08.2007] Institutional research plan: CEZ:AV0Z40720504 Keywords : solid-liquid equilibrium * adduct * ternary system Subject RIV: CF - Physical ; Theoretical Chemistry

  17. Structural analysis and aggregation propensity of reduced and nonreduced glycated insulin adducts.

    Science.gov (United States)

    Alavi, Parnian; Yousefi, Reza; Amirghofran, Sara; Karbalaei-Heidari, Hamid Reza; Moosavi-Movahedi, Ali Akbar

    2013-06-01

    The milieu within pancreatic β cells represents a favorable environment for glycation of insulin. Therefore, in this study, insulin samples were individually subjected to glycation under reducing and nonreducing conditions. As monitored by ortho-phthalaldehyde and fluorescamine assays, the reduced glycated insulin adduct demonstrates extensively higher level of glycation than the nonreduced glycated counterpart. Also, gel electrophoresis experiments suggest a significant impact of glycation under a reducing system on the level of insulin oligomerization. Furthermore, reduced and nonreduced glycated insulin adducts respectively exhibit full and partial resistance against dithiothreitol-induced aggregation. The results of thioflavin T and Congo red assays suggest the existence of a significant quantity of amyloid-like entities in the sample of reduced glycated insulin adduct. Both fluorescence and far-ultraviolet circular dichroism studies respectively suggest that the extents of unfolding and secondary structural alteration were closely correlated to the level of insulin glycation. Moreover, the surface tension of two glycated insulin adducts was inversely correlated to their glycation extents and to the quantity of exposed hydrophobic patches. Overall, the glucose-modified insulin molecules under reducing and nonreducing systems display different structural features having significant consequences on aggregation behaviors and surface tension properties. The particular structural constraints of glycated insulin may reduce the binding interaction of this hormone to its receptor which is important for both insulin function and clearance. PMID:23584594

  18. Noni juice reduces lipid peroxidation-derived DNA adducts in heavy smokers.

    Science.gov (United States)

    Wang, Mian-Ying; Peng, Lin; Jensen, Claude J; Deng, Shixin; West, Brett J

    2013-03-01

    Food plants provide important phytochemicals which help improve or maintain health through various biological activities, including antioxidant effects. Cigarette smoke-induced oxidative stress leads to the formation of lipid hydroperoxides (LOOHs) and their decomposition product malondialdehyde (MDA), both of which cause oxidative damage to DNA. Two hundred forty-five heavy cigarette smokers completed a randomized, double-blind, placebo-controlled clinical trial designed to investigate the effect of noni juice on LOOH- and MDA-DNA adducts in peripheral blood lymphocytes (PBLs). Volunteers drank noni juice or a fruit juice placebo every day for 1 month. DNA adducts were measured by (32)P postlabeling analysis. Drinking 29.5-118 mL of noni juice significantly reduced adducts by 44.6-57.4%. The placebo, which was devoid of iridoid glycosides, did not significantly influence LOOH- and MDA-DNA adduct levels in current smokers. Noni juice was able to mitigate oxidative damage of DNA in current heavy smokers, an activity associated with the presence of iridoids. PMID:24804023

  19. Redox and catalytic reactions of adducts of DNA with osmium tetroxide complexes on mercury electrodes

    Czech Academy of Sciences Publication Activity Database

    Havran, Luděk; Fojta, Miroslav; Jelen, František; Paleček, Emil

    Bratislava : Comenius University, 2001. s. 22. [International Symposium on BIOELECTROCHEMISTRY and BIOENERGETICS /16./. 01.06.2001-06.06.2001, Bratislava] Institutional research plan: CEZ:AV0Z5004920 Keywords : mercury electrodes * osmium tetroxide * adducts of DNA Subject RIV: BO - Biophysics

  20. Hemoglobin adducts of epoxybutene in workers occupationally exposed to 1,3-butadiene

    Czech Academy of Sciences Publication Activity Database

    Begemann, P.; Šrám, Radim; Neumann, H. G.

    2001-01-01

    Roč. 74, - (2001), s. 680-687. ISSN 0340-5761 Grant ostatní: EU(XC) CIPA-CT93-0228 Institutional research plan: CEZ:AV0Z5039906 Keywords : biomonitoring * hemoglobin adducts Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 1.558, year: 2001

  1. New adduct of abietane-type diterpene from Salvia leriifolia Benth.

    Science.gov (United States)

    Hussain, Amjad; Adhikari, Achyut; Iqbal Choudhary, M; Ayatollahi, Syed Abdulmajid; Atta-Ur-Rahman

    2016-07-01

    A new adduct of abietane-type diterpene, salvialeriicone (1), was isolated from Salvia leriifolia Benth., along with a new chemical entity nor-abietane diterpene, 2-isopropyl-8,8-dimethyl-7,8-dihydrophenanthrene-1,4,5(6H)-trione (2). Their structures were determined using mass spectrometry, and 1D- and 2D-NMR spectroscopy. PMID:27266891

  2. Peroxidase-catalyzed formation of (deoxy)guanosine adducts by Sudan I

    Czech Academy of Sciences Publication Activity Database

    Dračínský, Martin; Semanská, M.; Cvačka, Josef; Martínek, V.; Stiborová, M.

    Brno : Masaryk University, 2009. C32-C32. ISBN 978-80-86441-40-5. [Central European NMR Meeting. NMR Valtice /24./. 26.04.2009-29.04.2009, Valtice] Institutional research plan: CEZ:AV0Z40550506 Keywords : Sudan I * DNA adducts * NMR Subject RIV: CC - Organic Chemistry

  3. Adduct formation of ionic and nanoparticular silver with amino acids and glutathione

    Energy Technology Data Exchange (ETDEWEB)

    Blaske, Franziska; Stork, Lisa; Sperling, Michael; Karst, Uwe, E-mail: uk@uni-muenster.de [University of Muenster, Institute of Inorganic and Analytical Chemistry (Germany)

    2013-09-15

    To investigate the interaction of ionic and nanoparticular silver with amino acids and small peptides, an electrospray ionization time-of-flight mass spectrometry method was developed. Monomeric and oligomeric silver adducts were formed with amino acids including cysteine (Cys), methionine, histidine, lysine, or the tripeptide glutathione (GSH). The obtained spectra for ionic silver show clusters in different ratios between Ag{sup +} and the reaction partners (X) including [Ag{sub n}X{sub m} - (n + 1)H]{sup -} (n = 1-4, m = 1-3). Regarding Cys, adduct clusters up to n = 5 and m = 4 were observed as well. Considering silver-GSH interactions, even doubly charged oligomers occur generating [Ag{sub (a+1)}GSH{sub a} - (a + 3)H]{sup 2-} (a = 5-7) and [Ag{sub b}GSH{sub b} - (b + 2)H]{sup 2-} (b = 4-8) ions. {sup 1}H NMR data of free GSH compared to that after treatment with Ag{sup +} confirm sulfur-metal interactions due to changing chemical shifts for the protons located adjacent to the thiol group. Density functional theory calculations for silver-GSH clusters may explain the formation of experimentally recorded large clusters due to cooperative effects between silver and carboxylic acid side chains. Both sets of experiments indicate the presence of these adducts in the liquid phase. For silver nanoparticles, the respective data confirm the release of silver ions and the subsequent adduct formation.

  4. Computational Procedure to Replace a Bulky Flywheel for a Process Machine by a Combination of Appropriately Controlled VVVf Drive for Motor and a Smaller Flywheel

    Directory of Open Access Journals (Sweden)

    Manjusha Viraj Palandurkar

    2012-06-01

    Full Text Available Process machines with tougher duty cycles are subjected to wide fluctuations in load torque. These often need a bulky flywheel for torque equalization with disadvantages of torsional oscillations. This results into fatigue of mechanical power transmission elements leading subsequently to equipment failure causing prolonged and frequent down time which results into financial losses. A simpler acceptable alternative is proposed in this article. Suitably monitored VVVf drives and low moment of inertia offer a much better alternative, for improving the system behavior drastically. Controlling the power input to the main electric drive with VVVf technique can generate almost matching demand torque characteristics. A much smaller flywheel is able to improve the accuracy to have better torque matching. This paper deals with estimation of necessary moment of inertia of flywheel in view of minimizing the difference in the required demand torque characteristics and the generated supply torque characteristics.

  5. Effect of bulky substituents on thiopyrylium polymethine aggregation in the solid state: A theoretical evaluation of the implications for all-optical switching applications

    KAUST Repository

    Gieseking, Rebecca L.

    2014-11-25

    Polymethine dyes in dilute solutions display many of the optical properties required for all-optical switching applications. However, in thin films, aggregation and polymethine-counterion interactions can substantially modify their properties and limit their utility. Here, we examine the impact of a series of bulky substituents on the solid-state molecular packing of thiopyrylium polymethines by using a theoretical approach combining molecular-dynamics simulations and quantum-chemical calculations. Importantly, it is found that the positions of the substituents near the center and/or ends of the dye determine the extent to which aggregation is reduced; in particular, substituents near the polymethine center primarily modify the type of aggregation that is observed, while substituents near the polymethine ends reduce aggregation and aid in maintaining solution-like properties in the solid state. Our theoretical study elucidates relationships between molecular structure and bulk optical properties and provides design guidelines for all-optical switching materials.

  6. Bypass of Aflatoxin B[subscript 1] Adducts by the Sulfolobus solfataricus DNA Polymerase IV

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, Surajit; Brown, Kyle L.; Egli, Martin; Stone, Michael P. (Vanderbilt)

    2012-07-18

    Aflatoxin B{sub 1} (AFB{sub 1}) is oxidized to an epoxide in vivo, which forms an N7-dG DNA adduct (AFB{sub 1}-N7-dG). The AFB{sub 1}-N7-dG can rearrange to a formamidopyrimidine (AFB{sub 1}-FAPY) derivative. Both AFB{sub 1}-N7-dG and the {beta}-anomer of the AFB{sub 1}-FAPY adduct yield G {yields} T transversions in Escherichia coli, but the latter is more mutagenic. We show that the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) bypasses AFB{sub 1}-N7-dG in an error-free manner but conducts error-prone replication past the AFB{sub 1}-FAPY adduct, including misinsertion of dATP, consistent with the G {yields} T mutations observed in E. coli. Three ternary (Dpo4-DNA-dNTP) structures with AFB{sub 1}-N7-dG adducted template:primers have been solved. These demonstrate insertion of dCTP opposite the AFB{sub 1}-N7-dG adduct, and correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB{sub 1}-N7-dG:dC pair. The insertion of dTTP reveals hydrogen bonding between the template N3 imino proton and the O{sup 2} oxygen of dTTP, and between the template T O{sup 4} oxygen and the N3 imino proton of dTTP, perhaps explaining why this polymerase does not efficiently catalyze phosphodiester bond formation from this mispair. The AFB{sub 1}-N7-dG maintains the 5'-intercalation of the AFB{sub 1} moiety observed in DNA. The bond between N7-dG and C8 of the AFB{sub 1} moiety remains in plane with the alkylated guanine, creating a 16{sup o} inclination of the AFB{sub 1} moiety with respect to the guanine. A binary (Dpo4-DNA) structure with an AFB{sub 1}-FAPY adducted template:primer also maintains 5'-intercalation of the AFB{sub 1} moiety. The {beta}-deoxyribose anomer is observed. Rotation about the FAPY C5-N{sup 5} bond orients the bond between N{sup 5} and C8 of the AFB{sub 1} moiety out of plane in the 5'-direction, with respect to the FAPY base. The formamide group extends in the 3'-direction. This improves

  7. Quantitative analysis of positional isomers of triacylglycerols via electrospray ionization tandem mass spectrometry of sodiated adducts.

    Science.gov (United States)

    Herrera, Lisandra Cubero; Potvin, Michael A; Melanson, Jeremy E

    2010-09-01

    Herein we report a reversed-phase high-performance liquid chromatography tandem mass spectrometry (RP-HPLC/MS/MS) method for the analysis of positional isomers of triacylglycerols (TAGs) in vegetable oils. The fragmentation behavior of [M + X](+) ions (X = NH(4), Li, Na or Ag) was studied on a quadrupole-time-of-flight (Q-TOF) mass spectrometer under low-energy collision-induced dissociation (CID) conditions. Mass spectra that were dependent on the X(+) ion and the nature and position of the acyl substituents were observed for four pairs of 'AAB/ABA'-type TAGs, namely PPO/POP, OOP/OPO, LLO/LOL and OOL/OLO (where P is 16:0, palmitic acid; O is 18:1, oleic acid; and L is 18:2, linoleic acid). For the majority of [M + X](+) adducts, the loss of the fatty acid in the outer positions (sn-1 or sn-3) was favored over the loss in the central position (sn-2), which enabled the determination of the fractional abundance of the isomers. Ratios of the intensity of fragment ions at various AAB/ABA compositions produced linear calibration curves with positive slopes, comparable to those obtained traditionally by ESI-MS/MS of [M + NH(4)](+) adducts. The only exceptions were the [M + Ag](+) adducts of the PPO/POP system, which produced calibration curves with negative slopes. Sodium adducts provided the most consistent level of isomeric discrimination for the TAGs studied and also offered the most convenience in that they required no additive to the mobile phase. Therefore, calibration curve data derived from [M + Na](+) adducts were applied to the quantification of TAG regioisomers in sunflower and olive oils. The regiospecific analysis showed that palmitic acid was typically located at positions sn-1 or sn-3, whereas unsaturated fatty acids, oleic and linoleic acids were mostly found at the sn-2 position. PMID:20814981

  8. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

    2010-04-01

    This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

  9. Preparation and Evaluation of Aromatic Amine-Epoxidized Sunflower Free Fatty Acid Adducts As Corrosion Inhibitors in Curable Varnishes

    International Nuclear Information System (INIS)

    Five aromatic amines [o-, m- and p- Toluidine (o-T, m-T and p-T), p- anizidine (p-A) and p- chloroaniline (p-ClA)] were reacted with epoxidized sunflower free fatty acid (ESFA) under severe conditions of inert atmosphere and high temperature. The produced adducts were characterized physically, chemically and by IR spectroscopic analysis. Acid value and oxiran content of the prepared adducts were determined to confirm the participation of carboxylic groups and epoxy groups respectively in the reaction of ESFA with aromatic amines. The prepared adducts of (o-T-ESFA, m-T-ESFA, p-T-ESFA, p-A-ESFA and p-ClA-ESFA) were evaluated as corrosion inhibitors of mild steel in epoxy acrylate oligomer formulations curable by electron beam irradiation. Different concentrations of the prepared aromatic adducts were added in varnish formulations. Physical and mechanical measurements were carried out, in addition to corrosion resistance tests and weight loss of coated steel panels. The efficiency of adducts in varnishes formulation were determined, in which it was found that, the varnish formulations containing the prepared aromatic amine adducts could protect steel from corrosion. Superior corrosion inhibition efficiency was found for the varnish formula containing 0.6% p-A-ESFA adduct. The corrosion inhibition efficiency of the prepared aromatic amine in epoxy acrylate oligomer varnishes follows the order: p-A-ESFA > p-T-ESFA > m-T-ESFA > o-T-ESFA > p-ClA-ESFA

  10. Phosphatase activity in commercial spleen exonuclease decreases the recovery of benzo[a]pyrene and N-hydroxy-2-naphthylamine DNA adducts by 32P-postlabeling.

    Science.gov (United States)

    Adams, S P; Laws, G M; Selden, J R; Nichols, W W

    1994-05-15

    Spleen exonuclease, which degrades nucleic acids into single 3'-nucleotides, is used in the detection of DNA adducts by 32P-postlabeling. Contamination of the exonuclease with phosphatase activity can reduce the recovery of benzo[a]pyrene and N-hydroxy-2-naphthylamine DNA adducts by 32P-postlabeling. Four preparations of spleen exonuclease containing varying levels of phosphatase activity (2-naphthylamine DNA adducts. Surprisingly, recovery of these DNA adducts was nearly 10 times greater using nuclease P1 than when using 1-butanol extraction for adduct enrichment, since arylamine DNA adducts have previously been reported to be poorly detected by 32P-postlabeling after nuclease P1 treatment. Our data indicate that the hydrolysis of DNA by spleen exonuclease may be an important source of variability in both qualitative and quantitative analysis of adducts by 32P-postlabeling. PMID:8059938

  11. Elimination technique for alkali metal ion adducts from an electrospray ionization process using an on-line ion suppressor

    OpenAIRE

    NOZAKI, Kazuyoshi; TARUI, Akira; OSAKA, Issey; Kawasaki, Hideya; ARAKAWA, Ryuichi; 荒川, 隆一

    2010-01-01

    The effects of an on-line ion suppressor device on alkali metal ion adduct formations of the model compound tacrolimus were investigated. The base peak ion in the positive ion ESI-MS spectrum of tacrolimus was a sodium ion adduct, [M+Na]+. On the other hand, an ammonium ion adduct, [M+NH4]+, was the base peak ion in the full-scan mass spectrum of tacrolimus with a cation-exchange suppressor resin, and both [M+Na]+ and [M+K]+ were eliminated. These results indicate that the combination of an o...

  12. Adaptive Response Enzyme AlkB Preferentially Repairs 1-Methylguanine and 3-Methylthymine Adducts in Double-Stranded DNA.

    Science.gov (United States)

    Chen, Fangyi; Tang, Qi; Bian, Ke; Humulock, Zachary T; Yang, Xuedong; Jost, Marco; Drennan, Catherine L; Essigmann, John M; Li, Deyu

    2016-04-18

    The AlkB protein is a repair enzyme that uses an α-ketoglutarate/Fe(II)-dependent mechanism to repair alkyl DNA adducts. AlkB has been reported to repair highly susceptible substrates, such as 1-methyladenine and 3-methylcytosine, more efficiently in ss-DNA than in ds-DNA. Here, we tested the repair of weaker AlkB substrates 1-methylguanine and 3-methylthymine and found that AlkB prefers to repair them in ds-DNA. We also discovered that AlkB and its human homologues, ABH2 and ABH3, are able to repair the aforementioned adducts when the adduct is present in a mismatched base pair. These observations demonstrate the strong adaptability of AlkB toward repairing various adducts in different environments. PMID:26919079

  13. SYNTHESIS AND INFRARED STUDY OF SOME NEW MOLYBDATO AND HYDROGENOMOLYBDATO ADDUCTS AND COMPLEXES OF COBALT, ZINC, ANTIMONY AND CADMIUM CHLORIDES

    Directory of Open Access Journals (Sweden)

    SERIGNE FALLOU POUYE

    2014-01-01

    Full Text Available Five new molybdato (four and hydrogenomolybdato (one adducts and complexes have been synthesized and studied by infrared spectroscopy. The suggested structures are all discrete, the molybdate anion behaving as a trichelating, a monochelating, a bridging, a tetrachelating and a bichelating ligand. The environment around Zn, Co, Cd is tetrahedral or trigonal bipyramidal also for Zn - while being octahedral for Sb. The Cd pentanuclear adduct has a two metallic components structure, a tetranuclear anionic one with a tetrachelating molybdate, the second being a neutral dehydrated adduct component. The suggested structure for the hydrogenomolybdato adduct is discrete, the hydrogenomolybdate being present as a hydrogen bonded dimer behaves as a bridging bidentate ligand. The water molecules can be considered as a coordinating ligand or lattice. When secondary interactions through hydrogen bonds involving the water molecules are considered supramolecular architectures are obtained.

  14. Water-soluble noncovalent adducts of the heterometallic copper subgroup complexes and human serum albumin with remarkable luminescent properties.

    Science.gov (United States)

    Chelushkin, P S; Krupenya, D V; Tseng, Yu-Jui; Kuo, Ting-Yi; Chou, Pi-Tai; Koshevoy, I O; Burov, S V; Tunik, S P

    2014-01-25

    Novel water-soluble noncovalent adducts of the heterometallic copper subgroup complexes and human serum albumin (HSA) display strong phosphorescence, internalize into HeLa cells and can be used in time-resolved fluorescent imaging. PMID:24296768

  15. Polycyclic aromatic hydrocarbon-DNA adducts in cervix of women infected with carcinogenic human papillomavirus types: An immunohistochemistry study

    Energy Technology Data Exchange (ETDEWEB)

    Pratt, M. Margaret [Carcinogen-DNA Interactions Section, LCBG, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (United States)], E-mail: prattm@mail.nih.gov; Sirajuddin, Paul; Poirier, Miriam C. [Carcinogen-DNA Interactions Section, LCBG, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (United States); Schiffman, Mark [Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD (United States); Glass, Andrew G.; Scott, David R.; Rush, Brenda B. [Northwest Kaiser Permanente, Portland, OR (United States); Olivero, Ofelia A. [Carcinogen-DNA Interactions Section, LCBG, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD (United States); Castle, Philip E. [Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD (United States)

    2007-11-01

    Among women infected with carcinogenic human papillomavirus (HPV), there is a two- to five-fold increased risk of cervical precancer and cancer in women who smoke compared to those who do not smoke. Because tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons (PAHs), it was of interest to examine human cervical tissue for PAH-DNA adduct formation. Here, we measured PAH-DNA adduct formation in cervical biopsies collected in follow-up among women who tested positive for carcinogenic HPV at baseline. A semi-quantitative immunohistochemistry (IHC) method using antiserum elicited against DNA modified with r7,t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) was used to measure nuclear PAH-DNA adduct formation. Cultured human cervical keratinocytes exposed to 0, 0.153, or 0.331 {mu}M BPDE showed dose-dependent increases in r7,t8,t9-trihydroxy-c-10-(N{sup 2}deoxyguanosyl)-7,8,9, 10-tetrahydro-benzo[a]pyrene (BPdG) adducts. For BPdG adduct analysis, paraffin-embedded keratinocytes were stained by IHC with analysis of nuclear color intensity by Automated Cellular Imaging System (ACIS) and, in parallel cultures, extracted DNA was assayed by quantitative BPDE-DNA chemiluminescence immunoassay (CIA). For paraffin-embedded samples from carcinogenic HPV-infected women, normal-appearing cervical squamous epithelium suitable for scoring was found in samples from 75 of the 114 individuals, including 29 cases of cervical precancer or cancer and 46 controls. With a lower limit of detection of 20 adducts/10{sup 8} nucleotides, detectable PAH-DNA adduct values ranged from 25 to 191/10{sup 8} nucleotides, with a median of 75/10{sup 8} nucleotides. PAH-DNA adduct values above 150/10{sup 8} nucleotides were found in eight samples, and in three samples adducts were non-detectable. There was no correlation between PAH-DNA adduct formation and either smoking or case status. Therefore, PAH-DNA adduct formation as measured by this methodology did not appear

  16. Polycyclic aromatic hydrocarbon-DNA adducts in cervix of women infected with carcinogenic human papillomavirus types: An immunohistochemistry study

    International Nuclear Information System (INIS)

    Among women infected with carcinogenic human papillomavirus (HPV), there is a two- to five-fold increased risk of cervical precancer and cancer in women who smoke compared to those who do not smoke. Because tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons (PAHs), it was of interest to examine human cervical tissue for PAH-DNA adduct formation. Here, we measured PAH-DNA adduct formation in cervical biopsies collected in follow-up among women who tested positive for carcinogenic HPV at baseline. A semi-quantitative immunohistochemistry (IHC) method using antiserum elicited against DNA modified with r7,t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) was used to measure nuclear PAH-DNA adduct formation. Cultured human cervical keratinocytes exposed to 0, 0.153, or 0.331 μM BPDE showed dose-dependent increases in r7,t8,t9-trihydroxy-c-10-(N2deoxyguanosyl)-7,8,9, 10-tetrahydro-benzo[a]pyrene (BPdG) adducts. For BPdG adduct analysis, paraffin-embedded keratinocytes were stained by IHC with analysis of nuclear color intensity by Automated Cellular Imaging System (ACIS) and, in parallel cultures, extracted DNA was assayed by quantitative BPDE-DNA chemiluminescence immunoassay (CIA). For paraffin-embedded samples from carcinogenic HPV-infected women, normal-appearing cervical squamous epithelium suitable for scoring was found in samples from 75 of the 114 individuals, including 29 cases of cervical precancer or cancer and 46 controls. With a lower limit of detection of 20 adducts/108 nucleotides, detectable PAH-DNA adduct values ranged from 25 to 191/108 nucleotides, with a median of 75/108 nucleotides. PAH-DNA adduct values above 150/108 nucleotides were found in eight samples, and in three samples adducts were non-detectable. There was no correlation between PAH-DNA adduct formation and either smoking or case status. Therefore, PAH-DNA adduct formation as measured by this methodology did not appear related to the increased risk of

  17. Efficient CO2 capture by tertiary amine-functionalized ionic liquids through Li+-stabilized zwitterionic adduct formation

    OpenAIRE

    Yang, Zhen-zhen; He, Liang-Nian

    2014-01-01

    Highly efficient CO2 absorption was realized through formation of zwitterionic adducts, combining synthetic strategies to ionic liquids (ILs) and coordination. The essence of our strategy is to make use of multidentate cation coordination between Li+ and an organic base. Also PEG-functionalized organic bases were employed to enhance the CO2-philicity. The ILs were reacted with CO2 to form the zwitterionic adduct. Coordination effects between various lithium salts and neutral ligands, as well ...

  18. Benzo(a)pyrene-albumin adducts in humans exposed to polycyclic aromatic hydrocarbons in an industrial area of Poland.

    OpenAIRE

    Kure, E H; Andreassen, A; Ovrebø, S; Grzybowska, E; Fiala, Z; Strózyk, M; Chorazy, M; Haugen, A

    1997-01-01

    OBJECTIVES: The interaction of benzo(a)pyrene with serum albumin was measured in an attempt to identify the actual exposure and to evaluate albumin adduct measurements as biomarkers for exposure monitoring. METHODS: Benzo(a)pyrene-diol-epoxide (BPDE)-albumin adducts were measured by competitive enzyme linked immunosorbent assay (ELISA) in plasma of coke oven plant workers from three plants and from people living in a highly industrialised area of Silesia in Poland. Due to the high air concent...

  19. Significant Positive Correlation of Plasma BPDE-Albumin Adducts to Urinary 1-Hydroxypyrene in Coke Oven Workers

    Institute of Scientific and Technical Information of China (English)

    HONG WANG; TANG-CHUN WU; XIAO-BO YANG; AI-LIN LIU; HONG-YAN ZHEN; LIANG GUO; HUA-SHAN LIANG; YONG-YI BI; YUN BAI; YONG-WEN CHEN

    2007-01-01

    Objective To investigate the application of BPDE-albumin adducts as monitoring biomarkers for coke oven workers exposed to polycyclic aromatic hydrocarbons(PAHs)and to explore possible relationship between BPDE-albumin adducts and urinary 1-hydroxypyrene (1-OHP)levels in them.Methods Thirty-seven coke oven workers from a coke plant and 47 controls without the occupational exposure to PAHs were recruited in this study.The levels of plasma BPDE-albumin adducts and urinary 1-OHP were analyzed using high performance liquid chromatography.Results The median levels of BPDE-albumin adducts(42.10 fmol/mg albumin)and urinary 1-OHP(5.46 μmol/mol creatinine)were significantly higher in coke oven workers than in controls(14.16 fmol/mg albumin,2.96 μmol/mol creatinine,respectively;P<0.01).Multiple logistic regression analysis showed that coke oven workers were at higher risk of having BPDE-albumin adduct levels above 25.30 prnol/mg albumin(OR=1.79,P<0.01)and urinary 1-OHP levels above 4.13 μmol/mol creatinine(OR=2.45,P<0.05).There was a positive correlation between the levels of BPDE-albumin adducts and urinary 1-OHP in all subjects(rs=0.349,P<0.01).Conclusion BPDE-albumin adduct is a useful biomarker for monitoring long-term exposure to PAHs,and plasma BPDE-albumin adducts level is significantly correlated to urinary 1-OHP levels in coke oven workers.

  20. Mass spectrometry-based quantification of myocardial protein adducts with acrolein in an in vivo model of oxidative stress

    OpenAIRE

    Wu, Jianyong; Stevens, Jan F.; Maier, Claudia S.

    2011-01-01

    Acrolein exposure leads to the formation of protein-acrolein adducts. Protein modification by acrolein has been associated with various chronic diseases including cardiovascular and neurodegenerative diseases. Here we report an analytical strategy that enables the quantification of Michael-type protein adducts of acrolein in mitochondrial proteome samples using liquid chromatography in combination with tandem mass spectrometry and selected ion monitoring (LC-MS/MS SRM) analysis. Our approach ...

  1. Pulse radiolysis study of reaction of bull serum albumin electron adduct with oxygen. Polychromatic kinetics of reaction with adsorbed oxygen

    International Nuclear Information System (INIS)

    By the method of pulse radiolysis the reaction of bull serum albumin electron adduct with oxygen is investigated. As pulsed radiation source electron linear accelerators with particle energy of 8.0 and 4.5 MeV and pulse time of 40 ns and 2.2 μs, respectively have been used. It is assumed that the disappearance of protein electron adduct occurs in the course of its interaction with oxygen adsorbed on protein globular molecule

  2. Contribution of artifacts to N-methylated piperazine cyanide adduct formation in vitro from N-alkyl piperazine analogs.

    Science.gov (United States)

    Zhang, Minli; Resuello, Christina M; Guo, Jian; Powell, Mark E; Elmore, Charles S; Hu, Jun; Vishwanathan, Karthick

    2013-05-01

    In the liver microsome cyanide (CN)-trapping assays, piperazine-containing compounds formed significant N-methyl piperazine CN adducts. Two pathways for the N-methyl piperazine CN adduct formation were proposed: 1) The α-carbon in the N-methyl piperazine is oxidized to form a reactive iminium ion that can react with cyanide ion; 2) N-dealkylation occurs followed by condensation with formaldehyde and dehydration to produce N-methylenepiperazine iminium ion, which then reacts with cyanide ion to form the N-methyl CN adduct. The CN adduct from the second pathway was believed to be an artifact or metabonate. In the present study, a group of 4'-N-alkyl piperazines and 4'-N-[¹³C]methyl-labeled piperazines were used to determine which pathway was predominant. Following microsomal incubations in the presence of cyanide ions, a significant percentage of 4'-N-[¹³C]methyl group in the CN adduct was replaced by an unlabeled natural methyl group, suggesting that the second pathway was predominant. For 4'-N-alkyl piperazine, the level of 4'-N-methyl piperazine CN adduct formation was limited by the extent of prior 4'-N-dealkylation. In a separate study, when 4'-NH-piperaziens were incubated with potassium cyanide and [¹³C]-labeled formaldehyde, 4'-N-[¹³C]methyl piperazine CN-adduct was formed without NADPH or liver microsome suggesting a direct Mannich reaction is involved. However, when [¹³C]-labeled methanol or potassium carbonate was used as the one-carbon donor, 4'-N-[¹³C]methyl piperazine CN adduct was not detected without liver microsome or NADPH present. The biologic and toxicological implications of bioactivation via the second pathway necessitate further investigation because these one-carbon donors for the formation of reactive iminium ions could be endogenous and readily available in vivo. PMID:23431111

  3. Evidence for phosphorus bonding in phosphorus trichloride-methanol adduct: a matrix isolation infrared and ab initio computational study.

    Science.gov (United States)

    Joshi, Prasad Ramesh; Ramanathan, N; Sundararajan, K; Sankaran, K

    2015-04-01

    The weak interaction between PCl3 and CH3OH was investigated using matrix isolation infrared spectroscopy and ab initio computations. In a nitrogen matrix at low temperature, the noncovalent adduct was generated and characterized using Fourier transform infrared spectroscopy. Computations were performed at B3LYP/6-311++G(d,p), B3LYP/aug-cc-pVDZ, and MP2/6-311++G(d,p) levels of theory to optimize the possible geometries of PCl3-CH3OH adducts. Computations revealed two minima on the potential energy surface, of which, the global minimum is stabilized by a noncovalent P···O interaction, known as a pnictogen bonding (phosphorus bonding or P-bonding). The local minimum corresponded to a cyclic adduct, stabilized by the conventional hydrogen bonding (Cl···H-O and Cl···H-C interactions). Experimentally, 1:1 P-bonded PCl3-CH3OH adduct in nitrogen matrix was identified, where shifts in the P-Cl modes of PCl3, O-C, and O-H modes of CH3OH submolecules were observed. The observed vibrational frequencies of the P-bonded adduct in a nitrogen matrix agreed well with the computed frequencies. Furthermore, computations also predicted that the P-bonded adduct is stronger than H-bonded adduct by ∼1.56 kcal/mol. Atoms in molecules and natural bond orbital analyses were performed to understand the nature of interactions and effect of charge transfer interaction on the stability of the adducts. PMID:25772403

  4. Lewis Acid-Base Adduct Approach for High Efficiency Perovskite Solar Cells.

    Science.gov (United States)

    Lee, Jin-Wook; Kim, Hui-Seon; Park, Nam-Gyu

    2016-02-16

    Since the first report on the long-term durable 9.7% solid-state perovskite solar cell employing methylammonium lead iodide (CH3NH3PbI3), mesoporous TiO2, and 2,2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'-spirobifluorene (spiro-MeOTAD) in 2012, following the seed technologies on perovskite-sensitized liquid junction solar cells in 2009 and 2011, a surge of interest has been focused on perovskite solar cells due to superb photovoltaic performance and extremely facile fabrication processes. The power conversion efficiency (PCE) of perovskite solar cells reached 21% in a very short period of time. Such an unprecedentedly high photovoltaic performance is due to the intrinsic optoelectronic property of organolead iodide perovskite material. Moreover, a high dielectric constant, sub-millimeter scale carrier diffusion length, an underlying ferroelectric property, and ion migration behavior can make organolead halide perovskites suitable for multifunctionality. Thus, besides solar cell applications, perovskite material has recently been applied to a variety fields of materials science such as photodetectors, light emitting diodes, lasing, X-ray imaging, resistive memory, and water splitting. Regardless of application areas, the growth of a well-defined perovskite layer with high crystallinity is essential for effective utilization of its excellent physicochemical properties. Therefore, an effective methodology for preparation of high quality perovskite layers is required. In this Account, an effective methodology for production of high quality perovskite layers is described, which is the Lewis acid-base adduct approach. In the solution process to form the perovskite layer, the key chemicals of CH3NH3I (or HC(NH2)2I) and PbI2 are used by dissolving them in polar aprotic solvents. Since polar aprotic solvents bear oxygen, sulfur, or nitrogen, they can act as a Lewis base. In addition, the main group compound PbI2 is known to be a Lewis acid. Thus, PbI2 has a chance

  5. Large eccentric strength increase using the Copenhagen Adduction exercise in football

    DEFF Research Database (Denmark)

    Ishøi, L; Sørensen, C N; Kaae, N M; Jørgensen, L B; Hölmich, P; Serner, A

    2016-01-01

    Hip adductor injuries are frequent in football, and players with low adductor strength appear to be at increased risk of injury. High adductor muscle activity has been shown in the Copenhagen Adduction exercise (CA); however, an associated strength gain has not been investigated. This study aims to...... implemented in-season with an 8-week progressive training program elicited a large significant increase in EHAD, EHAB, and EHAD/EHAB ratio....... examine the eccentric hip adduction strength (EHAD) gain using the CA in-season. Two U-19 sub-elite football teams, including 24 football players, were randomized to either an 8-week supervised progressive training program in addition to the usual training (intervention) or to continue training as usual...

  6. Monitoring the apple polyphenol oxidase-modulated adduct formation of phenolic and amino compounds.

    Science.gov (United States)

    Reinkensmeier, Annika; Steinbrenner, Katrin; Homann, Thomas; Bußler, Sara; Rohn, Sascha; Rawel, Hashadrai M

    2016-03-01

    Minimally processed fruit products such as smoothies are increasingly coming into demand. However, they are often combined with dairy ingredients. In this combination, phenolic compounds, polyphenoloxidases, and amino compounds could interact. In this work, a model approach is presented where apple serves as a source for a high polyphenoloxidase activity for modulating the reactions. The polyphenoloxidase activity ranged from 128 to 333nakt/mL in different apple varieties. From these, 'Braeburn' was found to provide the highest enzymatic activity. The formation and stability of resulting chromogenic conjugates was investigated. The results show that such adducts are not stable and possible degradation mechanisms leading to follow-up products formed are proposed. Finally, apple extracts were used to modify proteins and their functional properties characterized. There were retaining antioxidant properties inherent to phenolic compounds after adduct formation. Consequently, such interactions may also be utilized to improve the textural quality of food products. PMID:26471529

  7. Preparation, properties and application of lanthanide thenoyltrifluoroacetonate adducts with diaza-15-crown-5

    International Nuclear Information System (INIS)

    The interaction of the whole series of lanthanide thenoyltrifluoroacetonates (TTA) with diaza-15-crown-5 (DA15C5) has been studied by conductometric and luminescence methods in aqueous ethanol solutions. The composition of the adducts has been found to be Ln : TA : DA15C5 = 1 : 3 : 1, the logarithms of their conditional stability constants are (2.05 - 2.45) ± (0.04 - 0.06). The mechanism of europium luminescence quenching in the adducts by foreign lanthanide ions has been established. A luminescence method for determination of europium in high purity lanthanide oxides and sulfides and gallium-gadolinium garnet has been worked out with detection limits of 5 x 10-6% and 5 x 10-7% respectively

  8. Bulkiness or aromatic nature of tyrosine-143 of actin is important for the weak binding between F-actin and myosin-ADP-phosphate

    Energy Technology Data Exchange (ETDEWEB)

    Gomibuchi, Yuki [Graduate School of Science and Engineering, Teikyo University, Toyosatodai 1-1, Utsunomiya 320-8551 (Japan); Uyeda, Taro Q.P. [Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, AIST Tsukuba Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562 (Japan); Wakabayashi, Takeyuki, E-mail: tw007@nasu.bio.teikyo-u.ac.jp [Graduate School of Science and Engineering, Teikyo University, Toyosatodai 1-1, Utsunomiya 320-8551 (Japan); Department of Judo Therapy, Faculty of Medical Technology, Teikyo University, Toyosatodai 1-1, Utsunomiya 320-8551 (Japan)

    2013-11-29

    Highlights: •The effect of mutation of Tyr143 that becomes more exposed on assembly was examined. •Mutation of tyrosine-143 of Dictyostelium actin changed actin polymerizability. •The bulkiness or aromatic nature of Tyr143 is important for the weak binding. •The weak interaction between myosin and actin strengthened by Tyr143Trp mutation. -- Abstract: Actin filaments (F-actin) interact with myosin and activate its ATPase to support force generation. By comparing crystal structures of G-actin and the quasi-atomic model of F-actin based on high-resolution cryo-electron microscopy, the tyrosine-143 was found to be exposed more than 60 Å{sup 2} to the solvent in F-actin. Because tyrosine-143 flanks the hydrophobic cleft near the hydrophobic helix that binds to myosin, the mutant actins, of which the tyrosine-143 was replaced with tryptophan, phenylalanine, or isoleucine, were generated using the Dictyostelium expression system. It polymerized significantly poorly when induced by NaCl, but almost normally by KCl. In the presence of phalloidin and KCl, the extents of the polymerization of all the mutant actins were comparable to that of the wild-type actin so that the actin-activated myosin ATPase activity could be reliably compared. The affinity of skeletal heavy meromyosin to F-actin and the maximum ATPase activity (V{sub max}) were estimated by a double reciprocal plot. The Tyr143Trp-actin showed the higher affinity (smaller K{sub app}) than that of the wild-type actin, with the V{sub max} being almost unchanged. The K{sub app} and V{sub max} of the Tyr143Phe-actin were similar to those of the wild-type actin. However, the activation by Tyr143Ile-actin was much smaller than the wild-type actin and the accurate determination of K{sub app} was difficult. Comparison of the myosin ATPase activated by the various mutant actins at the same concentration of F-actin showed that the extent of activation correlates well with the solvent-accessible surface areas (ASA

  9. DNA adduct formation by ochratoxin A?: A review of the available evidence

    OpenAIRE

    Dekant, Wolfgang

    2005-01-01

    Abstract The mycotoxin ochratoxin A (OTA) is a potent nephrotoxin and renal carcinogen in rodents. However, the mechanism of OTA-induced tumour formation is unknown and conflicting results regarding the potential of OTA to react with DNA have been obtained. While experiments using radiolabelled (3H or 14C) OTA and liquid scintillation counting or accelerator mass spectrometry indicate lack of formation of covalent DNA-adducts, spots detected by 32P-postlabelling have been attribute...

  10. Polyamines stimulate the formation of mutagenic 1,N 2-propanodeoxyguanosine adducts from acetaldehyde

    OpenAIRE

    Theruvathu, Jacob A.; Jaruga, Pawel; Nath, Raghu G.; Dizdaroglu, Miral; Brooks, P. J.

    2005-01-01

    Alcoholic beverage consumption is associated with an increased risk of upper gastrointestinal cancer. Acetaldehyde (AA), the first metabolite of ethanol, is a suspected human carcinogen, but the molecular mechanisms underlying AA carcinogenicity are unclear. In this work, we tested the hypothesis that polyamines could facilitate the formation of mutagenic α-methyl-γ-hydroxy-1,N 2-propano-2′-deoxyguanosine (Cr-PdG) adducts from biologically relevant AA concentrations. We found that Cr-PdG addu...

  11. Formation of an adduct between fosfomycin and glutathione: a new mechanism of antibiotic resistance in bacteria.

    OpenAIRE

    Arca, P; Rico, M; Braña, A F; Villar, C J; Hardisson, C; Suárez, J E

    1988-01-01

    Plasmid-borne resistance to fosfomycin in bacteria is due to modification of the antibiotic molecule by a glutathione S-transferase that catalyzes the formation of a covalent bond between the sulfhydryl residue of the cysteine in glutathione and the C-1 of fosfomycin. This reaction results in opening of the epoxide ring of the antibiotic to form an inactive adduct, the structure of which was confirmed by nuclear magnetic resonance. Dialyzed extracts prepared from resistant Escherichia coli st...

  12. Loss of Dermatan-4-Sulfotransferase 1 Function Results in Adducted Thumb-Clubfoot Syndrome

    OpenAIRE

    Dündar, Munis; Müller, Thomas; Zhang, Qi; Pan, Jing; Steinmann, Beat; Vodopiutz, Julia; Gruber, Robert; Sonoda, Tohru; Krabichler, Birgit; Utermann, Gerd; Baenziger, Jacques U.; Zhang, Lijuan; Janecke, Andreas R.

    2009-01-01

    Adducted thumb-clubfoot syndrome is an autosomal-recessive disorder characterized by typical facial appearance, wasted build, thin and translucent skin, congenital contractures of thumbs and feet, joint instability, facial clefting, and coagulopathy, as well as heart, kidney, or intestinal defects. We elucidated the molecular basis of the disease by using a SNP array-based genome-wide linkage approach that identified distinct homozygous nonsense and missense mutations in CHST14 in each of fou...

  13. DFT study on adduct reaction paths of GaN MOCVD growth

    Institute of Scientific and Technical Information of China (English)

    SHI; JunCao; ZUO; Ran; MENG; SuCi

    2013-01-01

    The adduct reaction paths for GaN growth by metal organic chemical vapor deposition (MOCVD) were studied by quantum chemical calculations employing density functional theory (DFT). Five possible adduct reaction paths with or without the ex-cess NH3were proposed and the corresponding potential energy surfaces were calculated. From the calculation results, it is concluded that after the formation of DMGNH2from TMG:NH3, the further decomposition paths have very slim probability because of the high energy barriers; whereas the oligomerization pathway to form oligomers [DMGNH2]x(x=2, 3) is probable,because of zero energy barrier. Since the oligomers tend to further polymerize, the nanoparticles are easily formed through this path. When NH3is in excess, TMG:NH3 tends to combine with the second NH3to form two new complexes: the coordination-bonded compound H3N:TMG:NH3and the hydrogen-bonded compound TMG:NH3 NH3. The formation of hydrogen-bonded compound TMG:NH3 NH3 will be more probable because of the lower energy than H3N:TMG:NH3. By comparing the potential energy surfaces in five adduct reaction paths, we postulate that, under the growth conditions of GaN MOCVD, the formation of hydrogen-bonded compound TMG:NH3 NH3 followed by the reversible decomposition may be the main reaction path for GaN thin film growth; while the adduct oligomerization path to generate oligomers [DMGNH2]2 and [DMGNH2]3might be the main reaction path for nanoparticles formation.

  14. Triple helix-forming oligonucleotides target psoralen adducts to specific chromosomal sequences in human cells.

    OpenAIRE

    Oh, D H; Hanawalt, P C

    1999-01-01

    The ability to target photochemical adducts to specific genomic DNA sequences in cells is useful for studying DNA repair and mutagenesis in intact cells, and also as a potential mode of gene-specific therapy. Triple helix-forming DNA oligonucleotides linked to psoralen (psoTFOs) were designed to deliver UVA-induced psoralen photoadducts to two distinct sequences within the human interstitial collagenase gene. A primer extension assay demonstrated that the appropriate psoTFO selectively damage...

  15. SOME NEW SULFATO AND HYDROGENOSULFATO ADDUCTS: SYNTHESIS, INFRARED AND MÖSSBAUER STUDIES

    Directory of Open Access Journals (Sweden)

    Alain Wattiaux

    2010-07-01

    Full Text Available Eight organotin (IV (mainly sulfato adducts have been synthesized and studied by spectroscopic methods. While considering the anionic component, the suggested structures are discrete; supramolecular architectures are obtained with secondary interactions through NH----Cl and NH----O hydrogen bonds while considering the cations, the anions behaving as monochelating, bridging or monocoordinating ligands, the environment around the tin (IV centre being octahedral. Tetrahedral SnMe2Cl2 has been characterized spectroscopically.

  16. Thermogravimetric and calorimetric study of cadmium iodide adducts with cyclic ureas

    International Nuclear Information System (INIS)

    Adducts of general formula CdI2·nL [n=1 and 2; L: ethyleneurea (eu) and propyleneurea (pu)] were synthesized by a solid state route and characterized by elemental analysis, infrared spectroscopy, thermogravimetry and reaction solution calorimetry. The infrared results shown that eu and pu coordinate through oxygen atom. All adducts release the ligand molecules in a single mass loss step, suggesting that, in the bisadducts, both ligand molecules are in equivalent coordination sites, exhibiting similar bond enthalpies. For all thermogravimetric curves, the first mass loss step is associated with the release of ligand molecules and the second one with the sublimation of cadmium iodide: CdI2·nL(s)→CdI2(s)+nL(g); CdI2(s)→CdI2(g). The observed thermal stability trend is: CdI2·eu (228 deg. C) > CdI2·pu (213 deg. C) > CdI2·2pu (200) > CdI2·2eu (186 deg. C). The standard molar reaction enthalpy in condensed phase: CdI2(cr)+nL(cr)=CdI2·nL(cr); ΔrHmθ, were obtained from reaction-solution calorimetry, to give the following values for mono and bisadducts: -7.16 and -27.61, -4.99 and -9.07 kJ mol-1 for eu and pu adducts, respectively. Decomposition (ΔDHmθ) and lattice (ΔMHmθ) enthalpies, as well as the mean cadmium-oxygen bond dissociation enthalpy, D(Cd-O), were calculated for all adducts

  17. Free flow electrophoresis separation and AMS quantitation of {sup 14}C-naphthalene-protein adducts

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Bruce A., E-mail: bbuchholz@llnl.go [Center for AMS, LLNL, 7000 East Avenue, Livermore, CA 94551 (United States); Haack, Kurt W.; Sporty, Jennifer L. [Center for AMS, LLNL, 7000 East Avenue, Livermore, CA 94551 (United States); Buckpitt, Alan R.; Morin, Dexter [Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States)

    2010-04-15

    Naphthalene is a volatile aromatic hydrocarbon to which humans are exposed from a variety of sources including mobile air sources and cigarette smoke. Naphthalene produces dose-(concentration)dependent injury to airway epithelial cells of murine lung which is observed at concentrations well below the current occupational exposure standard. Toxicity is dependent upon the cytochrome P450 mediated metabolic activation of the parent substrate to unstable metabolites which become bound covalently to tissue proteins. Nearly 70 proteins have been identified as forming adducts with reactive naphthalene metabolites using in vitro systems but very little work has been conducted in vivo because reasonably large amounts (100 muCi) of {sup 14}C labeled parent compound must be administered to generate detectable adduct levels on storage phosphor screens following separation of labeled proteins by 2D gel electrophoresis. The work described here was done to provide proof of concept that protein separation by free flow electrophoresis followed by AMS detection of protein fractions containing protein bound reactive metabolites would provide adducted protein profiles in animals dosed with trace quantities of labeled naphthalene. Mice were administered 200 mg/kg naphthalene intraperitoneally at a calculated specific activity of 2 DPM/nmol (1 pCi/nmol) and respiratory epithelial tissue was obtained by lysis lavage 4 h post injection. Free flow electrophoresis (FFE) separates proteins in the liquid phase over a large pH range (2.5-11.5) using low molecular weight acids and bases to modify the pH. The apparatus separates fractions into standard 96-well plates that can be used in other protein analysis techniques. The buffers of the fractions have very high carbon content, however, and need to be dialyzed to yield buffers compatible with {sup 14}C-AMS. We describe the processing techniques required to couple FFE to AMS for quantitation of protein adducts.

  18. Preparation and characterization of the adducts between lanthanide methanesulfonates and thioxane oxide

    International Nuclear Information System (INIS)

    The preparation and characterization of the adduct between lanthanide methanesulphonates and thioxane oxide are presented. The compounds characterization by conductance measurements, X-ray powder patterns, infrared, visible and fluorescence spectra, TG, DTG and DTA curves was made. According to the X-ray patterns, three isomorphous series were obtained: a-La-Gd b-Tb-Dy and c-Ho-Lu, Y. (M.J.C.)

  19. uvrC gene function has no specific role in repair of N-2-aminofluorene adducts.

    OpenAIRE

    Bichara, M; Fuchs, R P

    1987-01-01

    In Escherichia coli, plasmid DNA modified with N-2-aminofluorene adducts survived equally well in wild-type, uvrA, or uvrB strains. Increased sensitivity was found in uvrC and uvrD strains. Moreover, N-2-aminofluorene-mediated toxicity in the uvrC background was reversed when an additional uvrA mutation was introduced into the strain.

  20. Glutathione transferase A4-4 resists adduction by 4-hydroxynonenal☆

    OpenAIRE

    Shireman, Laura M.; Kripps, Kimberly A.; Balogh, Larissa M.; Conner, Kip P.; Whittington, Dale; Atkins, William M.

    2010-01-01

    4-Hydroxy-2-trans-nonenal (HNE) is a lipid peroxidation product that contributes to the pathophysiology of several diseases with components of oxidative stress. The electrophilic nature of HNE results in covalent adduct formation with proteins, fatty acids and DNA. However, it remains unclear whether enzymes that metabolize HNE avoid inactivation by it. Glutathione transferase A4-4 (GST A4-4) plays a significant role in the elimination of HNE by conjugating it with glutathione (GSH), with cat...

  1. 32P-Postlabelling/HPLC analysis of various styrene-induced DNA adducts in mice

    Czech Academy of Sciences Publication Activity Database

    Koskinen, M.; Vodička, Pavel; Vodičková, L.; Hemminki, K.

    2001-01-01

    Roč. 6, č. 3 (2001), s. 175-189. ISSN 1354-750X R&D Projects: GA ČR GA313/99/1460 Grant ostatní: GA-(EU) QLK4-1999-01368 Institutional research plan: CEZ:AV0Z5039906 Keywords : DNA adducts Subject RIV: EA - Cell Biology Impact factor: 1.118, year: 2001

  2. Kinetics of formation of specific styrene oxide adducts in double-stranded DNA

    Czech Academy of Sciences Publication Activity Database

    Koskinen, M.; Vodičková, L.; Vodička, Pavel; Warner, S. C.; Hemminki, K.

    2001-01-01

    Roč. 138, č. 2 (2001), s. 111-124. ISSN 0009-2797 R&D Projects: GA ČR GA313/99/1460 Grant ostatní: EU(XC) QLK4-1999-01368 Institutional research plan: CEZ:AV0Z5039906 Keywords : biomonitoring * DNA adducts Subject RIV: EA - Cell Biology Impact factor: 1.706, year: 2001

  3. Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity

    OpenAIRE

    James, Laura; Yan, Ke; Pence, Lisa; Simpson, Pippa; Bhattacharyya, Sudeepa; Gill, Pritmohinder; Letzig, Lynda; Kearns, Gregory; Beger, Richard

    2015-01-01

    Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure ...

  4. The 1:1 adduct of caffeine and 2-(1,3-dioxoisoindolin-2-ylacetic acid

    Directory of Open Access Journals (Sweden)

    Moazzam H. Bhatti

    2011-09-01

    Full Text Available In the crystal structure of the title adduct [systematic name: 2-(1,3-dioxoisoindolin-2-ylacetic acid–1,3,7-trimethyl-1,2,3,6-tetrahydro-7H-purine-2,6-dione (1/1], C8H10N4O2·C10H7NO4, the components are linked by an O—H...N hydrogen-bond and no proton transfer occurs.

  5. Role of Scaphoid in the Abduction and Adduction Movements of Wrist Joint

    Directory of Open Access Journals (Sweden)

    Sadik I Shaikh

    2013-06-01

    Full Text Available Background: Being a carpal bone scaphoid has an important role in wrist movements. Wrist joint is a synovial modified ellipsoid joint where movements like flexion, extension and adduction, abduction take place around two axes (transverse and antero-posterior. These movements at the wrist joint are associated with considerable range of movements at the mid carpal joint, as same group of muscles act on both of these joints. Methodology: A study has been done amongst 120 persons at the tertiary care hospital during the period from 2006-07 to detect the important movements of scaphoid bone specially during the abduction and adduction of wrist joint (which occur in association with the intercarpal joints and also to detect whether such movements have any speciality in the population. Results: In fully abducted position, it was 45o among 53.3% subjects and the average among all the subjects was 60o. So, the degree of abduction was 30o. The extent of movement was more in adduction (ie, 1.90 cm - 1.03 cm = 0.87 cm than in abduction (ie, 1.03 cm - 0.72 cm = 0.31cm. Conclusion: It was found in this study that the scaphoid acts as a link bone between the two rows of carpal bones and prevents the buckling of midcarpal joint especially of the capitato- lunate joint interface. [Natl J Med Res 2013; 3(3.000: 253-256

  6. Protein adducts of the prostate carcinogen PhIP in children

    Energy Technology Data Exchange (ETDEWEB)

    Lawrence Livermore National Laboratory

    2004-02-20

    Prostate cancer is the second leading cause of cancer death in men in the United States. few epidemiology studies have indicated that exposure to PhIP, a rodent prostate carcinogen formed in meat during cooking, may be an important risk factor for prostate cancer in humans. Therefore, a highly sensitive biomarker assay is urgently needed to clarify the role of PhIP in prostate cancer. The goal of this project is to develop an assay that can be used to more accurately quantify human exposure to PhIP and potential prostate cancer risk. Our hypothesis is that an Accelerator Mass Spectrometry-based method can be developed to measure protein adducts of PhIP in the blood of humans. This will provide a measure of the internal dose, as well as the capacity for carcinogen bioactivation to a form that can initiate the cancer process. Towards this goal, we have characterized an adduct formed by PhIP in vitro with the amino acid cysteine. This adduct should provide a biomarker of dietary PhIP exposure and potential prostate cancer risk that could be used to identify individuals for prevention and for monitoring the effect chemoprevention strategies.

  7. The reversibility of the glutathionyl-quercetin adduct spreads oxidized quercetin-induced toxicity

    International Nuclear Information System (INIS)

    Quercetin is one of the most prominent dietary antioxidants. During its antioxidant activity, quercetin becomes oxidized into its o-quinone/quinone methide QQ. QQ is toxic since it instantaneously reacts with thiols of, e.g., proteins. In cells, QQ will initially form an adduct with glutathione (GSH), giving GSQ. We have found that GSQ is not stable; it dissociates continuously into GSH and QQ with a half life of 2 min. Surprisingly, GSQ incubated with 2-mercapto-ethanol (MSH), a far less reactive thiol, results in the conversion of GSQ into the MSH-adduct MSQ. A similar conversion of GSQ into relatively stable protein thiol-quercetin adducts is expected. With the dithiol dihydrolipoic acid (L(SH)2), quercetin is formed out of GSQ. These results indicate that GSQ acts as transport and storage of QQ. In that way, the initially highly focussed toxicity of QQ is dispersed by the formation of GSQ that finally spreads QQ-induced toxicity, probably even over cells

  8. Molecular structures of five adducts assembled from p-dimethylaminobenzaldehyde and organic acids

    Science.gov (United States)

    Jin, Shouwen; Wang, Lanqing; Liu, Hui; Liu, Li; Zhang, Huan; Wang, Daqi; Li, Minghui; Guo, Jianzhong; Guo, Ming

    2016-07-01

    Five adducts 1-5 derived from p-dimethylaminobenzaldehyde have been prepared and characterized by X-ray diffraction analysis, IR, mp, and elemental analysis. Of the five adducts two are organic salts (1, and 2) and the other three (3-5) are cocrystals. In salts 1, and 2, the L molecules are protonated. The supramolecular architectures of the adducts 1-5 involve extensive intermolecular N-H⋯O, O-H⋯O, O-H⋯S, and C-H⋯O hydrogen bonds as well as other non-covalent interactions. The role of weak and strong non-covalent interactions in the crystal packing is ascertained. The complexes displayed 2D/3D framework structure for the synergistic effect of the various non-covalent interactions. The results presented herein tell that the strength and directionality of the N-H⋯O, O-H⋯O, and O-H⋯S hydrogen bonds between organic acids and p-dimethylaminobenzaldehyde are sufficient to bring about the formation of binary cocrystals or organic salts.

  9. Suicide of EMT-6 tumor cells by decays from radioactively-labelled sensitizer adducts

    International Nuclear Information System (INIS)

    Nitroaromatic radiosensitizers become metabolically bound preferentially to hypoxic cells and at least 10/sup 9/ adducts/cell can be tolerated as non-toxic. EMT-6 tumor cells have been incubated in hypoxia in the presence of /sup 3/H-Misonidazole and /sup 125/I-Azomycin Riboside for various times and the amount of /sup 3/H or /sup 125/I bound/cell was determined. Cells were stored as monolayers at 250C for up to 96 hr to accumulate radioactive decays and transferred at various times to 370C for colony-forming assays. No radiation inactivation was measured in cells which had incorporated at least 10/sup 6/ /sup 3/H or 10/sup 5/ /sup 125/I atoms. Previous studies had shown that -- 1% of MISO adducts to EMT-6 cells was associated with cellular DNA. These data indicate that the radiation-induced damage produced by these quantities of bound /sup 3/H or /sup 125/I causes little or not cell inactivation. The results of current studies to measure the colony-forming ability of sensitizer-labelled cells which have been stored in liquid nitrogen to facilitate the accumulation of more decays will be reported. These data suggest that a ''sensitizer-adduct suicide technique'' as a hypoxic cell selective adjunct to other cancer therapies is not feasible. These data are also instructive for those who attempt to develop radiolabelled ''tumor specific'' antibodies for therapeutic purposes

  10. Differential repair of platinum-DNA adducts in human bladder and testicular tumor continuous cell lines

    International Nuclear Information System (INIS)

    The formation and removal of four platinum-DNA adducts were immunochemically quantitated in cultured cells derived from a human bladder carcinoma cell line (RT112) and from two lines derived from germ cell tumors of the testis (833K and SUSA), following exposure in vitro to 16.7 microM (5 micrograms/ml) cisplatin. RT112 cells were least sensitive to the drug and were proficient in the repair of all four adducts, whereas SUSA cells, which were 5-fold more sensitive, were deficient in the repair of DNA-DNA intrastrand cross-links in the sequences pApG and pGpG. Despite expressing a similar sensitivity to SUSA cells, 833K cells were proficient in the repair of all four adducts, although less so than the RT112 bladder tumor cells. In addition, SUSA cells were unable to repair DNA-DNA interstrand cross-links whereas 50-85% of these lesions were removed in RT112 and 833K cells 24 h following drug exposure. It is possible that the inability of SuSa cells to repair platinated DNA may account for their hypersensitivity to cisplatin

  11. 32P-postlabelling analysis of DNA adducted with urinary mutagens from smokers of black tobacco.

    Science.gov (United States)

    Peluso, M; Castegnaro, M; Malaveille, C; Talaska, G; Vineis, P; Kadlubar, F; Bartsch, H

    1990-08-01

    In order to characterize the tobacco-derived mutagens excreted in the urine of tobacco smokers, 32P-postlabelling techniques were used to examine DNA adducts formed from these mutagens with calf thymus DNA in the presence of a metabolic activation system (rat liver S9, Aroclor 1254-induced, with or without acetyl coenzyme A). Using either nuclease P1 or butanol extraction procedures, four-six and three spots, respectively, were reproducibly found on the autoradiograms in the case of the urine extract from two smokers of black tobacco. Using the urinary extract from a non-smoker, only three faint spots were detected after nuclease P1 enrichment. DNA adducts produced in smokers' urine were then compared with those formed by four N-hydroxyarylamines, N-hydroxy-2-amino-3,8-dimethyl-3H-imidazo[4,5-f]quinoxaline, N-hydroxy-2-amino-3-methyl-imidazo[4,5-f]quinoxaline, N-hydroxy-2-naphthylamine and N-hydroxy-4-aminobiphenyl. Visual inspection revealed that none of the reference aromatic amines contributed to the adduct pattern produced by the urinary mutagen(s). However, primary aromatic amines are mainly implicated as urinary mutagens because: (i) they produce frameshift mutations in Salmonella typhimurium strains, (ii) they are easily extractable with blue cotton and (iii) their mutagenicity is abolished by a nitrite treatment procedure for deamination. PMID:2387016

  12. Synthesis and Structural Characterization of Lithium and Titanium Complexes Bearing a Bulky Aryloxide Ligand Based on a Rigid Fused-Ring s-Hydrindacene Skeleton.

    Science.gov (United States)

    Kanazawa, Shoya; Ohira, Taishi; Goda, Shun; Hayakawa, Naoki; Tanikawa, Tomoharu; Hashizume, Daisuke; Ishida, Yutaka; Kawaguchi, Hiroyuki; Matsuo, Tsukasa

    2016-07-01

    The bulky aryl alcohols, (Rind)OH (1) [Rind = EMind (a) and Eind (b)], based on the rigid fused-ring 1,1,3,3,5,5,7,7-octa-R-substituted s-hydrindacene skeleton were prepared by the reaction of (Rind)Li with nitrobenzene followed by protonation. The treatment of 1 with (n)BuLi affords the lithium aryloxide dimers [(Rind)OLi(THF)]2 (2) or trimers [(Rind)OLi]3 (3), depending on the employed solvents (THF = tetrahydrofuran). The salt metathesis reaction of [(EMind)OLi(THF)]2 (2a) with TiCl4(THF)2 leads to the formation of the mononuclear diamagnetic mono- and bis(aryloxide) Ti(IV) complexes, [(EMind)O]TiCl3(THF) (4a) and [(EMind)O]2TiCl2 (5a). We also isolated a trace amount of the tris(aryloxide) Ti(IV) complex, [(EMind)O]3TiCl (6a). The reaction between 2a and TiCl3(THF)3 resulted in the isolation of the mononuclear paramagnetic mono- and bis(aryloxide) Ti(III) complexes, [(EMind)O]TiCl2(THF)2 (7a) and [(EMind)O]2TiCl(THF)2 (8a). The discrete monomeric structures of the titanium complexes 4a, 5a, 6a, 7a, and 8a were determined by X-ray crystallography. PMID:27284975

  13. Comparative study on pyrido[3,4-b]pyrazine-based sensitizers by tuning bulky donors for dye-sensitized solar cells.

    Science.gov (United States)

    Zhang, Xiaoyu; Mao, Jiangyi; Wang, Dan; Li, Xin; Yang, Jiabao; Shen, Zhongjin; Wu, Wenjun; Li, Jing; Ågren, Hans; Hua, Jianli

    2015-02-01

    Dye-sensitized solar cells (DSSCs) with cobalt electrolytes have gained increasing attention. In this Research Article, two new pyrido[3,4-b]pyrazine-based sensitizers with different cores of bulky donors (indoline for DT-1 and triphenylamine for DT-2) were designed and synthesized for a comparative study of their photophysical and electrochemical properties and device performance and were also analyzed through density functional theory calculations. The results of density function theory calculations reveal the limited electronic communication between the biphenyl branch at the cis-position of N-phenylindoline and the indoline core, which could act as an insulating blocking group and inhibit the dye aggregation and charge recombination at the interface of TiO2/dye/electrolyte. As expected, DSSCs based on DT-1 with cobalt redox electrolyte gained a higher photoelectric conversion efficiency of 8.57% under standard AM 1.5 G simulated sunlight, with Jsc = 16.08 mA cm(-2), Voc = 802 mV, and FF = 0.66. Both electrochemical impedance spectroscopy (EIS) and intensity-modulated photovoltage spectroscopy (IMVS) suggest that charge recombination in DSSCs based on DT-1 is much less than that in their counterparts of DT-2, owing to the bigger donor size and the insulating blocking branch in the donor of DT-1. PMID:25580622

  14. Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose

    International Nuclear Information System (INIS)

    Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75 mg/kg bw, and diHOPrVal levels were measured 24 h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R2 = 0.943). Blood sampling at different time points (1, 10, 20, or 40 days) from four groups administered glycidol at 12 mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61 days), with the calculated first-order elimination rate constant (kel) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (kval) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The kval was 6.7 ± 1.1 and 5.6 ± 1.3 (pmol/g globin per μMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from kval and diHOPrVal levels were in agreement with the area under the (concentration–time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment. - Highlight: • Glycidol-hemoglobin adduct (diHOPrVal) was characterized for exposure evaluation. • We studied the kinetics of diHOPrVal formation and elimination in vitro and in vivo. • Dose dependent formation and chemical stability were confirmed in the rat study. • In vivo dose (AUC) of glycidol could be estimated from diHOPrVal levels. • diHOPrVal is considered

  15. Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo

    Directory of Open Access Journals (Sweden)

    Ming W. Chou

    2005-04-01

    Full Text Available Pyrrolizidine alkaloids are naturally occurring genotoxic chemicals produced by a large number of plants. The high toxicity of many pyrrolizidine alkaloids has caused considerable loss of free-ranging livestock due to liver and pulmonary lesions. Chronic exposure of toxic pyrrolizidine alkaloids to laboratory animals induces cancer. This investigation studies the metabolic activation of retrorsine, a representative naturally occurring tumorigenic pyrrolizidine alkaloid, and shows that a genotoxic mechanism is correlated to the tumorigenicity of retrorsine. Metabolism of retrorsine by liver microsomes of F344 female rats produced two metabolites, 6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP, at a rate of 4.8 ± 0.1 nmol/mg/min, and retrorsine-N-oxide, at a rate of 17.6±0.5 nmol/mg/min. Metabolism was enhanced 1.7-fold by using liver microsomes prepared from dexamethasone-treated rats. DHP formation was inhibited 77% and retrorsine N-oxide formation was inhibited 29% by troleandomycin, a P450 3A enzyme inhibitor. Metabolism of retrorsine with lung, kidney, and spleen microsomes from dexamethasone-treated rats also generated DHP and the N-oxide derivative. When rat liver microsomal metabolism of retrorsine occurred in the presence of calf thymus DNA, a set of DHP-derived DNA adducts was formed; these adducts were detected and quantified by using a previously developed 32P-postlabeling/HPLC method. These same DNA adducts were also found in liver DNA of rats gavaged with retrorsine. Since DHP-derived DNA adducts are suggested to be potential biomarkers of riddelliine-induced tumorigenicity, our results indicate that (i similar to the metabolic activation of riddelliine, the mechanism of retrorsine-induced carcinogenicity in rats is also through a genotoxic mechanism involving DHP; and (ii the set of DHP-derived DNA adducts found in liver DNA of rats gavaged with retrorsine or riddelliine can serve as biomarkers for the

  16. Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose

    Energy Technology Data Exchange (ETDEWEB)

    Honda, Hiroshi, E-mail: honda.hiroshi@kao.co.jp [R and D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497 (Japan); Törnqvist, Margareta [Department of Materials and Environmental Chemistry, Environmental Chemistry Unit, Stockholm University, SE-106 91 Stockholm (Sweden); Nishiyama, Naohiro [R and D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497 (Japan); Kasamatsu, Toshio, E-mail: kasamatsu.toshio@kao.co.jp [R and D Safety Science Research, Kao Corporation, 2606 Akabane, Ichikai-Machi, Haga-Gun, Tochigi 321-3497 (Japan)

    2014-03-15

    Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75 mg/kg bw, and diHOPrVal levels were measured 24 h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R{sup 2} = 0.943). Blood sampling at different time points (1, 10, 20, or 40 days) from four groups administered glycidol at 12 mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61 days), with the calculated first-order elimination rate constant (k{sub el}) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (k{sub val}) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The k{sub val} was 6.7 ± 1.1 and 5.6 ± 1.3 (pmol/g globin per μMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from k{sub val} and diHOPrVal levels were in agreement with the area under the (concentration–time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment. - Highlight: • Glycidol-hemoglobin adduct (diHOPrVal) was characterized for exposure evaluation. • We studied the kinetics of diHOPrVal formation and elimination in vitro and in vivo. • Dose dependent formation and chemical stability were confirmed in the rat study. • In vivo dose (AUC) of glycidol could be estimated from diHOPrVal levels

  17. In vitro hemoglobin adduct formation in blood from rats, mice and humans using 14C-phenol

    International Nuclear Information System (INIS)

    Hemoglobin (Hb) adducts may be useful biomarkers of exposures to chemicals. The mechanisms of Hb adduct formation were studied to enable better extrapolations of rodent studies to human exposure situations. Resuspended red blood cells (RBC) obtained from male F344/N rats, B6C3F1 mice and humans were incubated with 50 nmoles 14C-phenol/ml for 60 min in the presence of liver S9 from each species. Globin was isolated and analyzed for bound 14C. 14C-Phenol-derived Hb adduct levels from rat, mouse and human RBC incubations were 1.66 ± 0.02, 0.82 ± 0.09, and 0.58 ± 0.10 pmoles of adducts/mg globin (X ± SE; n=3-6), respectively. Preincubating RBC with maleimide, a sulfhydryl blocker, reduced adduct formation in rat, mouse and human RBC by 22.4 ± 2.7, 62.1 ± 3.8, and 1.40 ± 0.02%, respectively. RBC incubation with maleimide and subsequent measurement of free sulfhydryls in isolated globin showed that maleimide was able to bind to only 36.4 ± 4.4, 59.1 ± 3.6 and 21.4 ± 1.2 of the cysteine (Cys) sulfhydryls in Hb from rats, mice and humans, respectively. These studies suggest that humans are less efficient in forming Hb adducts than rodents. Also, the contribution of Cys binding to the total adducts formed on Hb may be greater in rodents than humans, due to the accessibility of Hb

  18. Photochemical Reaction of 7,12-Dimethylbenz[a]anthracene (DMBA and Formation of DNA Covalent Adducts

    Directory of Open Access Journals (Sweden)

    Peter P. Fu

    2005-04-01

    Full Text Available DMBA, 7,12-dimethylbenz[a]anthracene, is a widely studied polycyclic aromatic hydrocarbon that has long been recognized as a probable human carcinogen. It has been found that DMBA is phototoxic in bacteria as well as in animal or human cells and photomutagenic in Salmonella typhimurium strain TA102. This article tempts to explain the photochemistry and photomutagenicity mechanism. Light irradiation converts DMBA into several photoproducts including benz[a]anthracene-7,12-dione, 7-hydroxy-12-keto-7-methylbenz[a]anthracene, 7,12-epidioxy-7,12-dihydro-DMBA, 7-hydroxymethyl-12-methylbenz[a]anthracene and 12-hydroxymethyl-7-methylbenz[a]anthracene. Structures of these photoproducts have been identified by either comparison with authentic samples or by NMR/MS. At least four other photoproducts need to be assigned. Photo-irradiation of DMBA in the presence of calf thymus DNA was similarly conducted and light-induced DMBA-DNA adducts were analyzed by 32P-postlabeling/TLC, which indicates that multiple DNA adducts were formed. This indicates that formation of DNA adducts might be the source of photomutagenicity of DMBA. Metabolites obtained from the metabolism of DMBA by rat liver microsomes were reacted with calf thymus DNA and the resulting DNA adducts were analyzed by 32P-postlabeling/TLC under identical conditions. Comparison of the DNA adduct profiles indicates that the DNA adducts formed from photo-irradiation are different from the DNA adducts formed due to the reaction of DMBA metabolites with DNA. These results suggest that photo-irradiation of DMBA can lead to genotoxicity through activation pathways different from those by microsomal metabolism of DMBA.

  19. Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells

    International Nuclear Information System (INIS)

    Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6 μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. - Highlights: • PM forms ovarian DNA adducts. • DNA damage marker γH2AX increased by PM exposure. • PM induces ovarian DNA double strand break repair

  20. Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells

    Energy Technology Data Exchange (ETDEWEB)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2015-02-01

    Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6 μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. - Highlights: • PM forms ovarian DNA adducts. • DNA damage marker γH2AX increased by PM exposure. • PM induces ovarian DNA double strand break repair.

  1. Formation of 1,4-dioxo-2-butene-derived adducts of 2′-deoxyadenosine and 2′-deoxycytosine in oxidized DNA

    OpenAIRE

    Chen, Bingzi; Vu, Choua C.; Byrns, Michael C.; Peter C. Dedon; Peterson, Lisa A.

    2006-01-01

    Oxidation of deoxyribose in DNA produces a variety of electrophilic residues that are capable of reacting with nucleobases to form adducts such as M1dG, the pyrimidopurinone adduct of dG. We now report that deoxyribose oxidation in DNA leads to the formation of oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA. We previously demonstrated that these adducts arise in reactions of nucleosides and DNA with trans-1,4-dioxo-2-butene, the β-elimination product of the 2-phosphoryl-1,4-dioxobutane ...

  2. Synthesis of perfluoroalkylated bulky triarylamines

    OpenAIRE

    Alameddine, Bassam; Savary, Corinne; Aebischer, Olivier; Jenny, Titus A

    2007-01-01

    The synthesis of two new triarylamine compounds bearing perfluoroalkylated side chains is described. Good thermal stabilities combined with a blue emission make these compounds promising candidates for materials applications.

  3. Effects of steaming-made changes in physicochemical properties of Y-zeolite on cracking of bulky 1,3,5-triisopropylbenzene and coke formation

    Energy Technology Data Exchange (ETDEWEB)

    Bazyari, A.; Hosseinpour, N. [Catalysis and Nanostructured Materials Laboratory, School of Chemical Engineering, University of Tehran, P.O. Box 11155/4563, Tehran (Iran); Khodadadi, A.A.; Mortazavi, Y. [Catalysis and Nanostructured Materials Laboratory, School of Chemical Engineering, University of Tehran, P.O. Box 11155/4563, Tehran (Iran); Oil and Gas Center of Excellence, University of Tehran, P.O. Box 11155/4563, Tehran (Iran)

    2009-10-15

    The effects of acidic properties and structural changes of Y zeolite, produced by steaming, on the zeolite cracking activity, coking tendency and distribution of various products during catalytic conversion of bulky 1,3,5-triisopropylbenzene (TIPB) are reported. NaY zeolite with framework Si/Al ratio of 2.4 was synthesized by a hydrothermal method and ammonium exchanged. The zeolite was dealuminated by a temperature-programmed steaming to form USY1 and USY2 zeolites with framework Si/Al ratio of 8.1 and 12.3 respectively. The catalysts were characterized by XRD, XRF, SEM, AAS, NH{sub 3}-TPD and N{sub 2} adsorption-desorption techniques. The samples were in-situ activated at 748 K and evaluated by TIPB cracking at 623 K. The coke content of the catalyst beds was estimated by TPO using an FT-IR gas cell. The results of activity measurements reveal that the dealuminated zeolites lead to lower cracking activity initially; while, they exhibit higher activity at longer times. In addition, a slight modification of the window diameter of Y zeolite, as revealed by pore size distribution analyses, alters the diffusion limitation of the reactant and products through the pores of the zeolite and significantly affects the adsorbent-adsorbate interactions. TPO experiments show that compared to the precursor zeolite, lower amount of coke is formed on the dealuminated catalysts possessing lower density of acid sites. However, the coke formed on USY samples is heavier than that formed on its precursor Y zeolite. This may be attributed to the larger pores shaped in the dealuminated catalysts which in turn provide suitable places for coke formation and growth. (author)

  4. Stage I-IIA Non-Bulky Hodgkin's Lymphoma. Is Further Distinction Based on Prognostic Factors Useful? The Stanford Experience

    Energy Technology Data Exchange (ETDEWEB)

    Advani, Ranjana H., E-mail: radvani@stanford.edu [Department of Medicine, Division of Medical Oncology, Stanford University Medical Center, Stanford, California (United States); Hoppe, Richard T. [Department of Radiation Oncology, Stanford University Medical Center, Stanford, California (United States); Maeda, Lauren S. [Department of Medicine, Division of Medical Oncology, Stanford University Medical Center, Stanford, California (United States); Baer, David M. [Northern California Kaiser Permanente, Oakland, California (United States); Mason, Joseph [Northern California Kaiser Permanente, San Jose, California (United States); Rosenberg, Saul A.; Horning, Sandra J. [Department of Medicine, Division of Medical Oncology, Stanford University Medical Center, Stanford, California (United States)

    2011-12-01

    Purpose: In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center. Methods and Materials: This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n = 84 patients) or 20-Gy (n = 17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors. Results: At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n = 55%; European Organization for Research and Treatment of Cancer, n = 33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n = 61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p = 0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged. Conclusions: The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

  5. Comparative analysis of the influence of bulky β-alkyl substituents on fluorescent properties of some series of spatially distorted meso-phenyl substituted porphyrins

    Science.gov (United States)

    Sagun, E. I.; Zenkevich, E. I.

    2013-11-01

    We present results of our systematic investigation and comparative analysis of the spectral-kinetic properties of absorption and fluorescence of two series of related planar porphyrins in liquid media at 293 K, in which deviations from the planarity are caused by contact steric interactions of eight peripheral β-pyrrole methyl (-CH3) or ethyl (-C2H5) groups with a successively increasing number (from one to four) and varying position of meso-phenyl (Ph) substituents in the porphyrin macrocycle. It is substantiated that considerable differences between the spectral-kinetic properties of absorption and fluorescence of the octaethyl- and octamethylporphyrin molecules, which have the same number of meso-phenyl substituents, are caused by fundamentally different roles played by β-ethyl and β-methyl groups, which differ in volume and which determine differences in the character of steric interactions and the efficiency of the dynamic relaxation of the tetrapyrrole macrocycle. It is revealed that there is a difference between calculated f theor and experimentally determined f exp values of the fluorescence probability, which is caused by conformational rearrangements of spatially distorted porphyrin macrocycles in the S 1 excited state, which reduce the oscillator strength and lower the energy of the long-wavelength transition S 0 → S 1. It is found that the chemical nature, the size, and the number of bulky -CH3 or -C2H5 β-pyrrole groups affect weakly rate constants of fluorescence quenching by molecular oxygen and do not create noticeable steric hindrances for contact interactions of the oxygen molecule with the π-conjugated system of the tetrapyrrole macrocycle.

  6. Formation and persistence of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo

    International Nuclear Information System (INIS)

    The rat mammary carcinogen, N-hydroxy-2-acetylaminofluorene (N-hydroxy-2-AAF), has been proposed to be metabolically activated by mammary cytosolic N,O-acetyltransferase to a DNA binding species. To test this hypothesis, adult female Sprague-Dawley derived CD rats were treated, i.p., with 4.0 mg/kg [ring-3H]N-hydroxy-2-AAF. After 4 h, 1, 3, 14, and 28 days, the animals were killed, the mammary epithelium DNA was isolated and the carcinogen-deoxyribonucleoside adducts present were analyzed by high pressure liquid chromatography. At each time, only one adduct was detected and it was chromatographically identical to N-(deoxyguanosin-8-yl)-2-aminofluorene. The level of the adduct was maximal at 4 h (1.5 adducts/10(6) nucleotides) and then decreased, following first order kinetics with a t1/2 of 14.2 days. The detection of a single non-acetylated aminofluorene adduct is consistent with N,O-acyltransferase being involved in the metabolic activation of N-hydroxy-2-AAF in the rat mammary gland

  7. Determining protein adducts of fipexide: mass spectrometry based assay for confirming the involvement of its reactive metabolite in covalent binding.

    Science.gov (United States)

    Sleno, Lekha; Varesio, Emmanuel; Hopfgartner, Gérard

    2007-01-01

    Fipexide is a nootropic drug, withdrawn from the market due to its idiosyncratic drug reactions causing adverse effects in man. Previous work on its metabolites has identified several potential reactive metabolites which could be implicated in protein binding. Here, we investigated the formation of these metabolites in rat and human hepatocytes. Based on these results, the o-quinone of fipexide (FIP), formed via the demethylenation reaction through a catechol intermediate, was chosen for further investigation. Studies were then pursued in order to relate this metabolite to protein binding, and thus better understand potential mechanisms for the toxicity of the parent compound. An assay was developed for determining the fipexide catechol-cysteine adduct in the microsomal protein fractions following in vitro incubations. This method digests the entire protein fraction into amino acids, followed by the detection of the Cys-metabolite adduct by liquid chromatography/mass spectrometry (LC/MS). We have designed a strategy where drug metabolism taking place in microsomal incubations and involved in protein binding can be assessed after the proteins have been digested, with the detection of the specific amino acid adduct. In this study, the structure of the fipexide adduct was hypothesized using knowledge previously gained in glutathione and N-acetylcysteine trapping experiments. Acetaminophen was used as a positive control for detecting a drug metabolite-cysteine adduct by LC/MS. This approach has the potential to be applicable as a protein-binding assay in early drug discovery without the need for radioactive compounds. PMID:18022964

  8. Cysteine amide adduct formation from carboxylic acid drugs via UGT-mediated bioactivation in human liver microsomes.

    Science.gov (United States)

    Harada, H; Toyoda, Y; Endo, T; Kobayashi, M

    2015-10-01

    Although chemical trapping has been widely used to evaluate cytochrome P450-mediated drug bioactivation, thus far, only a few in vitro-trapping studies have been performed on UDP-glucuronosyltransferase (UGT)-mediated drug bioactivation. In this study, we used cysteine (Cys) as trapping agent to gain new insights into the UGT-mediated bioactivation involving acyl glucuronides of carboxylic acid drugs. Diclofenac, ketoprofen and ibuprofen were incubated in human liver microsomes with UDPGA and Cys, followed by analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The N-acyl-Cys amide adduct of diclofenac was characterized by mass analysis and was detectable even in photodiode array analysis. Our data indicated that the formation of such adducts reflects the reactivity of the corresponding acyl glucuronides. In addition, it was suggested that the adduct formation requires an N-terminal Cys moiety with both a free amine and a free thiol group, from the results using various cysteine derivatives. We propose that the S-acyl-Cys thioester adduct can form via transacylation of an acyl glucuronide and can then form to an N-acyl-Cys amide adduct through intramolecular S- to N-acyl rearrangement. This series of the reactions has important implications as a possible bioactivation mechanism for covalent binding of carboxylic acid drugs to macromolecules. PMID:26601426

  9. Tracking matrix effects in the analysis of DNA adducts of polycyclic aromatic hydrocarbons.

    Science.gov (United States)

    Klaene, Joshua J; Flarakos, Caroline; Glick, James; Barret, Jennifer T; Zarbl, Helmut; Vouros, Paul

    2016-03-25

    LC-MS using electrospray ionization is currently the method of choice in bio-organic analysis covering a wide range of applications in a broad spectrum of biological media. The technique is noted for its high sensitivity but one major limitation that hinders achievement of its optimal sensitivity is the signal suppression due to matrix inferences introduced by the presence of co-extracted compounds during the sample preparation procedure. The analysis of DNA adducts of common environmental carcinogens is particularly sensitive to such matrix effects as sample preparation is a multistep process which involves "contamination" of the sample due to the addition of enzymes and other reagents for digestion of the DNA in order to isolate the analyte(s). This problem is further exacerbated by the need to reach low levels of quantitation (LOQ in the ppb level) while also working with limited (2-5μg) quantities of sample. We report here on the systematic investigation of ion signal suppression contributed by each individual step involved in the sample preparation associated with the analysis of DNA adducts of polycyclic aromatic hydrocarbon (PAH) using as model analyte BaP-dG, the deoxyguanosine (dG) adduct of benzo[a]pyrene (BaP). The individual matrix contribution of each one of these sources to analyte signal was systematically addressed as were any interactive effects. The information was used to develop a validated analytical protocol for the target biomarker at levels typically encountered in vivo using as little as 2μg of DNA and applied to a dose response study using a metabolically competent cell line. PMID:26607319

  10. Characterization of quinone derived protein adducts and their selective identification using redox cycling based chemiluminescence assay.

    Science.gov (United States)

    Elgawish, Mohamed Saleh; Kishikawa, Naoya; Ohyama, Kaname; Kuroda, Naotaka

    2015-07-17

    The cytotoxic mechanism of many quinones has been correlated to covalent modification of cellular proteins. However, the identification of relevant proteins targets is essential but challenging goals. To better understand the quinones cytotoxic mechanism, human serum albumin (HSA) was incubated in vitro with different concentration of menadione (MQ). In this respect, the initial nucleophilic addition of proteins to quinone converts the conjugates to redox-cycling quinoproteins with altered conformation and secondary structure and extended life span than the short lived, free quinones. The conjugation of MQ with nucleophilic sites likewise, free cysteine as well as ɛ-amino group of lysine residue of HSA has been found to be in concentration dependent manner. The conventional methods for modified proteins identification in complex mixtures are complicated and time consuming. Herein, we describe a highly selective, sensitive, simple, and fast strategy for quinoproteins identification. The suggested strategy exploited the unique redox-cycling capability of quinoproteins in presence of a reductant, dithiothreitol (DTT), to generate reactive oxygen species (ROS) that gave sufficient chemiluminescence (CL) when mixed with luminol. The CL approach is highly selective and sensitive to detect the quinoproteins in ten-fold molar excess of native proteins without adduct enrichment. The approach was also coupled with gel filtration chromatography (GFC) and used to identify adducts in complex mixture of proteins in vitro as well as in rat plasma after MQ administration. Albumin was identified as the main protein in human and rat plasma forming adduct with MQ. Overall, the identification of quinoproteins will encourage further studies of toxicological impact of quinones on human health. PMID:26044383

  11. A mini-review on Biginelli adducts with notable pharmacological properties

    Directory of Open Access Journals (Sweden)

    Ângelo de Fátima

    2015-05-01

    Full Text Available Since the disclosure of Biginelli reaction by the chemist Pietro Biginelli, functionalized 3,4-dihydropyrimidin-2(1H-ones/thiones (DHPMs have emerged as prototypes for the design of compounds with a broad variety of biological activities. This mini-review describes over 100 Biginelli adducts demonstrated to be promising anticancer, inhibitors of calcium channel, anti-inflammatory, antimicrobial and antioxidant agents. Thus, this compilation presents the most notable in vitro and in vivo results for such fascinating class of organic compounds.

  12. Mutagenic properties of the 8-amino-2'-deoxyguanosine DNA adduct in mammalian cells.

    OpenAIRE

    X. Tan; Suzuki, N; Johnson, F; Grollman, A P; Shibutani, S

    1999-01-01

    The DNA adduct 8-amino-2'-deoxyguanosine (8-amino-dG) is found in liver DNA of rats treated with the hepatocarcinogen 2-nitropropane. Site-specifically modified oligodeoxynucleotides were used to explore the mutagenic potential of 8-amino-dG in simian kidney (COS-7) cells. Oligodeoxynucleotides (5'-TCCTCCTX1G2CCTCTC and 5'-TCCTCCTG1X2CCTCTC, X = dG or 8-amino-dG) with the lesion positioned at codon 60 or 61 of the non-coding strand of the human c-Ha- ras1 gene were inserted into single-strand...

  13. Cisplatin–DNA adducts inhibit translocation of the Ku subunits of DNA-PK

    OpenAIRE

    Turchi, John J.; Henkels, Karen M.; Zhou, Yun

    2000-01-01

    We have determined the effect of cisplatin–DNA damage on the ability of the DNA-dependent protein kinase (DNA-PK) to interact with duplex DNA molecules in vitro. The Ku DNA binding subunits of DNA-PK display a reduced ability to translocate on duplex DNA containing cisplatin–DNA adducts compared to control, undamaged duplex DNA. The decreased rates of translocation resulted in a decrease in the association of the p460 catalytic subunit of DNA-PK (DNA-PKcs) with the Ku–DNA complex. In addition...

  14. STM/STS observation of ferrocene derivative adduct to C60 on HOPG

    International Nuclear Information System (INIS)

    The C60ONCFn cycloadduct (Fn=ferrocene) was prepared in the reaction between C60 and ferrocene oxime, the ferrocene derivative was bound to C60 at the 6-6 bond by a heterocyclic oxygen-nitrogen-carbon ring; the compound was stable in air. The compound dissolved in dichloroethane was deposited on HOPG and observed by UHV STM/STS methods. The molecules of C60ONCFn formed several-microns-long straight chains with clearly visible adducted groups pointing to one side of the chain. The STM/STS observations are discussed within the terms of semiempirical quantum chemical molecular modeling

  15. Shape of the Adduct Formic Acid-Dimethyl Ether: A Rotational Study.

    Science.gov (United States)

    Evangelisti, Luca; Spada, Lorenzo; Li, Weixing; Ciurlini, Anna; Grabow, Jens-Uwe; Caminati, Walther

    2016-05-12

    Formic acid and dimethyl ether are combined in a supersonic expansion to form a molecular adduct with the two subunits held together by a "classical" OH···O hydrogen bond and a bifurcated weak CH2···O hydrogen bond. The rotational spectra of the parent and of two (13)C isotopologues in natural abundance show that the complex has Cs symmetry, with the heavy atom symmetry planes of HCOOH and (CH3)2O perpendicular to each other. PMID:27102727

  16. TRANSPLATIN-CONJUGATED TRIPLEX-FORMING OLIGONUCLEOTIDES FORM ADDUCTS WITH BOTH STRANDS OF DNA

    OpenAIRE

    Campbell, Meghan A.; Miller, Paul S.

    2009-01-01

    Triplex-forming oligonucleotides (TFOs) can bind to polypurine•polypyrimidine tracts in DNA and as a consequence, perturb normal functioning of a targeted gene. The effectiveness of such anti-gene TFOs can potentially be enhanced by covalent attachment of the TFO to its DNA target. Here we report that attachment of N-7-platinated guanine nucleosides to the 3′- and/or 5′-ends of oligopyrimidine TFOs enables these TFOs to form highly stable adducts with target DNA deoxyguanosines or deoxyadenos...

  17. Electron transfer from nucleobase electron adducts to 5-bromouracil: a radiation chemical study

    International Nuclear Information System (INIS)

    Electron transfer to 5-bromouracil from their nucleobase electron adducts and their protonated forms has been studied by product analysis. When an electron is transferred to 5-bromouracil, the ensuing 5-bromouracil radical anion rapidly loses a bromide ion. The uracilyl radical thus formed reacts with added t-butanol, yielding uracil. From the uracil yields measured as a function of (N)/(5-BrU) after γ-radiolysis of Ar-saturated solutions it is concluded that the hetero atom protonated forms transfer electron quantitatively to 5-bromouracil. (author). 3 refs., 1 fig

  18. Preparation of SRN1-Type Coupling Adducts from Aliphatic gem-Dinitro Compounds in Ionic Liquids

    Directory of Open Access Journals (Sweden)

    Seiichi Toyoshima

    2012-04-01

    Full Text Available SRN1-type coupling adducts are readily prepared by the reaction between a-sulfonylesters or a-cyanosulfones and gem-dinitro compounds in ionic liquids. The reactions progress smoothly and recovered ionic liquids can be used for several iterations, as long as they are washed with water to remove alkali metallic salts. The reaction rate is slower than the corresponding SRN1 reaction in DMSO, but no acceleration on irradiation or no inhibition in the presence of m-DNB are observed.

  19. Lead tetraacetate oxidation of the Diels-Alder adduct of 7-dehydrocholestryl acetate with maleic anhydride

    Directory of Open Access Journals (Sweden)

    MIHAILO LJ. MIHAILOVIC

    2000-03-01

    Full Text Available The Diels-Alder adduct (3, obtained by cycloaddition of 7-dehydrocholesteryl acetate (1 and maleic anhydride (2, was heated at ca. 90°C with a large excess of lead tetraacetate in pyridine solution for 5 h. Under these conditions, compound 3 underwent lactonization with the participation of the olefinic D6-double bond to give two isomeric monolactone derivatives, 9 and 10 (in a total yield of ca. 6%, and the bislactone product 11 (in 11.5% yield. The starting material was recovered in 36% yield.

  20. Chemical biology of mutagenesis and DNA repair: cellular responses to DNA alkylation

    OpenAIRE

    Shrivastav, Nidhi; Li, Deyu; Essigmann, John M.

    2009-01-01

    The reaction of DNA-damaging agents with the genome results in a plethora of lesions, commonly referred to as adducts. Adducts may cause DNA to mutate, they may represent the chemical precursors of lethal events and they can disrupt expression of genes. Determination of which adduct is responsible for each of these biological endpoints is difficult, but this task has been accomplished for some carcinogenic DNA-damaging agents. Here, we describe the respective contributions of specific DNA les...

  1. Formation and persistence of sterigmatocystin-DNA adducts in rat liver determined via 32P-postlabeling analysis

    International Nuclear Information System (INIS)

    A 32P-postlabeling method has been employed to detect the in vitro and in vivo modification of DNA by the mycotoxin sterigmatocystin (ST). Dose-dependent ST-DNA adduct formation was detected in the liver of male Fischer 344 rats over a 27-fold range of ST administered. In addition, ST-DNA adducts, formed in rats given a 9 mg/kg dose, were found to persist up to 105 days after treatment at a level of 0.5% of the 2-h value. Loss of these adducts from liver DNA was observed to exhibit a triphasic profile: rapid loss during the first 24 h followed by a slower decline from 1 to 14 days post dosing and an extremely slow decline from day 14 to 105 post treatment. This experimental approach to the study of mycotoxin-DNA interactions permits the quantitative description of DNA modification in ST-treated animals. (Auth.)

  2. Myeloperoxidase - 463A variant reduces benzo(a)pyrene diol epoxide DNA adducts in skin of coal tar treated patients

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, M.; Godschalk, R.; Alexandrov, K.; Cascorbi, I.; Kriek, E.; Ostertag, J.; Van Schooten, F.J.; Bartsch, H. [German Cancer Research Center, Heidelberg (Germany). Div. of Toxicology & Cancer Risk Factors

    2001-07-01

    The skin of atopic dermatitis patients provides an excellent model to study the role of inflammation in benzo(a)pyrene (BaP) activation, since these individuals are often topically treated with ointments containing high concentrations of BaP. The authors determined, by HPLC with fluorescence detection, the BaP diol epoxide (BPDE)-DNA adduct levels in human skin after topical treatment with coal tar and their modulation by the -453G into A myeloperoxidase (MPO) polymorphism, which reduces MPO mRNA expression. The data show for the first time: (i) the in vivo formation of BPDE-DNA adducts in human skin treated with coal tar; (ii) that the MPO-463AA/AG genotype reduced BPDE-DNA adduct levels in human skin.

  3. Efficient CO2 capture by tertiary amine-functionalized ionic liquids through Li+-stabilized zwitterionic adduct formation

    Directory of Open Access Journals (Sweden)

    Zhen-Zhen Yang

    2014-08-01

    Full Text Available Highly efficient CO2 absorption was realized through formation of zwitterionic adducts, combining synthetic strategies to ionic liquids (ILs and coordination. The essence of our strategy is to make use of multidentate cation coordination between Li+ and an organic base. Also PEG-functionalized organic bases were employed to enhance the CO2-philicity. The ILs were reacted with CO2 to form the zwitterionic adduct. Coordination effects between various lithium salts and neutral ligands, as well as the CO2 capacity of the chelated ILs obtained were investigated. For example, the CO2 capacity of PEG150MeBu2N increased steadily from 0.10 to 0.66 (mol CO2 absorbed per mol of base through the formation of zwitterionic adducts being stabilized by Li+.

  4. Association between plasma BPDE‐Alb adduct concentrations and DNA damage of peripheral blood lymphocytes among coke oven workers

    Science.gov (United States)

    Wang, Hong; Chen, Weihong; Zheng, Hongyan; Guo, Liang; Liang, Huashan; Yang, Xiaobo; Bai, Yun; Sun, Jianya; Su, Yougong; Chen, Yongwen; Yuan, Jing; Bi, Yongyi; Wei, Qingyi; Wu, Tangchun

    2007-01-01

    Objectives Coke oven emissions (COE) containing polycyclic aromatic hydrocarbons (PAHs) can induce both benzo[a]pyrene‐r‐7, t‐8, t‐9,c‐10‐tetrahydotetrol‐albumin (BPDE‐Alb) adducts and DNA damage. However, the relation between these biomarkers for early biological effects is not well documented in coke oven workers. Methods In this study, the authors recruited 207 male workers exposed to COE and 102 controls not exposed to COE in the same steel plant in northern China. They measured BPDE‐Alb adduct concentrations in plasma with reverse‐phase high performance liquid chromatography and DNA damage in peripheral blood lymphocytes with alkaline comet assay. Results The results showed that the median concentration of BPDE‐Alb adducts in the exposed group (34.36 fmol/mg albumin) was significantly higher than that in the control group (21.90 fmol/mg albumin, p = 0.012). The mean Olive tail moment (Olive TM) of DNA damage in the exposed and control groups were 1.20 and 0.63, respectively (p = 0.000). Multivariate logistic regression analysis revealed that the odds ratio (OR) for BPDE‐Alb adduct and Olive TM associated with the exposure were 1.72 (95% CI 1.06 to 2.81) and 1.96 (95% CI 1.20 to 3.19), respectively. These results show significant correlations between the concentrations of BPDE‐Alb adduct and Olive TM levels in exposed group (r = 0.235, p = 0.001) but not in control group (r = 0.093, p = 0.353). Conclusion The results suggest that occupational exposure to COE may induce both BPDE–Alb adducts and DNA damage in the lymphocytes of coke oven workers and that these two markers are useful for monitoring exposure to COE in the workplace. PMID:17449561

  5. Accumulation of miscoding etheno-DNA adducts and highly expressed DNA repair during liver fluke-induced cholangiocarcinogenesis in hamsters.

    Science.gov (United States)

    Dechakhamphu, Somkid; Pinlaor, Somchai; Sitthithaworn, Paiboon; Bartsch, Helmut; Yongvanit, Puangrat

    2010-09-10

    Infection by Opisthorchis viverrini, a risk factor for cholangiocarcinoma (CCA) may act through chronic inflammation, oxidative stress and lipid peroxidation (LPO)-related damage and growth stimuli. 1,N6-etheno-2'-deoxyadenosine (epsilondA), and 3,N4-etheno-2'-deoxycytidine (epsilondC), markers for LPO-derived DNA damage were highly increased in white blood cell and urine of O. viverrini-infected Thai patients. In order to investigate tissue specificity etheno adducts were measured in a cholangiocarcinogenesis model, in O. viverrini-infected hamsters that had received N-nitrosodimethylamine (NDMA, 12.5 ppm in dw) for 2 months. epsilondA- and epsilondC-levels were analyzed in paraffin-embedded liver sections by a novel immunohistochemical method, from 21 up to 180 days post-O. viverrini-infection. In inflamed areas of the liver, etheno adducts were localized in the nuclei of inflammatory cells and in the epithelial lining of the bile duct. Semi-quantitative image analysis showed higher adduct levels in the liver of O. viverrini-infected hamsters, treated with or w/o NDMA when compared with untreated controls. Levels were found highest in the liver of O. viverrini-infected plus NDMA-treated hamsters. Adducts increased in an age-dependent manner from O. viverrini-infection until CCA development. Increased adduct formation paralleled histopathological changes in plasma alkaline phosphatase (ALP) activity, bile duct hyperplasia, dysplasia, precancerous lesions, and CCA appearance. Also elevated expression of alkyladenine DNA glycosylase (AAG), which excises 1,N6-ethenoadenine (epsilonA) was linked to higher adduct formation, suggesting imbalanced repair. Our results implicate accumulation of inflammation-related, promutagenic DNA damage in target tissue and possibly imbalanced repair in the onset of cholangiocarcinogenesis. PMID:20541562

  6. Benzene-derived N2-(4-hydroxyphenyl)-deoxyguanosine adduct: UvrABC incision and its conformation in DNA

    Energy Technology Data Exchange (ETDEWEB)

    Hang, Bo; Rodriguez, Ben; Yang, Yanu; Guliaev, Anton B.; Chenna, Ahmed

    2010-06-14

    Benzene, a ubiquitous human carcinogen, forms DNA adducts through its metabolites such as p-benzoquinone (p-BQ) and hydroquinone (HQ). N(2)-(4-Hydroxyphenyl)-2'-deoxyguanosine (N(2)-4-HOPh-dG) is the principal adduct identified in vivo by (32)P-postlabeling in cells or animals treated with p-BQ or HQ. To study its effect on repair specificity and replication fidelity, we recently synthesized defined oligonucleotides containing a site-specific adduct using phosphoramidite chemistry. We here report the repair of this adduct by Escherichia coli UvrABC complex, which performs the initial damage recognition and incision steps in the nucleotide excision repair (NER) pathway. We first showed that the p-BQ-treated plasmid was efficiently cleaved by the complex, indicating the formation of DNA lesions that are substrates for NER. Using a 40-mer substrate, we found that UvrABC incises the DNA strand containing N(2)-4-HOPh-dG in a dose- and time-dependent manner. The specificity of such repair was also compared with that of DNA glycosylases and damage-specific endonucleases of E. coli, both of which were found to have no detectable activity toward N(2)-4-HOPh-dG. To understand why this adduct is specifically recognized and processed by UvrABC, molecular modeling studies were performed. Analysis of molecular dynamics trajectories showed that stable G:C-like hydrogen bonding patterns of all three Watson-Crick hydrogen bonds are present within the N(2)-4-HOPh-G:C base pair, with the hydroxyphenyl ring at an almost planar position. In addition, N(2)-4-HOPh-dG has a tendency to form more stable stacking interactions than a normal G in B-type DNA. These conformational properties may be critical in differential recognition of this adduct by specific repair enzymes.

  7. Etheno-DNA adduct formation in rats gavaged with linoleic acid, oleic acid and coconut oil is organ- and gender specific

    Energy Technology Data Exchange (ETDEWEB)

    Fang Qingming [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 69120 Heidelberg (Germany); Nair, Jagadeesan [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 69120 Heidelberg (Germany)], E-mail: j.nair@dkfz.de; Sun Xin [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 69120 Heidelberg (Germany); Hadjiolov, Dimiter [National Oncological Centre, Sofia (Bulgaria); Bartsch, Helmut [Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 69120 Heidelberg (Germany)

    2007-11-01

    Intake of linoleic acid (LA) increased etheno-DNA adducts induced by lipid peroxidation (LPO) in white blood cells (WBC) of female but not of male volunteers [J. Nair, C.E. Vaca, I. Velic, M. Mutanen, L.M. Valsta, H. Bartsch, High dietary {omega}-6 polyunsaturated fatty acids drastically increase the formation of etheno-DNA adducts in white blood cells of female subjects, Cancer Epidemiol. Biomarkers Prev. 6 (1997) 597-601]. Etheno-adducts were measured in rats gavaged with LA, oleic acid (OA) and saturated fatty acid rich coconut oil for 30 days. DNA from organs and total WBC was analyzed for 1, N{sup 6}-ethenodeoxyadenosine ({epsilon}dA) and 3, N{sup 4}-ethenodeoxycytidine ({epsilon}dC) by immunoaffinity/{sup 32}P-postlabeling. Colon was the most affected target with LA-treatment, where etheno-adducts were significantly elevated in both sexes. In WBC both adducts were elevated only in LA-treated females. Unexpectedly, OA treatment enhanced etheno-adduct levels in prostate 3-9 fold. Our results in rodents confirm the gender-specific increase of etheno-adducts in WBC-DNA, likely due to LPO induced by redox-cycling of 4-hydroxyestradiol. Colon was a target for LPO-derived DNA-adducts in both LA-treated male and female rats, supporting their role in {omega}-6 PUFA induced colon carcinogenesis.

  8. Eccentric and Isometric Hip Adduction Strength in Male Soccer Players With and Without Adductor-Related Groin Pain An Assessor-Blinded Comparison

    DEFF Research Database (Denmark)

    Thorborg, Kristian; Branci, Sonia; Nielsen, Peter Martin;

    2014-01-01

    .5 ± 2.5 years, and the mean age of the asymptomatic controls was 22.9 ± 2.4 years. Isometric hip strength (adduction, abduction, and flexion) and eccentric hip strength (adduction) were assessed with a handheld dynamometer using reliable test procedures and a blinded assessor. RESULTS: Eccentric hip...

  9. STABILITY OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF BENZENE OXIDE AND 1,4-BENZOQUINONE AFTER ADMINISTRATION OF BENZENE TO F344 RATS

    Science.gov (United States)

    The stability of cysteinyl adducts of benzene oxide (BO) and mono-S-substituted cysteinyl adducts of 1,4-benzoquinone (1,4-BQ) was investigated in both hemoglobin (Hb) and albumin (Alb) following administration of a single oral dose of 400 mg [U-14C/13C6]benzene/kg body weight ...

  10. Pulse radiolysis investigation of the reaction of the electronic adduct of bovine serum albumin with oxygen. Polychromatic kinetics of the reaction with adsorbed oxygen

    International Nuclear Information System (INIS)

    The method of pulse radiolysis was used to investigate the reaction of the electronic adduct of bovine serum albumin with oxygen. It was suggested that the disappearance of the electronic adduct of the protein occurs in the course of its interaction with oxygen adsorbed on the globular protein molecule

  11. DIFFERENCES IN DETECTION OF DNA ADDUCTS IN THE 32P-POSTLABELING ASSAY AFTER EITHER 1-BUTANOL EXTRACTION OR NUCLEASE P1 TREATMENT

    Science.gov (United States)

    The use of nuclease Pl treatment and 1-butanol extraction to increase the sensitivity of the 32P-postlabe1ling assay for DNA adducts have been compared. lthough similar results were obtained with the two methods for standard adducts formed with benzo(a)pyrene diol epoxide I, nucl...

  12. Acute and sub-acute effects of repetitive kicking on hip adduction torque in injury-free elite youth soccer players

    DEFF Research Database (Denmark)

    Jensen, Jesper; Bandholm, Thomas; Hölmich, Per;

    2014-01-01

    Hip adduction strength is important for kicking and acceleration in soccer players. Changes in hip adduction strength may therefore have an effect on soccer players' athletic performance. The purpose of this study was to investigate the acute and sub-acute effects of a kicking drill session on hi...

  13. Fast repair of oxidizing OH radical adducts of dGMP, dAMP and DNA by hydroxycinnamic acid derivatives. A pulse radiolytic study

    International Nuclear Information System (INIS)

    Using a pulse radiolytic technique, it has been demonstrated that the interaction of oxidizing OH adducts of DNA with hydroxycinnamic acid derivatives proceeds via an electron transfer process with rate constant of (5-7) x 108dm3mol-1s-1. Besides, the rate for fast repair of OH adducts of dAMP and DNA (ssDNA and dsDNA) are slower than the corresponding rate for the rest OH adducts of DNA constituents, such as dGMP (2-3*109 dm1mol-1s-1). The slower rate for oxidizing OH adduct of dAMP and DNA has indicated that repair of oxidizing OH adduct of dAMP may be the rate determining process during the interaction of hydroxycinnamic acid derivatives with OH adduct of DNA containing the varieties of OH adducts of DNA components. On other hand, the yields for oxidizing OH radical adduct with dGMP and dAMP were determined to be 50% and 30% respectively

  14. Molar ratios of therapeutic water-soluble phenothiazine⋅water-insoluble phospholipid adducts reveal a Fibonacci correlation and a putative link for structure–activity relationships

    DEFF Research Database (Denmark)

    Keyzer, Hendrik; Fey, S. J.; Thornton, Barry;

    2015-01-01

    larger than that of the self-associated pure PTH. In summary, the reproducibility and similarity of the measurements using different PTH derivatives and PL suggests that similar adducts are formed in all the cases. We propose that the PTH$PL adduct has a “helical shape” showing Fibonacci properties...

  15. Etheno-DNA adduct formation in rats gavaged with linoleic acid, oleic acid and coconut oil is organ- and gender specific

    International Nuclear Information System (INIS)

    Intake of linoleic acid (LA) increased etheno-DNA adducts induced by lipid peroxidation (LPO) in white blood cells (WBC) of female but not of male volunteers [J. Nair, C.E. Vaca, I. Velic, M. Mutanen, L.M. Valsta, H. Bartsch, High dietary ω-6 polyunsaturated fatty acids drastically increase the formation of etheno-DNA adducts in white blood cells of female subjects, Cancer Epidemiol. Biomarkers Prev. 6 (1997) 597-601]. Etheno-adducts were measured in rats gavaged with LA, oleic acid (OA) and saturated fatty acid rich coconut oil for 30 days. DNA from organs and total WBC was analyzed for 1, N6-ethenodeoxyadenosine (εdA) and 3, N4-ethenodeoxycytidine (εdC) by immunoaffinity/32P-postlabeling. Colon was the most affected target with LA-treatment, where etheno-adducts were significantly elevated in both sexes. In WBC both adducts were elevated only in LA-treated females. Unexpectedly, OA treatment enhanced etheno-adduct levels in prostate 3-9 fold. Our results in rodents confirm the gender-specific increase of etheno-adducts in WBC-DNA, likely due to LPO induced by redox-cycling of 4-hydroxyestradiol. Colon was a target for LPO-derived DNA-adducts in both LA-treated male and female rats, supporting their role in ω-6 PUFA induced colon carcinogenesis

  16. Coulometric Titrations in Wine Samples: Studies on the Determination of S(IV) and the Formation of Adducts

    Science.gov (United States)

    Lowinsohn, Denise; Bertotti, Mauro

    2002-01-01

    In this experiment, the sulfite in white wine samples is quantified by coulometric titration with iodine, using a procedure that minimizes errors due to air oxidation. Some aspects of the distinction of S(IV) forms in such matrices are discussed on the basis of the formation of adducts between sulfite and carbonyl compounds present in the wine. The reactivity of these S(IV)-bound compounds toward the reaction with iodine is addressed and the stability of the adducts as the sample pH is changed is discussed. See Letter re: this article.

  17. DNA adduct formation and oxidative stress in colon and liver of Big Blue rats after dietary exposure to diesel particles

    DEFF Research Database (Denmark)

    Dybdahl, Marianne; Risom, Lotte; Møller, Peter;

    2003-01-01

    in liver accompanied by enhanced vitamin C levels. In plasma, we found no significant effects on oxidative damage to proteins and lipids, antioxidant enzymes or vitamin C levels. Our data indicate that gastrointestinal exposure to DEP induces DNA adducts and oxidative stress resulting in DNA strand breaks...... on oxidative DNA damage (8-oxodG) in colon or liver DNA or in the urine. However, the mRNA expression of OGG1, encoding an enzyme involved in repair of 8-oxodG, was increased by DEP in both liver and colon. DNA adduct levels measured by 32P-post-labelling were elevated in colon and liver, and the expression...

  18. Recognition and repair of the CC-1065-(N3-Adenine)-DNA adduct by the UVRABC nuclease

    Energy Technology Data Exchange (ETDEWEB)

    Tang, M.; Lee, C.S.; Doisy, R.; Ross, L.; Needham-VanDevanter, D.R.; Hurley, L.H.

    1988-02-09

    The recognition and repair of the helix-stabilizing and relatively nondistortive CC-1065-(N3-adenine)-DNA adduct by UVRABC nuclease has been investigated both in vivo with phi X174RFI DNA by a transfection assay and in vitro by a site-directed adduct in a 117 base pair fragment from M13mp1. CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis which binds within the minor groove of DNA through N3 of adenine. In contrast to the helix-destabilizing and distortive modifications of DNA caused by ultraviolet light or N-acetoxy-2-(acetylamino)fluorene, CC-1065 increases the melting point of DNA and decreases the S1 nuclease activity. Using a viral DNA-Escherichia coli transfection system, the authors have found that the uvrA, uvrB, and uvrC genes, which code for the major excision repair proteins for UV- and NAAAF-induced DNA damage, are also involved in the repair of CC-1065-DNA adducts. In contrast, the uvrD gene product, which has been found to be involved in the repair of UV damage, has no effect in repairing CC-1065-DNA adducts. Purified UVRA, UVRB, and UVRC proteins must work in concert to incise the drug-modified phi X174RFI DNA. Using a site-directed and multiple CC-1065 modified (MspI-BstNI) 117 base pair fragment from M13mp1, they have found that UVRABC nuclease incises at the eight phosphodiester bond on the 5' side of the CC-1065-DNA adduct on the drug-modified strand. The enzymes do not cut the noncovalently modified strand. The DNA sequence and/or helix-stabilizing effect of multiple adducts may determine the recognition and/or incision of the drug-DNA adduct by UVRABC nuclease. These results are discussed in relation to the structure of the CC-1065-DNA adduct and the effect of drug binding on local DNA structure.

  19. Recognition and repair of the CC-1065-(N3-Adenine)-DNA adduct by the UVRABC nuclease

    International Nuclear Information System (INIS)

    The recognition and repair of the helix-stabilizing and relatively nondistortive CC-1065-(N3-adenine)-DNA adduct by UVRABC nuclease has been investigated both in vivo with phi X174RFI DNA by a transfection assay and in vitro by a site-directed adduct in a 117 base pair fragment from M13mp1. CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis which binds within the minor groove of DNA through N3 of adenine. In contrast to the helix-destabilizing and distortive modifications of DNA caused by ultraviolet light or N-acetoxy-2-(acetylamino)fluorene, CC-1065 increases the melting point of DNA and decreases the S1 nuclease activity. Using a viral DNA-Escherichia coli transfection system, the authors have found that the uvrA, uvrB, and uvrC genes, which code for the major excision repair proteins for UV- and NAAAF-induced DNA damage, are also involved in the repair of CC-1065-DNA adducts. In contrast, the uvrD gene product, which has been found to be involved in the repair of UV damage, has no effect in repairing CC-1065-DNA adducts. Purified UVRA, UVRB, and UVRC proteins must work in concert to incise the drug-modified phi X174RFI DNA. Using a site-directed and multiple CC-1065 modified (MspI-BstNI) 117 base pair fragment from M13mp1, they have found that UVRABC nuclease incises at the eight phosphodiester bond on the 5' side of the CC-1065-DNA adduct on the drug-modified strand. The enzymes do not cut the noncovalently modified strand. The DNA sequence and/or helix-stabilizing effect of multiple adducts may determine the recognition and/or incision of the drug-DNA adduct by UVRABC nuclease. These results are discussed in relation to the structure of the CC-1065-DNA adduct and the effect of drug binding on local DNA structure

  20. 2-Aminofluorene metabolism and DNA adduct formation by mononuclear leukocytes from rapid and slow acetylator mouse strains.

    Science.gov (United States)

    Levy, G N; Chung, J G; Weber, W W

    1994-02-01

    Following exposure of mice to the arylamine carcinogen 2-aminofluorene, DNA-carcinogen adducts can be found in the target tissues liver and bladder, and also in circulating leukocytes. Evidence is presented here that mouse mononuclear leukocytes (MNL) are capable of metabolizing 2-aminofluorene to DNA-binding metabolites which give rise to the adducts found in the MNL. Both lymphocytes and monocytes were able to acetylate arylamines during 18 h of culture. The degree of acetylation was determined by the N-acetyltransferase genotype of the mice as shown through use of acetylator congenic strains which differ only in the Nat-2 gene. Cultured MNL from rapid acetylator mice (C57BL/6J and A.B6-Natr) produced about twice as much N-acetylaminofluorene from 2-aminofluorene and 6- to 8-fold as much N-acetyl-p-aminobenzoic acid from p-aminobenzoic acid as cells from slow acetylator mice (B6.A-Nat(s) and A/J). Other differences in arylamine metabolism by MNL in culture were observed and shown to be due to genetic factors, currently unidentified, other than N-acetyltransferase. DNA adduct formation following incubation of MNL with the arylamine carcinogen 2-aminofluorene was related to both acetylation capacity and to other genetic metabolic factors in the mouse genome. MNL from rapid acetylator mice with the C57BL/6J background (B6) had 3-fold the DNA adduct levels of cells from the corresponding slow acetylator congenic (B6.A-Nat(s)). Similarly, MNL from rapid acetylator mice with the A/J background (A.B6-Natr) had twice the DNA adduct levels of those from their corresponding slow congenic (A). Adduct levels in MNL from C57BL/6J were nearly the same as those of MNL from A/J, again indicating the involvement of loci other than acetylation in DNA adduct formation. The finding of genetically dependent arylamine carcinogen metabolism and DNA adduct formation in cultured MNL suggests the possibility of using cultured MNL for assessing individual susceptibility to arylamine

  1. Fast repair of dAMP hydroxyl radical adduct by verbascoside via electron transfer

    Institute of Scientific and Technical Information of China (English)

    石益民; 王文锋; 姚思德; 林维真; 韩镇辉; 师彦平; 贾忠建; 郑荣梁

    1999-01-01

    DNA damaged by oxygen radicals has been implicated as a causative event in a number of degenerative diseases, including cancer and aging. So it is very impotant to look for ways in which either oxygen radicals are scavenged prior to DNA damage or damaged DNA is repaired to supplement the cells’ inadequate repair capacity. The repair activity and its mechanism of verbaseoside, isolated from Pedicularis species, towards dAMP-OH·was studied with pulse radiolytic technique. On pulse irradiation of nitrous oxide saturated 2 mmol/L dAMP aqueous solution containing verbascoside, the transient absorption spectrum of the hydroxyl adduct of dAMP decayed with the formation of that of the phenoxyl radical of verbascoside well under 100 microseconds after electron pulse irradiation. The result indicated that dAMP hydroxyl adducts can be repaired by verbascoside. The rate constants of the repair reaction was deduced to be 5.9×108 dm3·mol-1·s-1. A deeper understanding of this new repair mechanism will undo

  2. The formation of argpyrimidine, a methylglyoxal-arginine adduct, in the nucleus of neural cells

    International Nuclear Information System (INIS)

    Methylglyoxal (MG) is an endogenous metabolite in glycolysis and forms stable adducts primarily with arginine residues of intracellular proteins. The biological role of this modification in cell function is not known. In the present study, we found that a MG-detoxification enzyme glyoxalase I (GLO1) is mainly expressed in the ventricular zone (VZ) at embryonic day 16 which neural stem and progenitor cells localize. Moreover, immunohistochemical analysis revealed that argpyrimidine, a major MG-arginine adduct, is predominantly produced in cortical plate neurons not VZ during cerebral cortex development and is exclusively located in the nucleus. Immunoblotting experiment showed that the formation of argpyrimidine occurs on some nuclear proteins of cortical neurons. To our knowledge, this is first report of the argpyrimidine formation in the nucleus of neuron. These findings suggest that GLO1, which is dominantly expressed in the embryonic VZ, reduces the intracellular level of MG and suppresses the formation of argpyrimidine in neural stem and progenitor cells. Argpyrimidine may contribute to the neural differentiation and/or the maintenance of the differentiated state via the modification of nuclear proteins.

  3. Formation of BH3 Adducts with Pyridine-2-Methylaminophosphine ligands: An experimental and computational study

    Indian Academy of Sciences (India)

    Harinath Adimulam; Dwijendra P Kukri; Bhabani S Mallik; Tarun K Panda

    2016-01-01

    The reaction of pyridine-2-methylaminophosphine [C5H4N-CH2NHPPh2] (1) and pyridine-2-methylphosphinoselenoic amide [C5H4N-CH2NHP(Se)Ph2] (2) with BH3·SMe2 yields the corresponding adducts [C5H4N(BH3)-CH2NHP(BH3)Ph2] (1a), and [C5H4N(BH3)-CH2NHP(Se)Ph2] (2a), respectively. The solid state structures of both the compounds were established by single crystal X-ray diffraction analysis. The phosphorus and the pyridine nitrogen atoms are coordinated to the boron atom in the case of 1a whereas only pyridine nitrogen atom is attached to the BH3 group in the case of 2a. To understand the nature of P-B/ N-B bonds and to compare the basicities of pyridine nitrogen, amino nitrogen and phosphorus atoms, density functional theoretical (DFT) calculations were performed on the BH3 adducts 1a and 2a. The results are consistent with the experimental results.

  4. Influence of bulky N-substituents on the formation of lanthanide triple helical complexes with a ligand derived from bis(benzimidazole)pyridine: structural and thermodynamic evidence.

    Science.gov (United States)

    Muller, G; Bünzli, J C; Schenk, K J; Piguet, C; Hopfgartner, G

    2001-06-01

    The planar aromatic tridentate ligand 2,6-bis(1-S-neopentylbenzimidazol-2-yl)pyridine (L(11)) reacts with Ln(III) (Ln = La-Lu) in acetonitrile to give the successive complexes [Ln(L(11))(n)](3+) (n = 1-3). However, stability constants determined by spectrophotometry and NMR titrations show that formation of the tris complexes is not favored, log K(3) being around 1 for La(III) and Eu(III), while no such species could be evidenced for the smaller Lu(III) ion. The X-ray structures of L(11) (monoclinic, P2(1), a = 13.4850(12) A, b = 12.0243(11) A, c = 16.4239(14) A, beta = 103.747(7) degrees ), [La(ClO(4))(2)(L(11))(2)](3)[La(ClO(4))(2)(H(2)O)(L(11))(2)](ClO(4))(4).15MeCN (1a, monoclinic, P2(1), a = 21.765(4) A, b = 30.769(6) A, c = 21.541(5) A, beta = 116.01(3) degrees ), and [Eu(L(11))(3)](ClO(4))(3).4.28MeCN (5a, monoclinic, P1, a = 14.166(3) A, b = 19.212(4) A, c = 21.099(4) A, alpha = 108.91(3) degrees, beta = 98.22(3) degrees, gamma = 108.40(3) degrees ) have been solved. In 1a, two different types of complex cations are evidenced, both containing 10-coordinate La(III) ions. In the first type, both perchlorate anions are bidentate, while in the second type, one perchlorate is monodentate, the 10th coordination position being occupied by a water molecule. In 5a the three ligands are not equivalent. Ligands A and B are wrapped in a helical way and are mirror images of each other, while ligand C lies almost perpendicular to the two other ones. This stems from the steric hindrance generated by the bulky neopentyl groups with the consecutive loss of any stabilizing interstrand pi-stacking interactions. This explains the low stability of the tris complexes and the difficulty of isolating them and points to the importance of the steric factors in the design of self-assembled triple helical lanthanide-containing functional edifices [Ln(L(i))(3)](3+). PMID:11375674

  5. Surprisingly Different Reaction Behavior of Alkali and Alkaline Earth Metal Bis(trimethylsilyl)amides toward Bulky N-(2-Pyridylethyl)-N'-(2,6-diisopropylphenyl)pivalamidine.

    Science.gov (United States)

    Kalden, Diana; Oberheide, Ansgar; Loh, Claas; Görls, Helmar; Krieck, Sven; Westerhausen, Matthias

    2016-07-25

    N-(2,6-Diisopropylphenyl)-N'-(2-pyridylethyl)pivalamidine (Dipp-N=C(tBu)-N(H)-C2 H4 -Py) (1), reacts with metalation reagents of lithium, magnesium, calcium, and strontium to give the corresponding pivalamidinates [(tmeda)Li{Dipp-N=C(tBu)-N-C2 H4 -Py}] (6), [Mg{Dipp-N=C(tBu)-N-C2 H4 -Py}2 ] (3), and heteroleptic [{(Me3 Si)2 N}Ae{Dipp-N=C(tBu)-N-C2 H4 -Py}], with Ae being Ca (2 a) and Sr (2 b). In contrast to this straightforward deprotonation of the amidine units, the reaction of 1 with the bis(trimethylsilyl)amides of sodium or potassium unexpectedly leads to a β-metalation and an immediate deamidation reaction yielding [(thf)2 Na{Dipp-N=C(tBu)-N(H)}] (4 a) or [(thf)2 K{Dipp-N=C(tBu)-N(H)}] (4 b), respectively, as well as 2-vinylpyridine in both cases. The lithium derivative shows a similar reaction behavior to the alkaline earth metal congeners, underlining the diagonal relationship in the periodic table. Protonation of 4 a or the metathesis reaction of 4 b with CaI2 in tetrahydrofuran yields N-(2,6-diisopropylphenyl)pivalamidine (Dipp-N=C(tBu)-NH2 ) (5), or [(thf)4 Ca{Dipp-N=C(tBu)-N(H)}2 ] (7), respectively. The reaction of AN(SiMe3 )2 (A=Na, K) with less bulky formamidine Dipp-N=C(H)-N(H)-C2 H4 -Py (8) leads to deprotonation of the amidine functionality, and [(thf)Na{Dipp-N=C(H)-N-C2 H4 -Py}]2 (9 a) or [(thf)K{Dipp-N=C(H)-N-C2 H4 -Py}]2 (9 b), respectively, are isolated as dinuclear complexes. From these experiments it is obvious, that β-metalation/deamidation of N-(2-pyridylethyl)amidines requires bases with soft metal ions and also steric pressure. The isomeric forms of all compounds are verified by single-crystal X-ray structure analysis and are maintained in solution. PMID:27355970

  6. Differences in detection of DNA adducts in the 32P-postlabelling assay after either 1-butanol extraction or nuclease Pl treatment

    International Nuclear Information System (INIS)

    The use of nuclease P1 treatment and 1-butanol extraction to increase the sensitivity of the 32P-postlabelling assay for DNA adducts have been compared. Although similar results were obtained with the two methods for standard adducts formed with benzo(a)pyrene diol epoxide I, nuclease P1 treatment resulted in a significant reduction in detection of major adducts 1-amino-6-nitropyrene, 1-amino-8-nitropyrene, 2-aminofluorene, 2-naphthylamine and 4-aminobiphenyl modified DNAs, but not following the 32P-postlabelling analysis of 2-acetylaminofluorene modified DNA. These results suggest that at least initially, both modications of the 32P-postlabelling assay should be used for the detection of unknown adducts or for adducts derived from nitro-aromatics and aromatic amines

  7. Differences in detection of DNA adducts in the 32P-postlabelling assay after either 1-butanol extraction or nuclease P1 treatment.

    Science.gov (United States)

    Gallagher, J E; Jackson, M A; George, M H; Lewtas, J; Robertson, I G

    1989-04-01

    The use of nuclease P1 treatment and 1-butanol extraction to increase the sensitivity of the 32P-postlabelling assay for DNA adducts have been compared. Although similar results were obtained with the two methods for standard adducts formed with benzo[a]pyrene diol epoxide I (BPDE-I), nuclease P1 treatment resulted in a significant reduction in detection of major adducts from 1-amino-6-nitropyrene (1-amino-6-NP), 1-amino-8-nitropyrene (1-amino-8-NP), 2-aminofluorene (2-AF), 2-naphthylamine (2-NA) and 4-aminobiphenyl (4-ABP) modified DNAs, but not following the 32P-postlabelling analysis of 2-acetylaminofluorene (2-AAF) modified DNA. These results suggest that, at least initially, both modifications of the 32P-postlabelling assay should be used for the detection of unknown adducts or for adducts derived from nitroaromatics and aromatic amines. PMID:2540901

  8. Facile Synthesis of N-Tosyl Aza-Baylis-Hillman Adducts of Acrylamide via a Pd-Catalyzed Hydration of Nitrile to Amide

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Sun; Kim, Yu Mi; Kim, Jae Nyoung [Chonnam National Univ., Gwangju (Korea, Republic of)

    2010-03-15

    We developed an efficient palladium-catalyzed two-step protocol for the synthesis of N-tosyl aza-Baylis-Hillman adducts of acrylamide. The method involved the preparation of the corresponding Baylis-Hillman adducts of acrylonitrile and the following Pd-catalyzed hydration of nitrile with acetaldoxime. The Baylis-Hillman reaction, which involves the coupling of activated vinyl compounds with electrophiles under the catalytic influence of a tertiary amine, gives rise to adducts, so called Baylis-Hillman adducts, with a new stereocenter and has proven to be a very useful carbon-carbon bond-forming method in the synthesis of highly functionalized molecules. As the activated vinyl compounds, various compounds have been used in the Baylis-Hillman reaction including acrylates, acrylonitrile, vinyl ketones, vinyl sulfones and acrylamides. However, among the activated vinyl compounds acrylamide has not been used much for the synthesis of the corresponding Baylis-Hillman adducts due to its sluggish reactivity.

  9. Facile Synthesis of N-Tosyl Aza-Baylis-Hillman Adducts of Acrylamide via a Pd-Catalyzed Hydration of Nitrile to Amide

    International Nuclear Information System (INIS)

    We developed an efficient palladium-catalyzed two-step protocol for the synthesis of N-tosyl aza-Baylis-Hillman adducts of acrylamide. The method involved the preparation of the corresponding Baylis-Hillman adducts of acrylonitrile and the following Pd-catalyzed hydration of nitrile with acetaldoxime. The Baylis-Hillman reaction, which involves the coupling of activated vinyl compounds with electrophiles under the catalytic influence of a tertiary amine, gives rise to adducts, so called Baylis-Hillman adducts, with a new stereocenter and has proven to be a very useful carbon-carbon bond-forming method in the synthesis of highly functionalized molecules. As the activated vinyl compounds, various compounds have been used in the Baylis-Hillman reaction including acrylates, acrylonitrile, vinyl ketones, vinyl sulfones and acrylamides. However, among the activated vinyl compounds acrylamide has not been used much for the synthesis of the corresponding Baylis-Hillman adducts due to its sluggish reactivity

  10. Miscoding properties of 1,N{sup 6}-ethanoadenine, a DNA adduct derived from reaction with antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

    Energy Technology Data Exchange (ETDEWEB)

    Hang, Bo; Guliaev, Anton B.; Chenna, Ahmed; Singer, B.

    2003-03-05

    1,N{sup 6}-Ethanoadenine (EA) is an exocyclic adduct formed from DNA reaction with the antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). To understand the role of this adduct in the mechanism of mutagenicity or carcinogenicity by BCNU, an oligonucleotide with a site-specific EA was synthesized using phosphoramidite chemistry. We now report the in vitro miscoding properties of EA in translesion DNA synthesis catalyzed by mammalian DNA polymerases (pols) {alpha}, {beta}, {eta} and {iota}. These data were also compared with those obtained for the structurally related exocyclic adduct, 1,N{sup 6}-ethenoadenine ({var_epsilon}A). Using a primer extension assay, both pols {alpha} and {beta} were primarily blocked by EA or {var_epsilon}A with very minor extension. Pol {eta} a member of the Y family of polymerases, was capable of catalyzing a significant amount of bypass across both adducts. Pol {eta} incorporated all four nucleotides opposite EA and {var_epsilon}A, but with differential preferences and mainly in an error-prone manner. Human pol {iota}, a paralog of human pol {eta}, was blocked by both adducts with a very small amount of synthesis past {var_epsilon}A. It incorporated C and, to a much lesser extent, T, opposite either adduct. In addition, the presence of an A adduct, e.g. {var_epsilon}A, could affect the specificity of pol {iota} toward the template T immediately 3 feet to the adduct. In conclusion, the four polymerases assayed on templates containing an EA or {var_epsilon}A showed differential bypass capacity and nucleotide incorporation specificity, with the two adducts not completely identical in influencing these properties. Although there was a measurable extent of error-free nucleotide incorporation, all these polymerases primarily misincorporated opposite EA, indicating that the adduct, similar to {var_epsilon}A, is a miscoding lesion.

  11. Detection of 1,N2-propanodeoxyguanosine adducts of 2-hexenal in organs of Fischer 344 rats by a 32P-post-labeling technique.

    Science.gov (United States)

    Schuler, D; Eder, E

    1999-07-01

    2-Hexenal is an alpha,beta-unsaturated carbonyl compound which is mutagenic, genotoxic and forms cyclic 1,N2-propanodeoxyguanosine adducts like similar propenals for which carcinogenicity was shown, e.g. acrolein or crotonaldehyde. Since humans have a permanent intake of 2-hexenal via vegetarian food this genotoxic compound is considered to play a role in human carcinogenicity. The data base is, however, presently not sufficient for a cancer risk assessment. To date no long term carcinogenicity study on 2-hexenal has been published. Detection of respective DNA adducts of this substance in animals or humans could allow cancer risk assessment. Therefore, we have developed a 32P-post-labeling technique based on nuclease P1 enrichment and TLC separation of the labeled adducts. The respective adducts are stable over a wide pH range from pH 4 to pH 11 and relatively stable against nuclease P1. The detection limit was 0.03 adducts per 10(6) nucleotides and the recovery was 10%. With this method we have shown in vivo formation of 1,N 2-propanodeoxyguanosine adducts of 2-hexenal for the first time and found the respective DNA adducts in different organs of Fischer 344 rats after gavage of 500, 200 and 50 mg 2-hexenal/kg body wt. No adducts could be detected in the organs of untreated rats. There is a clear dependence of the adduct level and the CBI (covalent binding index) on the dose. The CBI of 2-hexenal calculated on the basis of our adduct levels is extremely low (0.06). Since intake of 2-hexenal via fruit and vegetables is very low the cancer risk from 2-hexenal intake via food must also be considered as very low according to a first raw estimation on the basis of CBI and intake. The situation deserves, however, a more precise risk assessment in the future. PMID:10383910

  12. Constraining the sensitivity of iodide adduct chemical ionization mass spectrometry to multifunctional organic molecules using the collision limit and thermodynamic stability of iodide ion adducts

    Science.gov (United States)

    Lopez-Hilfiker, Felipe D.; Iyer, Siddarth; Mohr, Claudia; Lee, Ben H.; D'Ambro, Emma L.; Kurtén, Theo; Thornton, Joel A.

    2016-04-01

    The sensitivity of a chemical ionization mass spectrometer (ions formed per number density of analytes) is fundamentally limited by the collision frequency between reagent ions and analytes, known as the collision limit, the ion-molecule reaction time, and the transmission efficiency of product ions to the detector. We use the response of a time-of-flight chemical ionization mass spectrometer (ToF-CIMS) to N2O5, known to react with iodide at the collision limit, to constrain the combined effects of ion-molecule reaction time, which is strongly influenced by mixing and ion losses in the ion-molecule reaction drift tube. A mass spectrometric voltage scanning procedure elucidates the relative binding energies of the ion adducts, which influence the transmission efficiency of molecular ions through the electric fields within the vacuum chamber. Together, this information provides a critical constraint on the sensitivity of a ToF-CIMS towards a wide suite of routinely detected multifunctional organic molecules for which no calibration standards exist. We describe the scanning procedure and collision limit determination, and we show results from the application of these constraints to the measurement of organic aerosol composition at two different field locations.

  13. Pulmonary heat shock protein expression after exposure to a metabolically activated Clara cell toxicant: relationship to protein adduct formation

    International Nuclear Information System (INIS)

    Heat shock proteins/stress proteins (Hsps) participate in regulation of protein synthesis and degradation and serve as general cytoprotectants, yet their role in lethal Clara cell injury is not clear. To define the pattern of Hsp expression in acute lethal Clara cell injury, mice were treated with the Clara cell-specific toxicant naphthalene (NA), and patterns of expression compared to electrophilic protein adduction and previously established organellar degradation and gluathione (GSH) depletion. In sites of lethal injury (distal bronchiole), prior to organellar degradation (1 h post-NA), protein adduction is detectable and ubiquitin, Hsp 25, Hsp 72, and heme-oxygenase 1 (HO-1) are increased. Maximal Hsp expression, protein adduction, and GSH depletion occur simultaneous (by 2-3 h) with early organelle disruption. Hsp expression is higher later (6-24 h), only in exfoliating cells. In airway sites (proximal bronchiole) with nonlethal Clara cell injury elevation of Hsp 25, 72, and HO-1 expression follows significant GSH depletion (greater than 50% 2 h post-NA). This data build upon our previous studies and we conclude that (1) in lethal (terminal bronchiole) and nonlethal (proximal bronchiole) Clara cell injury, Hsp induction is associated with the loss of GSH and increased protein adduction, and (2) in these same sites, organelle disruption is not a prerequisite for Hsp induction

  14. Thermodynamics and kinetics of reduction and species conversion at a hydrophobic surface for mitochondrial cytochromes c and their cardiolipin adducts

    International Nuclear Information System (INIS)

    Highlights: • Cytochrome c and its adduct with cardiolipin can be immobilized on a hydrophobic SAM. • Adsorbed cytochrome c and its adduct undergo extensive unfolding and axial ligand substitution. • An equilibrium between a six-coordinated and a five-coordinated form is observed in both cases. • The reduced five-coordinated form is stabilized by cardiolipin binding. • Immobilized cytochrome c exchanges electrons more slowly upon cardiolipin binding. - Abstract: Cytochrome c (cytc) and its adduct with cardiolipin (CL) were immobilized on a hydrophobic SAM-coated electrode surface yielding a construct which mimics the environment experienced by the complex at the inner mitochondrial membrane where it plays a role in cell apoptosis. Under these conditions, both species undergo an equilibrium between a six-coordinated His/His-ligated and a five-coordinated His/- ligated forms stable in the oxidized and in the reduced state, respectively. The thermodynamics of the oxidation-state dependent species conversion were determined by temperature-dependent diffusionless voltammetry experiments. CL binding stabilizes the immobilized reduced His/- ligated form of cytc which was found previously to catalytically reduce dioxygen. Here, this adduct is also found to show pseudoperoxidase activity, catalysing reduction of hydrogen peroxide. These effects would impart CL with an additional role in the cytc-mediated peroxidation leading to programmed cell death. Moreover, immobilized cytc exchanges electrons more slowly upon CL binding possibly due to changes in solvent reorganization effects at the protein-SAM interface

  15. Pyrrolizidine Alkaloid-Protein Adducts: Potential Non-invasive Biomarkers of Pyrrolizidine Alkaloid-Induced Liver Toxicity and Exposure.

    Science.gov (United States)

    Xia, Qingsu; Zhao, Yuewei; Lin, Ge; Beland, Frederick A; Cai, Lining; Fu, Peter P

    2016-08-15

    Pyrrolizidine alkaloids (PAs) are phytochemicals present in hundreds of plant species from different families widely distributed in many geographical regions around the world. PA-containing plants are probably the most common type of poisonous plants affecting livestock, wildlife, and humans. There have been many large-scale human poisonings caused by the consumption of food contaminated with toxic PAs. PAs require metabolic activation to generate pyrrolic metabolites to exert their toxicity. In this study, we developed a novel method to quantify pyrrole-protein adducts present in the blood. This method involves the use of AgNO3 in acidic ethanol to cleave the thiol linkage of pyrrole-protein (DHP-protein) adducts, and the resulting 7,9-di-C2H5O-DHP is quantified by HPLC-ES-MS/MS multiple reaction monitoring analysis in the presence of a known quantity of isotopically labeled 7,9-di-C2D5O-DHP internal standard. Using this method, we determined that diester-type PAs administered to rats produced higher levels of DHP-protein adducts than other types of PAs. The results suggest that DHP-protein adducts can potentially serve as minimally invasive biomarkers of PA exposure. PMID:27388689

  16. Formation of fractals by the self-assembly of interpolymer adducts of polymethacrylic acid with complementary polymers in aqueous solution

    Indian Academy of Sciences (India)

    Kandhasamy Durai Murugan; Arlin Jose Amali; Paramasivam Natarajan

    2012-03-01

    Interpolymer adducts of poly(methacrylic acid), (PMAA), with poly(vinylpyrrolidone) in presence of sodium chloride or potassium chloride form highly ordered fractal patterns in films on glass surface on drying at ambient temperature. The structure, morphology and the conditions under which the formation of fractal patterns occurs were investigated by SEM, EDX and confocal microscopic techniques. Self-organization of PMAA with complementary polymers such as poly(vinylpyrrolidone) is well-known and in the presence of sodium chloride formation of the fractals in films of the adducts is a novel observation. Fractal formation occurs due to the aggregation of interpolymer adducts. The composition of the fractals in the film is studied by EDX and confocal microscopic images of the fluorophores covalently bound to PMAA. In presence of salts, sodium chloride or potassium chloride, micellar like entities of 80 nm size were formed which further aggregate to form fractal patterns. It is suggested that the fractals result from the interpolymer adduct by Diffusion Limited Aggregation mechanism.

  17. Error prone translesion synthesis past gamma-hydroxypropano deoxyguanosine, the primary acrolein-derived adduct in mammalian cells.

    Science.gov (United States)

    Kanuri, Manorama; Minko, Irina G; Nechev, Lubomir V; Harris, Thomas M; Harris, Constance M; Lloyd, R Stephen

    2002-05-24

    8-Hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin- 10(3H)-one,3-(2'-deoxyriboside) (1,N(2)-gamma-hydroxypropano deoxyguanosine, gamma-HOPdG) is a major DNA adduct that forms as a result of exposure to acrolein, an environmental pollutant and a product of endogenous lipid peroxidation. gamma-HOPdG has been shown previously not to be a miscoding lesion when replicated in Escherichia coli. In contrast to those prokaryotic studies, in vivo replication and mutagenesis assays in COS-7 cells using single stranded DNA containing a specific gamma-HOPdG adduct, revealed that the gamma-HOPdG adduct was significantly mutagenic. Analyses revealed both transversion and transition types of mutations at an overall mutagenic frequency of 7.4 x 10(-2)/translesion synthesis. In vitro gamma-HOPdG strongly blocks DNA synthesis by two major polymerases, pol delta and pol epsilon. Replicative blockage of pol delta by gamma-HOPdG could be diminished by the addition of proliferating cell nuclear antigen, leading to highly mutagenic translesion bypass across this adduct. The differential functioning and processing capacities of the mammalian polymerases may be responsible for the higher mutation frequencies observed in this study when compared with the accurate and efficient nonmutagenic bypass observed in the bacterial system. PMID:11889127

  18. The association between submaximal quadriceps force steadiness and the knee adduction moment during walking in patients with knee osteoarthritis

    DEFF Research Database (Denmark)

    Sørensen, Tina Juul; Langberg, Henning; Aaboe, Jens;

    2011-01-01

    STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the relationship between quadriceps force steadiness and knee adduction moment during walking in patients with knee osteoarthritis (OA). BACKGROUND: Studies have shown that quadriceps force steadiness is impaired in patients with kne...

  19. In silico attempt for adduct agent(s) against malaria: Combination of chloroquine with alkaloids of Adhatoda vasica.

    Science.gov (United States)

    Swain, Shasank S; Sahu, Mahesh C; Padhy, Rabindra N

    2015-10-01

    With the aim of controlling drug resistant Plasmodium falciparum, a computational attempt of designing novel adduct antimalarial drugs through the molecular docking method of combining chloroquine with five alkaloids, individually is presented. These alkaloids were obtained from the medicinal plant, Adhatoda vasica. From the obtained individual docking values of important derivatives of quinine and chloroquine, as well as, individual alkaloids and adduct agents of chloroquine with Adhatoda alkaloids as ligands, it was discernible that the 'adduct agent-1 with chloroquine and adhatodine' combination had the minimum energy of interaction, as the docking score value of -11.144 kcal/mol against the target protein, triosephosphate isomerase (TIM), the key enzyme of glycolytic pathway. Drug resistance of P. falciparum is due to a mutation in the polypeptide of TIM. Moratorium of mutant TIM would disrupt the metabolism during the control of the drug resistant P. falciparum. This in silico work helped to locate the 'adduct agent-1 with chloroquine and adhatodine', which could be taken up by pharmacology for further development of this compound as a new drug against drug resistant Plasmodium. PMID:26142781

  20. The relevance and significance of O6-, N7-Alkylguanines and N3-Alkyladenine DNA adducts from tobacco smoke.

    Czech Academy of Sciences Publication Activity Database

    Chadt, Jiří; Koskinen, M.; Vodička, Pavel

    Vídeň, 2006. [Tobacco Herm Reduction and Perception of Risk. 08.03.2006-11.03.2006, Vídeň] R&D Projects: GA ČR GA310/05/2626 Institutional research plan: CEZ:AV0Z50390512 Keywords : DNA Adduct Subject RIV: EB - Genetics ; Molecular Biology

  1. Analysis of hemoglobin adducts from acrylamide, glycidamide, and ethylene oxide in paired mother/cord blood samples from Denmark

    DEFF Research Database (Denmark)

    von Stedingk, Hans; Vikström, Anna C; Rydberg, Per;

    2011-01-01

    The knowledge about fetal exposure to acrylamide/glycidamide from the maternal exposure through food is limited. Acrylamide, glycidamide, and ethylene oxide are electrophiles and form adducts with hemoglobin (Hb), which could be used for in vivo dose measurement. In this study, a method for analy...

  2. Spectrum of styrene-induced DNA adducts: the relationship to other biomarkers and prospects in human biomonitoring

    Czech Academy of Sciences Publication Activity Database

    Vodička, Pavel; Koskinen, M.; Arand, M.; Hemminki, K.

    2002-01-01

    Roč. 511, - (2002), s. 239-254. ISSN 1383-5742 R&D Projects: GA ČR GA313/99/1460 Institutional research plan: CEZ:AV0Z5039906 Keywords : styrene * DNA adducts Subject RIV: FM - Hygiene Impact factor: 7.085, year: 2002

  3. Isolation of methylcarbamoyl-adducts of adenine and cytosine following in vitro reaction of methyl isocyanate with calf thymus DNA.

    Science.gov (United States)

    Segal, A; Solomon, J J; Li, F J

    1989-01-01

    Methylisocyanate (MIC) is the direct-acting acylating compound involved in the Bhopal, India disaster which occurred on December 3rd, 1984. The accidental release of MIC resulted in at least 2000 deaths, thousands of injuries and exposure of at least 200,000 people to varying amounts of MIC. We have studied how MIC reacts with 2'-deoxyribonucleosides at pH 7.0 and 37 degrees C for 1 h. MIC acylates exocyclic amino groups resulting in the following methylcarbamoyl (MC) adducts: N6-MC-Ade (0.5% yield) and N4-MC-dCyd (6%). No adducts were detected with dThd and dGuo. UV, NMR and mass spectrometry were employed to spectroscopically characterize these adducts. MIC was reacted with calf thymus DNA (pH 7.0, 37 degrees C, 1 h) and yielded N6-MC-Ade (0.3 nmol/mg DNA) and N4-MC-dCyd (2.0 nmol/mg DNA). The inability of others to observe genetic mutations by MIC in Salmonella and Drosophila is consistent with the exocyclic adducts at N4 of Cyt and N6 of Ade where normal hydrogen bonding can occur after rotation of the methylcarbamoyl group anti to the Watson-Crick side of the molecule assuming that MIC binds to DNA within the intact cell. PMID:2731306

  4. Dietary determinants for Hb-acrylamide and Hb-glycidamide adducts in Danish non-smoking women

    DEFF Research Database (Denmark)

    Outzen, Malene; Egeberg, Rikke; Dragsted, Lars; Christensen, Jane; Olesen, Pelle Thonning; Frandsen, Henrik Lauritz; Overvad, Kim; Tjønneland, Anne; Olsen, Anja

    2011-01-01

    Acrylamide (AA) is a probable human carcinogen that is formed in heat-treated carbohydrate-rich foods. The validity of FFQ to assess AA exposure has been questioned. The aim of the present cross-sectional study was to investigate dietary determinants of Hb-AA and Hb-glycidamide (GA) adducts. The...

  5. Structural aspects, thermal behavior, and stability of a self-assembled supramolecular polymer derived from flunixin–meglumine supramolecular adducts

    International Nuclear Information System (INIS)

    Highlights: ► The thermal behavior of flunixin–meglumine, a potent NSAID, was investigated. ► This supramolecular adduct self-assembled resulting in a polymer-like material. ► The supramolecular polymer showed a high molecular weight around 290 ± 88 MDa. ► NMR and FT-IR showed that hydrogen bonding can be responsible for the self-assembly. ► The stability of the supramolecular polymer was also studied and presented here. - Abstract: Flunixin–meglumine, a potent non-steroidal anti-inflammatory drug (NSAID) and a cyclo-oxygenase inhibitor for Veterinary use, is a hydrogen-bonded supramolecular adduct. Two monotropically related crystalline modifications (Forms I and II) were observed for a flunixin–meglumine sample. During the melt of form I, flunixin–meglumine adducts self-assembled by hydrogen bonds involving the hydroxyl groups from meglumine, resulting in an amorphous rigid glassy supramolecular polymer, which showed a high molecular weight around 290 ± 88 MDa and a glass transition around 49.5 °C. Both the adduct and the resulting supramolecular polymer were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance spectroscopy (NMR), Fourier transform-infrared spectroscopy (FT-IR), and weight-average molecular weight determination by light scattering. The chemical stability and morphological changes of the depolymerization process were also investigated for the supramolecular polymer, by DSC and scanning electron microscopy (SEM), respectively.

  6. Sorocenols G and H, Anti-MRSA Oxygen Heterocyclic Diels-Alder-type Adducts from Sorocea muriculata Roots

    Science.gov (United States)

    Bioassay-guided fractionation of a root extract of Sorocea muriculata led to the isolation and identification of two new oxygen heterocyclic Diels-Alder-type adducts, sorocenols G (1) and H (2), along with lupeol-3-(3'R-hydroxytetradecanoate) and oxyresveratrol. The structures of 1 and 2 were eluci...

  7. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

    International Nuclear Information System (INIS)

    At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose–response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia–reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter. - Highlights: • Extensive GSH depletion is not required for APAP-protein binding in the liver. • APAP-protein adducts appear in plasma at subtoxic doses. • Proteins are adducted in the cell and secreted out. • Coincidental liver injury increases plasma APAP-protein adducts at subtoxic doses

  8. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    McGill, Mitchell R.; Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Norris, Hye-Ryun K.; Slawson, Matthew H. [Center for Human Toxicology, University of Utah, Salt Lake City, UT (United States); Bajt, Mary Lynn; Xie, Yuchao; Williams, C. David [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Wilkins, Diana G.; Rollins, Douglas E. [Center for Human Toxicology, University of Utah, Salt Lake City, UT (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2013-06-15

    At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose–response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia–reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter. - Highlights: • Extensive GSH depletion is not required for APAP-protein binding in the liver. • APAP-protein adducts appear in plasma at subtoxic doses. • Proteins are adducted in the cell and secreted out. • Coincidental liver injury increases plasma APAP-protein adducts at subtoxic doses

  9. Isolation and identification of the adducts of mitomycin C and porfiromycin with DNA formed in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Chowdary, D.R.

    1989-01-01

    The antitumor antibiotics, mitomycin C (MC) and porfiromycin (PM), are shown to form covalent complexes with DNA in vitro, under reductive activation conditions (both chemical and enzymatic). Three major covalent adducts have been isolated and identified as (1) N{sup 2}-guanine adduct with MC (structure 4a), (2) N{sup 2}-guanine adduct with 10-decarbamoyl mitomycin ((10-DMC); structure 16a), and a bisadduct of MC linked to two Gs at their N{sup 2}-positions (structure 6). The adducts of PM with DNA formed in vitro are analogous (structures 19, 20, and 21). Formation of adducts 6 and 16a in CHO mammalian cells has been shown after exposing them to MC or 10-DMC, whereas formation of crosslink 6 in vivo has been demonstrated after injecting rats with MC. The experiments done in tissue cultures with (1a-{sup 3}H)-polyfiromycin show ({sup 3}H)-label in the unmodified A, G, and T thus suggesting the demethylation of PM to MC in cells. The methyl group containing ({sup 3}H) label was incorporated into nucleosides via de novo purine and thymidylate biosynthesis. A consolidated enzymatic scheme for the hydrolysis of MC-modified DNA has been established and the resistance of such DNA to cleavage by several nucleases has been shown. Thus, only DNase I/SVD/alkaline phosphatase or nuclease P{sub 1}/SVD/alkaline phosphatase combinations can degrade MC-modified DNA into nucleosides. A modified version of {sup 32}P-postlabeling has been developed with in vitro authentic standards and this can be conveniently used in the future to detect MC-modified lesions obtained in vivo. By utilizing the alkaline ethidium bromide fluorescence assay, the crosslinking effect of MC, PM, and 10-DMC has been shown to occur in cells.

  10. Formation of cigarette smoke-induced DNA adducts in the rat lung and nasal mucosa

    International Nuclear Information System (INIS)

    The formation of DNA adducts in the nasal, lung, and liver tissues of rats exposed daily to fresh smoke from a University of Kentucky reference cigarette (2R1) for up to 40 weeks was examined. The amount of smoke total particulate matter (TPM) inhaled and the blood carboxyhemoglobin (COHb) values averaged 5-5.5 mg smoke TPM/day/rat and 5.5%, respectively. The pulmonary AHH activity measured at the termination of each experiment showed an average increase of about two- to threefold in smoke-exposed groups. These observations suggested that animals effectively inhaled both gaseous and particulate phase constituents of cigarette smoke. DNAs from nasal, lung, and liver tissue were extracted and analyzed by an improved 32P-postlabeling procedure. The data demonstrate the DNA-damaging potential of long term fresh cigarette smoke exposure and suggest the ability of the tissue to partially recover from such damage following cessation of the exposure

  11. Adducts of rare earth hexafluoroacetylacetonates with amino acids. [Eu, Tb, Dy, La, Lu

    Energy Technology Data Exchange (ETDEWEB)

    Karasev, V.E.; Steblevskaya, N.I.; Shchelokov, R.N. (AN SSSR, Vladivostok. Inst. Khimii)

    1983-01-01

    Crystal different-ligand rare earth complexes with hexafluoroacetylacetone and amino acids of m(GFAA)/sub 3/ 2A composition, where m=La, Eu, Tb, Dy, Lu, A-glycine, ..cap alpha..-alanine, ..beta..-alanine, valine, norvaline, asparagine, proline, are extracted for the first time. IR spectroscopic and luminescent methods have been used to characterize compound composition. Amino acid is shown to be a neutral ligand coordinating through oxygen atom of carboxyl group with conservation of betaine structure. Analysis of Stark structure of /sup 5/D/sub 0/-/sup 7/F/sub 1/-transition in luminescence spectra of europium adducts points out monotonous decrease of ..delta..F/sub 1/ parameter from glycine to asparagine: gly > pro > ..cap alpha..-ala > hys > val > ..beta..-ala > Nsub(val) > ast.

  12. A Synthetic Aptamer-Drug Adduct for Targeted Liver Cancer Therapy.

    Directory of Open Access Journals (Sweden)

    Thu Le Trinh

    Full Text Available AS1411 (previously known as AGRO100 is a 26 nucleotide guanine-rich DNA aptamer which forms a guanine quadruplex structure. AS1411 has shown promising utility as a treatment for cancers in Phase I and Phase II clinical trials without causing major side-effects. AS1411 inhibits tumor cell growth by binding to nucleolin which is aberrantly expressed on the cell membrane of many tumors. In this study, we utilized a simple technique to conjugate a widely-used chemotherapeutic agent, doxorubicin (Dox, to AS1411 to form a synthetic Drug-DNA Adduct (DDA, termed as AS1411-Dox. We demonstrate the utility of AS1411-Dox in the treatment of hepatocellular carcinoma (HCC by evaluating the targeted delivery of Dox to Huh7 cells in vitro and in a murine xenograft model of HCC.

  13. Synthesis and crystal structure of a 1:2 adducts of aquatrifluoroboron and triphenylphosphine oxide

    International Nuclear Information System (INIS)

    Crystalline 1:2 adduct of aquatrifluoroboron and triphenylphosphine oxide: 1/2[BF3(Ho)] · Ph3Po(I) was prepared and studied by the method of X-ray diffraction analysis. The crystals are rhombic, space group Fdd2, a = 32.283, b = 20.162, c = 10.191 A, Z = 16. Molecule of [BF3(H2O)] is statistically disordered in reference to axis 2; population of all its atomic positions equals 0.5. Boron atom has a distorted tetrahedral coordination with B-O(w) donor-acceptor bond, its length being 1.568 (9) A. The B-F bond lengths fall within the range 1.378(8)-1.399(9) A

  14. Iodosylbenzene and iodylbenzene adducts of cerium(iv) complexes bearing chelating oxygen ligands.

    Science.gov (United States)

    Au-Yeung, Ka-Chun; So, Yat-Ming; Wang, Guo-Cang; Sung, Herman H-Y; Williams, Ian D; Leung, Wa-Hung

    2016-04-01

    Reactions of [Ce(IV)(LOEt)2Cl2] (LOEt(-) = [Co(η(5)-C5H5){P(O)(OEt)2}3](-)) and [Ce(μ-O){N(Pr(i)2PO)2}4Cl2] with PhIO afford the λ3-iodane complexes [Ce(IV)(LOEt)2{OI(Cl)Ph}2] and [Ce{N(Pr(i)2PO)2}3{OI(Cl)Ph}], respectively, whereas that between [Ce(IV)(LOEt)2Cl2] and PhIO2 or excess PhIO yields the λ5-iodane adduct [Ce(IV)(LOEt)2{OI(O)ClPh}2]. The crystal structures of the Ce(IV)λ3- and λ5-iodane complexes have been determined and their oxo transfer reactivities have been investigated. PMID:26956671

  15. Investigation on the optical and electrical properties of MMTG crystal: A Lewis base adduct

    Science.gov (United States)

    Vetha Potheher, I.; Rajarajan, K.; Vimalan, M.; Tamilselvan, S.; Jeyasekaran, R.; Sagayaraj, P.

    2011-09-01

    The growth of nonlinear optical single crystal of manganese mercury thiocyanate glycol monomethyl ether (MMTG), a Lewis base adduct of manganese mercury thiocyanate (MMTC), is reported. MMTG crystallizes in orthorhombic structure with Pca2 1 space group. The optical band gap energy of the sample is found to be 3.5 eV. The sample is thermally stable up to 145 °C. The grown crystal is characterized by photoluminescence, dielectric, dc conductivity, photoconductivity and SEM studies. From the photoluminescence study, the suitability of the material for blue and green light generation is confirmed. The electric and dielectric response of the grown crystal is studied as a function of temperature and the results are discussed. The dc activation energy of the sample is found to be 0.048 eV.

  16. Crystal structure of the bis(cyclohexylammonium succinate succinic acid salt adduct

    Directory of Open Access Journals (Sweden)

    Modou Sarr

    2015-08-01

    Full Text Available The crystal structure of the title salt adduct, 2C6H14N+·C4H4O42−·C4H6O4, consists of two cyclohexylammonium cations, one succcinate dianion and one neutral succinic acid molecule. Succinate dianions and succinic acid molecules are self-assembled head-to-tail through O—H...O hydrogen bonds and adopt a syn–syn configuration, leading to a strand-like arrangement along [101]. The cyclohexylammonium cations have a chair conformation and act as multidentate hydrogen-bond donors linking adjacent strands through intermolecular N—H...O interactions to both the succinate and the succinic acid components. This results in two-dimensional supramolecular layered structures lying parallel to (010.

  17. Crystal and molecular structure of adduct of 6-benzylaminopurine and 5-sulfosalicylic acid

    International Nuclear Information System (INIS)

    The crystal structure of adduct of 6-benzylaminopurine and 5-sulfosalicylic acid C19H25N5O10S 1 is studied using single-crystal diffraction (R = 0.0482 for 2852 reflections with I > 2σ(I)). The asymmetric unit of 1 contains one 6-benzylaminopurine molecule and one 5-sulfosalicylic acid molecule, as well as four lattice water molecules. Hydrogen bonds, formed by 6-benzylaminopurine and 5-sulfosalicylic acid, link the two molecules into one-dimensional chain (omitting four water molecules), further joined to two-dimensional layer network. Short ring-interactions with intra-chain π-π stacking are observed. The data of IR spectroscopy confirm the formation of the two-dimensional supramolecular layer structure. At last, a 3D supramolecular network constructs via hydrogen bonds.

  18. Main group adducts of carbon dioxide and related chemistry (LDRD 149938).

    Energy Technology Data Exchange (ETDEWEB)

    Barry, Brian M. (University of New Mexico, Albuquerque, NM); Kemp, Richard Alan; Stewart, Constantine A.; Dickie, Diane A. (University of New Mexico, Albuquerque, NM)

    2010-11-01

    This late-start LDRD was broadly focused on the synthetic attempts to prepare novel ligands as complexing agents for main group metals for the sequestration of CO{sub 2}. In prior work we have shown that certain main group (p block elements) metals such as tin and zinc, when ligated to phosphinoamido- ligands, can bind CO{sub 2} in a novel fashion. Rather than simple insertion into the metal-nitrogen bonds to form carbamates, we have seen the highly unusual complexation of CO{sub 2} in a mode that is more similar to a chemical 'adduct' rather than complexation schemes that have been observed previously. The overarching goal in this work is to prepare more of these complexes that can (a) sequester (or bind) CO{sub 2} easily in this adduct form, and (b) be stable to chemical or electrochemical reduction designed to convert the CO{sub 2} to useful fuels or fuel precursors. The currently used phosphinoamido- ligands appear at this point to be less-stable than desired under electrochemical reduction conditions. This instability is believed due to the more delicate, reactive nature of the ligand framework system. In order to successfully capture and convert CO{sub 2} to useful organics, this instability must be addressed and solved. Work described in the late-start LDRD was designed to screen a variety of ligand/metal complexes that a priori are believed to be more stable to polar solvents and possible mild hydrolytic conditions than are the phosphinoamido-ligands. Results from ligand syntheses and metal complexation studies are reported.

  19. Direct relationship between radiobiological hypoxia in tumors and monoclonal antibody detection of EF5 cellular adducts.

    Science.gov (United States)

    Lee, J; Siemann, D W; Koch, C J; Lord, E M

    1996-07-29

    While the potential importance of hypoxia in limiting the sensitivity of tumor cells to ionizing radiation has long been appreciated, methods for accurately quantifying the number of radiation-resistant hypoxic cells within tumors have been lacking. We have used the pentafluorinated derivative [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acet amide] of etanidazole (EF5), which binds selectively to hypoxic cells. The adducts formed between EF5 and cellular proteins in the hypoxic cells were detected using the specific monoclonal antibody (MAb), ELK3-51 conjugated to the flurochrome Cy3, and the number of hypoxic cells was quantified by flow cytometry. To verify the validity of this technique for the detection of hypoxic cells, mice bearing KHT sarcomas were treated with various agents to alter tumor oxygenation and hence vary the fraction of radiobiologically hypoxic tumor cells. The percentage of EF5 binding cells was then compared directly with the clonogenic survival of the tumor cells following radiation treatment under the various pretreatment conditions. The results showed that allowing the mice to breathe carbogen (5% CO2/95% O2) prior to irradiation reduced clonogenic cell survival approx. 6-fold and led to an absence of cells binding high levels of EF5. In contrast, pretreating the tumor-bearing animals with either hydralazine, which decreased tumor blood flow, or phenylhydrazine hydrochloride, which made the mice anemic, increased tumor cell survival following irradiation 2- to 4-fold, indicative of an increase in the fraction of hypoxic tumor cells. EF5 measurements made under identical conditions illustrated a shift in the cells in the tumor to high EF5 binding. Our results demonstrate that flow cytometric measurement by fluorescent MAb binding to EF5 adducts may relate directly to radiobiological hypoxia in KHT tumors measured by conventional methods. PMID:8707411

  20. A fenestration approach to arytenoid adduction for unilateral vocal cord paralysis. Results of 32 cases

    International Nuclear Information System (INIS)

    The objective of this study was to develop and evaluate the voice outcomes of an approach to arytenoid adduction (AA) for unilateral vocal cord paralysis through fenestration of the thyroid ala. Thirty-two patients with unilateral vocal cord paralysis underwent laryngoplasty using an approach to AA performed through fenestration of the thyroid ala combined with type I thyroplasty. Thirty-two patients with unilateral vocal cord paralysis were treated between October 2004 and February 2008. In all cases, maximum phonation time (MPT) and mean airflow rate (MFR) were measured before and after the operation. The voices were analyzed using shimmer and jitter. Two surgical windows were made in the lower part of the thyroid ala. The anterior one was for typical type I thyroplasty and the posterior one was for arytenoid adduction (AA). The locations of the two windows were determined based on three-dimensional computer tomography (3DCT) data. AA was performed by muscular process through the posterior window without releasing the cricothyroid joint. The operations were performed under local anesthesia with sedation. Vocal cord medialization was confirmed endoscopically during the operation. Twenty-nine of the 32 patients achieved an MPT of over 10 s after surgery. The other 3 cases, whose MPTs were 9 s after the operation, had low breathing capacity because of lung disease and normal side vocal cord sulcus. The MFRs, which ranged from 236 to 1908 ml/s before the operation, improved to under 200 ml/s except in 3 patients, whose MFRs were 210 ml/s, 214 ml/s and 216 ml/s. Jitter and shimmer improved significantly after the operation. Perceptual evaluation using the GRBAS scale also improved significantly. Our new procedure simplified the combination of AA and type I thyroplasty because the two treatments can be performed in the same operating field, obtaining good voice improvement. Determination of the surgical approach using 3DCT and endoscopic vocal cord observation may

  1. Determination of the major tautomeric form of the covalently modified adenine in the (+)-CC-1065-DNA adduct by 1H and 15N NMR studies

    International Nuclear Information System (INIS)

    (+)-CC-1065 is an extremely potent antitumor antibiotic produced by Streptomyces zelensis. The potent cytotoxic effects of the drug are thought to be due to the formation of a covalent adduct with DNA through N3 of adenine. Although the covalent linkage sites between (+)-CC-1065 and DNA have been determined, the tautomeric form of the covalently modified adenine in the (+)-CC-1065-DNA duplex adduct was not defined. The [6-15N]deoxyadenosine-labeled 12-mer duplex adduct was then studied by 1H and 15N NMR. One-dimensional NOE difference and two-dimensional NOESY 1H NMR experiments on the nonisotopically labeled 12-mer duplex adduct demonstrate that the 6-amino protons of the covalently modified adenine exhibit two signals at 9.19 and 9.08 ppm. Proton NMR experiments on the [6-15N]deoxyadenosine-labeled 12-mer duplex adduct show that the two resonance signals for adenine H6 observed on the nonisotopically labeled duplex adduct were split into doublets by the 15N nucleus with coupling constants of 91.3 Hz for non-hydrogen-bonded and 86.8 Hz for hydrogen-bonded amino protons. The authors conclude that the covalently modified adenine N6 of the (+)-CC-1065-12-mer duplex adduct is predominantly in the doubly protonated form, in which calculations predict that the C6-N6 bond is shortened and the positive charge is delocalized over the entire adenine molecule

  2. Screening for DNA adducts by data-dependent constant neutral loss-triple stage mass spectrometry with a linear quadrupole ion trap mass spectrometer.

    Science.gov (United States)

    Bessette, Erin E; Goodenough, Angela K; Langouët, Sophie; Yasa, Isil; Kozekov, Ivan D; Spivack, Simon D; Turesky, Robert J

    2009-01-15

    A two-dimensional linear quadrupole ion trap mass spectrometer (LIT/MS) was employed to simultaneously screen for DNA adducts of environmental, dietary, and endogenous genotoxicants, by data-dependent constant neutral loss scanning followed by triple-stage mass spectrometry (CNL-MS3). The loss of the deoxyribose (dR) from the protonated DNA adducts ([M + H - 116]+) in the MS/MS scan mode triggered the acquisition of MS3 product ion spectra of the aglycone adducts [BH2]+. Five DNA adducts of the tobacco carcinogen 4-aminobiphenyl (4-ABP) were detected in human hepatocytes treated with 4-ABP, and three DNA adducts of the cooked-meat carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) were identified in the livers of rats exposed to MeIQx, by the CNL-MS3 scan mode. Buccal cell DNA from tobacco smokers was screened for DNA adducts of various classes of carcinogens in tobacco smoke including 4-ABP, 2-amino-9H-pyrido[2,3-b]indole (AalphaC), and benzo[a]pyrene (BaP); the cooked-meat carcinogens MeIQx, AalphaC, and 2-amino-1-methyl-6-phenylmidazo[4,5-b]pyridine (PhIP); and the lipid peroxidation products acrolein (AC) and trans-4-hydroxynonenal (HNE). The CNL-MS3 scanning technique can be used to simultaneously screen for multiple DNA adducts derived from different classes of carcinogens, at levels of adduct modification approaching 1 adduct per 108 unmodified DNA bases, when 10 microg of DNA is employed for the assay. PMID:19086795

  3. Proceedings of a workshop on DNA adducts: Biological significance and applications to risk assessment Washington, DC, April 13-14, 2004

    International Nuclear Information System (INIS)

    In April 2004, the Health and Environmental Sciences Institute, a branch of the International Life Sciences Institute, with support from the National Institute of Environmental Health Sciences, organized a workshop to discuss the biological significance of DNA adducts. Workshop speakers and attendees included leading international experts from government, academia, and industry in the field of adduct detection and interpretation. The workshop initially examined the relationship between measured adduct levels in the context of exposure and dose. This was followed by a discussion on the complex response of cells to deal with genotoxic insult in complex, interconnected, and interdependent repair pathways. One of the major objectives of the workshop was to address the recurring question about the mechanistic and toxicological relevance of low-concentration measured adducts and the presentations in the session entitled 'Can low levels of DNA adducts predict adverse outcomes?' served as catalysts for further discussions on this subject during the course of the workshop. Speakers representing the regulatory community and industry reviewed the value, current practices, and limitations of utilizing DNA adduct data in risk assessment and addressed a number of practical questions pertaining to these issues. While no consensus statement emerged on the biological significance of low levels of DNA adducts, the workshop concluded by identifying the need for more experimental data to address this important question. One of the recommendations stemming from this workshop was the need to develop an interim 'decision-logic' or framework to guide the integration of DNA adduct data in the risk assessment process. HESI has recently formed a subcommittee consisting of experts in the field and other key stakeholders to address this recommendation as well as to identify specific research projects that could help advance the understanding of the biological significance of low levels of DNA

  4. Non-covalent nano-adducts of co-poly(ester amide) and poly(ethylene glycol): preparation, characterization and model drug-release studies.

    Science.gov (United States)

    Legashvili, Irakli; Nepharidze, Nino; Katsarava, Ramaz; Sannigrahi, Biswajit; Khan, Ishrat M

    2007-01-01

    Biodegradable, biocompatible poly(ester amide)s (co-PEAs), composed of amino acids, fatty diols and carboxylic acids, have been synthesized. To improve the performance of co-PEAs in Federal Drug Administration-approved solvents such as water and ethanol, these polymers were complexed with poly(ethylene glycol) (PEG) of 10 kDa molecular mass have been prepared by solution blending. The non-covalent adducts were purified by precipitation into hexanes. Co-PEAs are soluble in organic solvents but are insoluble in water and ethanol; however, the co-PEA/PEG (0.8:1, w/w) adducts are soluble in ethanol and slightly soluble in water. 2D-NOESY NMR spectroscopy suggests that the non-covalent adducts are held together by multiple non-covalent interactions between the -CH2- groups of the two polymers (co-PEA and PEG). Differential scanning calorimetry studies indicate that the two polymers are interacting in the non-covalent adducts; the thermal properties of the adducts are different from those of the pure polymers. The solid-state adduct structures have been determined by atomic force microscopy (AFM). By one sample preparation method, nanoscale pancake-like structures were observed with an average diameter of 260 nm and an average height of 16 nm. Films of co-PEAs and (co-PEA)/PEG adducts containing Rhodamine B Base (RhBB), a model hydrophobic drug, were prepared. From the adduct/RhBB film containing 3% RhBB, 20% of the total RhBB was released within the first 2 h. Film and adduct composition may be varied to obtain different release profiles. The studies reported here demonstrate that non-covalent conjugation is a relatively easy and effective approach in developing new materials for application as biomaterials. PMID:17623550

  5. 113Cd NMR studies of a 1:1 Cd adduct with an 18-residue finger peptide from HIV-1 nucleic acid binding protein, p7

    International Nuclear Information System (INIS)

    The Zn2+ and Cd2+ adducts with the 18-residue peptide comprising the amino acid sequence of the first finger (residues 13 through 30) of retroviral nucleic acid binding proteins p7 from HIV-1 (the causative agent of AIDS) have been prepared. 1H NMR data indicate that the metal adducts are 1:1 compounds that are stable in aqueous solutions for at least a month. The 113Cd NMR spectral results for the adduct are presented and analyzed. 26 references, 3 figures

  6. DNA adducts, benzo(a)pyrene monooxygenase activity, and lysosomal membrane stability in Mytilus galloprovincialis from different areas in Taranto coastal waters (Italy)

    International Nuclear Information System (INIS)

    The aim of this study was to investigate the impact of environmental pollution at different stations along the Taranto coastline (Ionian Sea, Puglia, Italy) using several biomarkers of exposure and the effect on mussels, Mytilus galloprovincialis, collected in October 2001 and October 2002. Five sampling sites were compared with a 'cleaner' reference site in the Aeronautics Area. In this study we also investigated the differences between adduct levels in gills and digestive gland. This Taranto area is the most significant industrial settlement on the Ionian Sea known to be contaminated by polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, heavy metals, etc. Exposure to PAHs was evaluated by measuring DNA adduct levels and benzo(a)pyrene monooxygenase activity (B(a)PMO); DNA adducts were analyzed by 32P-postlabeling with nuclease P1 enhancement in both gills and digestive glands to evaluate differences between DNA adduct levels in the two tissues. B(a)PMO was assayed in the microsomal fraction of the digestive glands as a result of the high expression of P450-metabolizing enzymes in this tissue. Lysosomal membrane stability, a potential biomarker of anthropogenic stress, was also evaluated in the digestive glands of mussels, by measuring the latent activity of β-N-acetylhexosaminidase. Induction of DNA adducts was evident in both tissues, although the results revealed large tissue differences in DNA adduct formation. In fact, gills showed higher DNA adduct levels than did digestive gland. No significant differences were found in DNA adduct levels over time, with both tissues providing similar results in both years. DNA adduct levels were correlated with B(a)PMO activity in digestive gland in both years (r=0.60 in 2001; r=0.73 in 2002). Increases were observed in B(a)PMO activity and DNA adduct levels at different stations; no statistical difference was observed in B(a)PMO activity over the two monitoring campaigns. The membrane labilization period

  7. Effects of Push-up Exercise with Hip Adduction on the COP Deviation and the Serratus Anterior and L1 Paraspinal Muscles

    OpenAIRE

    Kim, Min-Hee; Yoo, Won-Gyu

    2013-01-01

    [Purpose] This study investigated the effect of push-up exercise with hip adduction on the COP deviation and SA and L1 spinal muscle activation. [Subjects] Twelve males aged 20–30 years were recruited. [Methods] We measured the COP deviation and SA and L1 spinal muscle activities during push-up exercise with and without hip adduction [Results] The COP deviation significantly decreased and the SA and L1 spinal muscles were significantly increased during push-ups with hip adduction when compare...

  8. Tissue differences, dose-response relationship and persistence of DNA adducts in blue mussels (Mytilus edulis L.) exposed to benzo[a]pyrene

    International Nuclear Information System (INIS)

    Baltic Sea blue mussels (Mytilus edulis) were experimentally exposed to the genotoxic model substance benzo[a]pyrene (B[a]P) to study DNA adduct formation. The specific aims were (a) to examine where in the mussels the DNA adducts were formed, in gills or digestive gland; (b) to study the dose-response relationship between B[a]P exposure and DNA adduct formation; and (c) to examine the persistence of the formed adducts. A Scope for growth (SFG) study was also run to compare physiological responses of the mussels with the degree of DNA adduct formation. In an initial dose-response experiment, the mussels were exposed to 0, 5, 50, and 100 μg/l of tritium labelled B[a]P under semi-static conditions for 4 days, and thereafter the bioaccumulation of B[a]P and DNA adduct formation in different tissues was determined using liquid scintillation counting and 32P-postlabelling analysis, respectively. In a following exposure-depuration experiment, mussels were exposed to 17 μg/l of radiolabelled B[a]P under semi-static conditions for 6 days. B[a]P accumulation and DNA adduct formation were determined during the exposure, and B[a]P elimination and persistence of DNA adducts were studied during 28 days of depuration in uncontaminated water. The results revealed large tissue differences in DNA adduct formation. DNA adduct levels were not elevated in the digestive gland of the mussels at any exposure concentration (0-100 μg/l), even though the highest B[a]P tissue concentrations were found in the digestive gland (1.0±0.1 mg B[a]P/g tissue dry wt at 100 μg/l, mean±SE, n=12). DNA adducts were on the other hand formed in the gills, with the highest levels found in mussels exposed to 50 and 100 μg B[a]P/l, and a dose dependent increase in adduct levels (from 1.6 to 5.9 nmol adducts/mol nucleotides) from 0 to 50 μg B[a]P/l. In gills, DNA adduct levels increased with time during the 6-day exposure period in the exposure-depuration experiment, and then persisted for at least 2

  9. SEPARATION AND CHARACTERIZATION OF TETROL METABOLITES OF BENZO[A]PYRENE-DNA ADDUCTS USING HPLC AND SOLID-MATRIX ROOM TEMPERATURE LUMINESCENCE. (R824100)

    Science.gov (United States)

    AbstractFour tetrols of benzo[a]pyrene-DNA adducts were separated using reversed-phase high performance liquid chromatography. Chromatographic fractions containing a given tetrol were readily characterized with solid-matrix room temperature luminescence techniques. So...

  10. S-adenosyl-L-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry

    International Nuclear Information System (INIS)

    Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-L-methionine (SAMe) treatment 1 hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n = 5/group) were divided into the following groups and treated as indicated: Veh (15 ml/kg water, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg), and SAMe given 1 h after APAP (S + A). APAP toxicity was confirmed by an increase (p < 0.05) in plasma ALT (U/l) and liver weight/10 g body weight relative to the Veh, SAMe and S + A groups 4 h following APAP treatment. SAMe administered 1 h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10 g body weights were lower in the S + A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S + A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1. - Highlights: • Acetaminophen (APAP) toxicity protected by S-adenosylmethionine (SAMe) • 4-Hydroxynonenal adducted to sarcosine dehydrogenase • 4-Hydroxynonenal adducted to carbamoyl phosphate synthetase-1 • SAMe reduced APAP mediated CPS-1 mitochondrial leakage

  11. Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling.

    Science.gov (United States)

    Punt, Ans; Paini, Alicia; Spenkelink, Albertus; Scholz, Gabriele; Schilter, Benoit; van Bladeren, Peter J; Rietjens, Ivonne M C M

    2016-04-18

    Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions. PMID:26952143

  12. S-adenosyl-L-methionine protection of acetaminophen mediated oxidative stress and identification of hepatic 4-hydroxynonenal protein adducts by mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Brown, James Mike [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States); Kuhlman, Christopher [Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, AZ (United States); Terneus, Marcus V. [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States); Labenski, Matthew T. [Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, AZ (United States); Lamyaithong, Andre Benja; Ball, John G. [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States); Lau, Serrine S. [Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, AZ (United States); Valentovic, Monica A., E-mail: Valentov@marshall.edu [Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Huntington, WV (United States)

    2014-12-01

    Acetaminophen (APAP) hepatotoxicity is protected by S-adenosyl-L-methionine (SAMe) treatment 1 hour (h) after APAP in C57/Bl6 mice. This study examined protein carbonylation as well as mitochondrial and cytosolic protein adduction by 4-hydroxynonenal (4-HNE) using mass spectrometry (MS) analysis. Additional studies investigated the leakage of mitochondrial proteins and 4-HNE adduction of these proteins. Male C57/Bl6 mice (n = 5/group) were divided into the following groups and treated as indicated: Veh (15 ml/kg water, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg), and SAMe given 1 h after APAP (S + A). APAP toxicity was confirmed by an increase (p < 0.05) in plasma ALT (U/l) and liver weight/10 g body weight relative to the Veh, SAMe and S + A groups 4 h following APAP treatment. SAMe administered 1 h post-APAP partially corrected APAP hepatotoxicity as ALT and liver weight/10 g body weights were lower in the S + A group compared the APAP group. APAP induced leakage of the mitochondrial protein, carbamoyl phosphate synthase-1 (CPS-1) into the cytosol and which was reduced in the S + A group. SAMe further reduced the extent of APAP mediated 4-HNE adduction of CPS-1. MS analysis of hepatic and mitochondrial subcellular fractions identified proteins from APAP treated mice. Site specific 4-HNE adducts were identified on mitochondrial proteins sarcosine dehydrogenase and carbamoyl phosphate synthase-1 (CPS-1). In summary, APAP is associated with 4-HNE adduction of proteins as identified by MS analysis and that CPS-1 leakage was greater in APAP treated mice. SAMe reduced the extent of 4-HNE adduction of proteins as well as leakage of CPS-1. - Highlights: • Acetaminophen (APAP) toxicity protected by S-adenosylmethionine (SAMe) • 4-Hydroxynonenal adducted to sarcosine dehydrogenase • 4-Hydroxynonenal adducted to carbamoyl phosphate synthetase-1 • SAMe reduced APAP mediated CPS-1 mitochondrial leakage.

  13. New approaches for synthesis and analysis of adducts to N-terminal valine in hemoglobin from isocyanates, aldehydes, methyl vinyl ketone and diepoxybutane

    OpenAIRE

    Davies, Ronnie

    2009-01-01

    Human exposure to harmful compounds in the environment, from intake via food, occupational exposures or other sources, could have health implications. Exposure to reactive compounds/metabolites can be identified and quantified as hemoglobin (Hb) adducts by mass spectrometry. This thesis aimed at improved synthetic pathways for reference standards, and improved analytical methods for adducts to N-terminal valine in Hb from a range of reactive compounds; isocyanates, aldehydes, methyl vinyl ket...

  14. Simultaneous Screening of Glutathione and Cyanide Adducts Using Precursor Ion and Neutral Loss Scans-Dependent Product Ion Spectral Acquisition and Data Mining Tools

    Science.gov (United States)

    Jian, Wenying; Liu, Hua-Fen; Zhao, Weiping; Jones, Elliott; Zhu, Mingshe

    2012-05-01

    Drugs can be metabolically activated to soft and hard electrophiles, which are readily trapped by glutathione (GSH) and cyanide (CN), respectively. These adducts are often detected and structurally characterized using separate tandem mass spectrometry methods. We describe a new method for simultaneous screening of GSH and CN adducts using precursor ion (PI) and neutral loss (NL) scans-dependent product ion spectral acquisition and data mining tools on an triple quadrupole linear ion trap mass spectrometry. GSH, potassium cyanide, and their stable isotope labeled analogues were incubated with liver microsomes and a test compound. Negative PI scan of m/z 272 for detection of GSH adducts and positive NL scans of 27 and 29 Da for detection of CN adducts were conducted as survey scans to trigger acquisition of enhanced resolution (ER) spectrum and subsequent enhanced product ion (EPI) spectrum. Post-acquisition data mining of EPI data set using NL filters of 129 and 27 Da was then performed to reveal the GSH adducts and CN adducts, respectively. Isotope patterns and EPI spectra of the detected adducts were utilized for identification of their molecular weights and structures. The effectiveness of this method was evaluated by analyzing reactive metabolites of nefazodone formed from rat liver microsomes. In addition to known GSH- and CN-trapped reactive metabolites, several new CN adducts of nefazodone were identified. The results suggested that current approach is highly effective in the analysis of both soft and hard reactive metabolites and can be used as a high-throughput method in drug discovery.

  15. Synthesis of oxa-bridged derivatives from Diels–Alder bis-adducts of butadiene and 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene

    Directory of Open Access Journals (Sweden)

    Faiz Ahmed Khan

    2010-06-01

    Full Text Available Bis-adducts of 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene and 1,3-butadiene, generated in situ from 3-sulfolene, have been synthesized in excellent yield. Ruthenium catalyzed oxidation of the bis-adducts followed by a one-pot transformation of the resulting α-diketone furnished oxa-bridged compounds. Unambiguous stereochemical assignments of both diastereomeric series are reported.

  16. 32P-post-labelling analysis of DNA adducts formed in the upper gastrointestinal tissue of mice fed bracken extract or bracken spores.

    OpenAIRE

    A. C. Povey; D. Potter; O'Connor, P J

    1996-01-01

    Bracken toxicity to both domestic and laboratory animals is well established and tumours are formed when rodents are treated with either bracken extracts or bracken spores. In this study we have administered bracken spores and extract to mice in order to investigate whether such exposure leads to the formation of DNA adducts. DNA, isolated from the upper gastrointestinal tract and liver, was digested to 3'-nucleotides. Adducts were extracted with butanol, 32P-post-labelled, separated by thin ...

  17. Enhanced recognition of spin trapped radicals in complex mixtures: Deuterated nitronyl adducts provide a gas chromatographic/mass spectrometric marker

    International Nuclear Information System (INIS)

    The use of deuterated analogues of α-phenyl-N-tert-butyl nitrone (PBN) are reported for GC/MS analysis of spin trapping products. PBN-d9 and PBN-d14, deuterated in the tert-butyl group (the latter also deuterated in the phenyl ring), result in a more diagnostic fragment ion, C4D9+ (m/z = 66) which improves the recognition of PBN adducts in mixtures. This feature has helped identify a new 1,3-radical addition product of PBN-d9 formed during azobis(isobutyronitrile) thermolysis (addition of 2-cyano-2-propyloxyl followed by 2-cyano-2-propyl radicals). The 13C-trichloromethyl radical adduct of PBN-d14 produced during 13C-carbon tetrachloride incubation with rat liver microsomes was identified by GC/MS in a complicated biological extract mixture. 25 refs., 3 figs., 1 tab

  18. Biomonitoring of diesel exhaust-exposed workers. DNA and hemoglobin adducts and urinary 1-hydroxypyrene as markers of exposure

    DEFF Research Database (Denmark)

    Nielsen, Per Sabro; Andreassen, Åshild; Farmer, Peter B.;

    1996-01-01

    Diesel exhaust-exposed workers have been shown to have an increased risk of lung cancer. A battery of biomarkers were evaluated for their ability to assess differences in exposure to genotoxic compounds in bus garage workers and mechanics and controls. Lymphocyte DNA adducts were analyzed using t....... The study indicated that skin absorption of polycyclic aromatic hydrocarbons (PAH) might be an important factor to consider when studying PAH exposure from air pollution sources....... correlated with HPU but not with DNA adducts. The levels of HPU in urine were 0.11 micromol/mol creatinine compared to 0.05 in controls. All three assays applied were sensitive enough to evaluate a low level of exposure to environmental pollutants, with postlabelling and GC-MS as the most sensitive assays...

  19. Structure of cis-[Pt(NH3)(2-picoline)]2+ and DNA adduct and its bonding characteristics

    Institute of Scientific and Technical Information of China (English)

    JIA; Muxin; LIU; Kai; YANG; Zuoyin; CHEN; Guangju

    2004-01-01

    Several methods including molecular mechanics, molecular dynamics, ONIOM that combines quantum chemistry with molecular mechanics and standard quantum chemistry are used to study the configuration and electron structures of an adduct of the DNA segment d(ATACATG*G*TACATA)·d(TATGTACCATGTAT) with cis-[Pt(NH3)(2-Picoline)]2+. The investigation shows that the configuration optimized by ONIOM is similar to that determined by NMR. Strong chemical bonds between Pt of the complex and two N7s of neighboring guanines in the DNA duplex and hydrogen bond between the NH3 of the complex and O6 of a nearby guanine have a large impact on the configuration of the adduct. Chemical bonds, the aforementioned hydrogen bond, and the interaction between a methyl of the complex and a methyl of the base in close proximity are critical for the complex to specifically recognize DNA.

  20. The importance of Pyr(6-4)Pyo adducts for survival and mutation induction in mammalian cells

    International Nuclear Information System (INIS)

    The biological consequences of a variety of DNA photoproducts are being studied in Chinese hamster ovary cells. By comparing the rate of induction of resistance to 6-thioguanine following irradiation at 254 nm and 313 nm, the authors find a similar mutation rate at equitoxic doses. Thus, enhanced mutation frequency does not appear to be a consequence of Pyr(6-4)Pyo adducts, which are produced at 254 nm but not at 313 nm. When the level of dimerised photoproducts is measured in a radioimmunoassay, Pyr(6-4)Pyo adducts, which are highly antigenic, are readily detected. By comparing the kinetics of removal of antibody-binding sites following irradiation at 254mn and 313 nm, it is evident that these lesions are repaired at the same rate as cyclobutane dimers

  1. Nitric acid adduct formation during crystallization of barium and strontium nitrates and their co-precipitation from nitric acid media

    International Nuclear Information System (INIS)

    The molar solubilities of Ba, Sr and Pb nitrates in nitric acid as a function of total nitrate concentration is presented and described by the mass action law, indicating on formation of the adducts with nitric acid. Precipitates of Ba(NO3)2 and Sr(NO3)2 crystallized from nitric acid were studied by ISP OES and IR spectroscopy. The data obtained confirmed formation of metastable adducts with nitric acid. IR and X-ray diffraction studies of the mixed salt systems indicated conversion of the mixed salts into (Ba,Sr)(NO3)2 solid solution of discrete structure in range of total nitrate ion concentration ∼6 mol/L. (author)

  2. Synthesis and activity of novel homodimers of Morita-Baylis-Hillman adducts against Leishmania donovani: A twin drug approach.

    Science.gov (United States)

    da Silva, Wagner A V; Rodrigues, Daniele C; de Oliveira, Ramon G; Mendes, Rhuan K S; Olegário, Tayná R; Rocha, Juliana C; Keesen, Tatjana S L; Lima-Junior, Claudio G; Vasconcellos, Mário L A A

    2016-09-15

    It is reported here the synthesis of novel Homodimers 12-19 of Morita-Baylis-Hillman adducts (MBHA) from one-pot Morita-Baylis-Hillman Reaction (MBHR) between aromatic aldehydes as eletrophiles and ethylene glycol diacrylate as Michael acceptor (35-94% yields) using cheap and green conditions. The bioactivities were evaluated against promastigote form of Leishmania donovani. All homodimers showed to be more potent than corresponding monomers. It is worth highlighting that the halogenated homodimers 17 and 18 (0.50μM) is almost 400 times more active than the corresponding monomer 10 and 1.24 times more potent than the second-line drug amphotericin B (0.62μM). Moreover, the selectivity index to 18 is very high (SIrb>400) far better than amphotericin B (SIrb=18.73). This is the first report of twin drugs strategy applied on Morita-Baylis-Hillman adducts. PMID:27520941

  3. DNA adduct formation and induction of apoptosis in rat liver epithelial "stem-like" cells exposed to carcinogenic PAHs

    Czech Academy of Sciences Publication Activity Database

    Topinka, Jan; Sevastyanova, Oksana; Marvanová, S.; Vondráček, Jan; Nováková, Zuzana; Krčmář, P.; Pěnčíková, K.; Machala, M.

    Los Angeles, 2007. s. 1. [Annual Meeting 2007. 14.04.2007-18.04.2007, Los Angeles] R&D Projects: GA AV ČR(CZ) KJB6004407 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702; CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : DNA adducts * cytochromes P450 * cytotoxicity Subject RIV: BO - Biophysics

  4. Analysis of DNA adducts of some low molecular weight aldehydes : Methods development and application in human biomonitoring

    OpenAIRE

    Fang, Jia-Long

    1997-01-01

    Doctoral Thesis present at the Karolinska Institute, 1997 Center for Nutrition and Toxicology Departrnent of Biosciences at NOVUM Karolinska Institute 141 57 Huddinge Malondialdehyde (MA), acetaldehyde (Aa) and methylglyoxal (MG) are ubiquitously present in the environment and endogenously forrned in animals and humans. They have been shown to be genotoxic and to readily react with DNA to form DNA adducts under physiological conditions. The present studies ...

  5. NEW HYDROGENOMOLYBDATO SnPh2 AND SnPh3 RESIDUE CONTAINING ADDUCT AND DERIVATIVE: SYNTHESIS AND INFRARED STUDY

    Directory of Open Access Journals (Sweden)

    SERIGNE FALLOU POUYE

    2014-08-01

    Full Text Available Three new organostannic complex, adduct and derivative have been synthesized and studied by infrared. Dimeric structures involving the cations were suggested on the basis of infrared data. The molybdate anion behaves as a non coordinating ligand-only involved in hydrogen bonds-, mono- or bicoordinating and always involved in hydrogen bonds. The environment of the tin centres is trigonal bipyramidal or octahedral.

  6. The 1:1 adduct of caffeine and 2-(1,3-dioxoisoindolin-2-yl)acetic acid

    Science.gov (United States)

    Bhatti, Moazzam H.; Yunus, Uzma; Saeed, Sohail; Shah, Syed Raza; Wong, Wing-Tak

    2011-01-01

    In the crystal structure of the title adduct [systematic name: 2-(1,3-dioxoisoindolin-2-yl)acetic acid–1,3,7-trimethyl-1,2,3,6-tetra­hydro-7H-purine-2,6-dione (1/1)], C8H10N4O2·C10H7NO4, the components are linked by an O—H⋯N hydrogen-bond and no proton transfer occurs. PMID:22058908

  7. The 1:1 adduct of caffeine and 2-(1,3-dioxoisoindolin-2-yl)acetic acid

    OpenAIRE

    Bhatti, Moazzam H.; Uzma Yunus; Sohail Saeed; Syed Raza Shah; Wing-Tak Wong

    2011-01-01

    In the crystal structure of the title adduct [systematic name: 2-(1,3-dioxoisoindolin-2-yl)acetic acid–1,3,7-trimethyl-1,2,3,6-tetrahydro-7H-purine-2,6-dione (1/1)], C8H10N4O2·C10H7NO4, the components are linked by an O—H...N hydrogen-bond and no proton transfer occurs.

  8. The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

    OpenAIRE

    Poljaková, Jitka; Eckschlager, Tomáš; Hraběta, Jan; Hřebačková, Jana; Smutný, Svatopluk; Frei, Eva; Martínek, Václav; Kizek, René; Stiborová, Marie

    2009-01-01

    Abstract Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the ...

  9. Determination of ginsenoside compound K in human plasma by liquid chromatography–tandem mass spectrometry of lithium adducts

    Directory of Open Access Journals (Sweden)

    Yunhui Chen

    2015-09-01

    Full Text Available Ginsenoside compound K (GCK, the main metabolite of protopanaxadiol constituents of Panax ginseng, easily produces alkali metal adduct ions during mass spectrometry particularly with lithium. Accordingly, we have developed a rapid and sensitive liquid chromatography–tandem mass spectrometric method for analysis of GCK in human plasma based on formation of a lithium adduct. The analyte and paclitaxel (internal standard were extracted from 50 µL human plasma using methyl tert-butyl ether. Chromatographic separation was performed on a Phenomenex Gemini C18 column (50 mm×2.0 mm; 5 μm using stepwise gradient elution with acetonitrile–water and 0.2 mmol/L lithium carbonate at a flow rate of 0.5 mL/min. Detection was performed in the positive ion mode using multiple reaction monitoring of the transitions at m/z 629→449 for the GCK-lithium adduct and m/z 860→292 for the adduct of paclitaxel. The assay was linear in the concentration range 1.00–1000 ng/mL (r2>0.9988 with intra- and inter-day precision of ±8.4% and accuracy in the range of −4.8% to 6.5%. Recovery, stability and matrix effects were all satisfactory. The method was successfully applied to a pharmacokinetic study involving administration of a single GCK 50 mg tablet to healthy Chinese volunteers.

  10. Specific adduction of plant lipid transfer protein by an allene oxide generated by 9-lipoxygenase and allene oxide synthase

    OpenAIRE

    Bakan, Benedicte; Hamberg, Mats; Perrocheau, Ludivine; Maume, Daniel; Rogniaux, Helene; Tranquet, Olivier; Rondeau, Corinne; Blein, J Pierre; Ponchet, Michel; Marion, Didier

    2006-01-01

    Lipid transfer proteins (LTPs) are ubiquitous plant lipid-binding proteins that have been associated with multiple developmental and stress responses. Although LTPs typically bind fatty acids and fatty acid derivatives in a non-covalent way, studies on the LTPs of barley seeds have identified an abundantly occurring covalently modified form, LTP1b, the lipid ligand of which has resisted clarification. In the present study, this adduct was identified as the {alpha}-ketol 9-hydroxy-10-oxo-12(Z)...

  11. Whole body exposure of mice to secondhand smoke induces dose-dependent and persistent promutagenic DNA adducts in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang-In [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States); Arlt, Volker M. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Yoon, Jae-In [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States); Cole, Kathleen J. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Pfeifer, Gerd P. [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States); Phillips, David H. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Besaratinia, Ahmad, E-mail: ania@coh.org [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States)

    2011-11-01

    Secondhand smoke (SHS) exposure is a known risk factor for lung cancer in lifelong nonsmokers. However, the underlying mechanism of action of SHS in lung carcinogenesis remains elusive. We have investigated, using the {sup 32}P-postlabeling assay, the genotoxic potential of SHS in vivo by determining the formation and kinetics of repair of DNA adducts in the lungs of mice exposed whole body to SHS for 2 or 4 months (5 h/day, 5 days/week), and an ensuing one-month recovery period. We demonstrate that exposure of mice to SHS elicits a significant genotoxic response as reflected by the elevation of DNA adduct levels in the lungs of SHS-exposed animals. The increases in DNA adduct levels in the lungs of SHS-exposed mice are dose-dependent as they are related to the intensity and duration of SHS exposure. After one month of recovery in clean air, the levels of lung DNA adducts in the mice exposed for 4 months remain significantly higher than those in the mice exposed for 2 months (P < 0.0005), levels in both groups being significantly elevated relative to controls (P < 0.00001). Our experimental findings accord with the epidemiological data showing that exposure to smoke-derived carcinogens is a risk factor for lung cancer; not only does the magnitude of risk depend upon carcinogen dose, but it also becomes more irreversible with prolonged exposure. The confirmation of epidemiologic data by our experimental findings is of significance because it strengthens the case for the etiologic involvement of SHS in nonsmokers' lung cancer. Identifying the etiologic factors involved in the pathogenesis of lung cancer can help define future strategies for prevention, early detection, and treatment of this highly lethal malignancy.

  12. Whole body exposure of mice to secondhand smoke induces dose-dependent and persistent promutagenic DNA adducts in the lung

    International Nuclear Information System (INIS)

    Secondhand smoke (SHS) exposure is a known risk factor for lung cancer in lifelong nonsmokers. However, the underlying mechanism of action of SHS in lung carcinogenesis remains elusive. We have investigated, using the 32P-postlabeling assay, the genotoxic potential of SHS in vivo by determining the formation and kinetics of repair of DNA adducts in the lungs of mice exposed whole body to SHS for 2 or 4 months (5 h/day, 5 days/week), and an ensuing one-month recovery period. We demonstrate that exposure of mice to SHS elicits a significant genotoxic response as reflected by the elevation of DNA adduct levels in the lungs of SHS-exposed animals. The increases in DNA adduct levels in the lungs of SHS-exposed mice are dose-dependent as they are related to the intensity and duration of SHS exposure. After one month of recovery in clean air, the levels of lung DNA adducts in the mice exposed for 4 months remain significantly higher than those in the mice exposed for 2 months (P < 0.0005), levels in both groups being significantly elevated relative to controls (P < 0.00001). Our experimental findings accord with the epidemiological data showing that exposure to smoke-derived carcinogens is a risk factor for lung cancer; not only does the magnitude of risk depend upon carcinogen dose, but it also becomes more irreversible with prolonged exposure. The confirmation of epidemiologic data by our experimental findings is of significance because it strengthens the case for the etiologic involvement of SHS in nonsmokers' lung cancer. Identifying the etiologic factors involved in the pathogenesis of lung cancer can help define future strategies for prevention, early detection, and treatment of this highly lethal malignancy.

  13. DNA adducts and oxidative DNA damage induced by organic extracts from PM2.5 in an acellular assay

    Czech Academy of Sciences Publication Activity Database

    Topinka, Jan; Rössner ml., Pavel; Milcová, Alena; Schmuczerová, Jana; Švecová, Vlasta; Šrám, Radim

    2011-01-01

    Roč. 202, č. 3 (2011), s. 186-192. ISSN 0378-4274 R&D Projects: GA MŠk 2B08005; GA MŽP(CZ) SP/1B3/8/08 Institutional research plan: CEZ:AV0Z50390512 Keywords : air pollution * genotoxicity * DNA adducts Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.230, year: 2011

  14. Scapular Notching on Kinematic Simulated Range of Motion After Reverse Shoulder Arthroplasty Is Not the Result of Impingement in Adduction

    OpenAIRE

    Laedermann, Alexandre; Gueorguiev, Boyko; Charbonnier, Caecilia; Stimec, Bojan; Fasel, Jean; Zderic, Ivan; Hagen, Jennifer; Walch, Gilles

    2015-01-01

    Abstract Impingement after reverse shoulder arthroplasty (RSA) is believed to occur from repetitive contact in adduction between the humeral component and the inferior scapular pillar. The primary purpose of this biomechanical study was to confirm the presence of different types of impingement and to examine which daily-life movements are responsible for them. A secondary aim was to provide recommendations on the type of components that would best minimize notching and loss of range of motion...

  15. Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation.

    Science.gov (United States)

    Lee, Hyun-Wook; Wang, Hsiang-Tsui; Weng, Mao-wen; Chin, Chiu; Huang, William; Lepor, Herbert; Wu, Xue-Ru; Rom, William N; Chen, Lung-Chi; Tang, Moon-shong

    2015-10-20

    Second-hand smoke (SHS) is associated with 20-30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL (p < 0.001), lung (p < 0.05), and bladder mucosa (p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair (p < 0.01) and base excision repair (p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly (p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers. PMID:26431382

  16. Structure and spectromagnetic properties of the superoxide radical adduct of DMPO in water: elucidation by theoretical investigations.

    Science.gov (United States)

    Houriez, Céline; Ferré, Nicolas; Siri, Didier; Tordo, Paul; Masella, Michel

    2010-09-16

    In the field of spin trapping chemistry, the design of more efficient radical traps can be assisted by the development of theoretical methods able to give a quantitative evaluation of the electron paramagnetic resonance (EPR) spectrum features of the spin-adduct radical, even before initiating the experimental work. The superoxide radical adduct of the 5,5-dimethyl-1-pyrroline-N-oxide nitrone (DMPO-OOH) has been reported in a huge number of papers devoted to the study of the oxidative stress. Here, we present for the first time the theoretical study of DMPO-OOH in an explicit water solution, based on the combined QM/MM//MD protocol we recently proposed, featuring a full coupling between the solute and all the explicit water molecules. Our results show that the DMPO-OOH EPR spectrum, whose interpretation is still debated, can be explained in the light of two sites in chemical exchange, in agreement with the most recent experimental data. Moreover, we demonstrate that each site consists of an equilibrium between the two main 5-membered ring conformations of DMPO-OOH. We provide also an analysis of the solvent contribution to the hyperfine coupling constants (hcc's) as well as an exhaustive study of the possible relationship between the hcc's and the main structural characteristics of DMPO-OOH. Our QM/MM//MD protocol appears thus to be an accurate theoretical tool allowing the investigation of the magnetic properties of large nitroxide spin adducts in complex environments. PMID:20722404

  17. Effect of Increased Water Intake on Urinary DNA Adduct Levels and Mutagenicity in Smokers: A Randomized Study

    Directory of Open Access Journals (Sweden)

    Inmaculada Buendia Jimenez

    2015-01-01

    Full Text Available The association between fluid intake and bladder cancer risk remains controversial. Very little is known about to which extent the amount of water intake influences the action of excreting toxics upon the urinary system. This proof of concept trial investigates the effect of water intake on mutagenesis in smokers, a high risk population for bladder cancer. Methods. Monocentric randomized controlled trial. Inclusion Criteria. Male subjects aged 2045–45 y/o, smokers, and small drinkers (24-hour urinary volume 700 mOsmol/kg. Outcomes. 4-ABP DNA adducts formation in exfoliated bladder cells in 24-hour urine collection and urinary mutagenicity in 24-hour urine. Test Group. Subjects consumed 1.5 L daily of the study product (EVIAN on top of their usual water intake for 50 days. Control Group. Subjects continued their usual lifestyle habits. Results. 65 subjects were randomized. Mean age was 30 y/o and mean cigarettes per day were 20. A slight decrease in adducts formation was observed between baseline and last visit but no statistically significant difference was demonstrated between the groups. Urinary mutagenicity significantly decreased. The study shows that increasing water intake decreases urinary mutagenicity. It is not confirmed by urinary adducts formation. Further research would be necessary.

  18. Redox proteomic profiling of neuroketal-adducted proteins in human brain: Regional vulnerability at middle age increases in the elderly.

    Science.gov (United States)

    Domínguez, Mayelín; de Oliveira, Eliandre; Odena, María Antonia; Portero, Manuel; Pamplona, Reinald; Ferrer, Isidro

    2016-06-01

    Protein lipoxidation was assessed in the parietal cortex (PC), frontal cortex (FC), and cingulate gyrus (CG) in middle-aged and old-aged individuals with no clinical manifestations of cognitive impairment, in order to increase understanding of regional brain vulnerability to oxidative damage during aging. Twenty-five lipoxidized proteins were identified in all the three regions although with regional specificities, by using redox proteomics to detect target proteins of neuroketals (NKT) adduction. The number of cases with NKT-adducted proteins was higher in old-aged individuals but most oxidized proteins were already present in middle-aged individuals. Differences in vulnerability to oxidation were dependent on the sub-cellular localization, secondary structure, and external exposition of certain amino acids. Lipoxidized proteins included those involved in energy metabolism, cytoskeleton, proteostasis, neurotransmission and O2/CO2, and heme metabolism. Total NKT and soluble oligomer levels were estimated employing slot-blot, and these were compared between age groups. Oligomers increased with age in PC and FC; NKT significantly increased with age in FC, whereas total NKT and oligomer levels were not modified in CG, thus highlighting differences in brain regional vulnerability with age. Oligomers significantly correlated with NKT levels in the three cortical regions, suggesting that protein NKT adduction parallels soluble oligomer formation. PMID:26968793

  19. Effect of Increased Water Intake on Urinary DNA Adduct Levels and Mutagenicity in Smokers: A Randomized Study

    Science.gov (United States)

    Buendia Jimenez, Inmaculada; Richardot, Pascaline; Picard, Pascaline; Lepicard, Eve M.; De Meo, Michel; Talaska, Glenn

    2015-01-01

    The association between fluid intake and bladder cancer risk remains controversial. Very little is known about to which extent the amount of water intake influences the action of excreting toxics upon the urinary system. This proof of concept trial investigates the effect of water intake on mutagenesis in smokers, a high risk population for bladder cancer. Methods. Monocentric randomized controlled trial. Inclusion Criteria. Male subjects aged 2045–45 y/o, smokers, and small drinkers (24-hour urinary volume 700 mOsmol/kg). Outcomes. 4-ABP DNA adducts formation in exfoliated bladder cells in 24-hour urine collection and urinary mutagenicity in 24-hour urine. Test Group. Subjects consumed 1.5 L daily of the study product (EVIAN) on top of their usual water intake for 50 days. Control Group. Subjects continued their usual lifestyle habits. Results. 65 subjects were randomized. Mean age was 30 y/o and mean cigarettes per day were 20. A slight decrease in adducts formation was observed between baseline and last visit but no statistically significant difference was demonstrated between the groups. Urinary mutagenicity significantly decreased. The study shows that increasing water intake decreases urinary mutagenicity. It is not confirmed by urinary adducts formation. Further research would be necessary. PMID:26357419

  20. Regional distribution of xenobiotic metabolizing enzymes and DNA adducts in the respiratory tract - relationship to respiratory epithelial populations

    International Nuclear Information System (INIS)

    Specific regions from one-half of the nasal, tracheal, bronchial, and pulmonary airways of dogs were excised and analyzed for the presence of xenobiotic metabolizing enzymes. Substrates for different isozymes of cytochrome P-450, including benzo[a]pyrene (BaP), nitropyrene (NP), ethoxycoumarin, and ethoxyresorufin as well as selected Phase II enzymes were measured. Experiments were also conducted in which rats were exposed nose-only to dilute diesel exhaust (10 mg particles/m3) for up to 12 weeks. DNA adducts were measured in various regions of the respiratory tract after the 12-week exposure, using the highly sensitive 32P-postlabeling assay. The data indicate that there are significant differences in the metabolic capability and DNA adduct distribution along the respiratory tract. Quantitative differences that were noted along the respiratory tract are probably due to both differences in the capability of a given region to metabolize the organic chemicals associated with diesel exhaust and differences in the deposition patterns of the diesel exhaust. Differences in the metabolic capability, and therefore DNA adduct distribution, along the respiratory tracts of different species could explain, in part, why certain portions of the respiratory tract are more susceptible to tumor formation than are other portions

  1. A new approach to the synthesis of monomers and polymers incorporating furan/maleimide Diels-Alder adducts

    Science.gov (United States)

    Banella, Maria Barbara; Gioia, Claudio; Vannini, Micaela; Colonna, Martino; Celli, Annamaria; Gandini, Alessandro

    2016-05-01

    The Diels-Alder reaction between furan and maleimide moieties is a well-known and widely used strategy to build bio-based macromolecular structures with peculiar properties. The furan-maleimide adducts are thermally reversible because they can be broken above about 120°C and recombined at lower temperatures. At the moment only the monomers exhibiting the furan or the maleimide moieties on their extremity are used in order to get linear or cross-linked polymeric structures. The innovative idea described here consists in using a monomer bearing two carboxylic acidic groups on its extremities and a furan-maleimide Diels-Alder adduct within its structure. This monomer can give rise to classical polycondensation reactions leading to polymers. These polymers (which are polyesters in the present case) can be broken at high temperatures in correspondence of the furane-maleimide Diels-Alder adduct leading to segments exhibiting furan or maleimide moieties at their extremities, which at lower temperature recombine leading to random or block copolymers.

  2. Collision-induced dissociation analysis of negative atmospheric ion adducts in atmospheric pressure corona discharge ionization mass spectrometry.

    Science.gov (United States)

    Sekimoto, Kanako; Takayama, Mitsuo

    2013-05-01

    Collision-induced dissociation (CID) experiments were performed on atmospheric ion adducts [M + R](-) formed between various types of organic compounds M and atmospheric negative ions R(-) [such as O2(-), HCO3(-), COO(-)(COOH), NO2(-), NO3(-), and NO3(-)(HNO3)] in negative-ion mode atmospheric pressure corona discharge ionization (APCDI) mass spectrometry. All of the [M + R](-) adducts were fragmented to form deprotonated analytes [M - H](-) and/or atmospheric ions R(-), whose intensities in the CID spectra were dependent on the proton affinities of the [M - H](-) and R(-) fragments. Precursor ions [M + R](-) for which R(-) have higher proton affinities than [M - H](-) formed [M - H](-) as the dominant product. Furthermore, the CID of the adducts with HCO3(-) and NO3(-)(HNO3) led to other product ions such as [M + HO](-) and NO3(-), respectively. The fragmentation behavior of [M + R](-) for each R(-) observed was independent of analyte type (e.g., whether the analyte was aliphatic or aromatic, or possessed certain functional groups). PMID:23479312

  3. Structural basis for recognition of 5'-phosphotyrosine adducts by TDP2

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Ke; Kurahash, Kayo; Gao, Rui; Tsutakawa, Susan E.; Tainer, John A.; Pommier, Yves; Aihara, Hideki

    2012-12-19

    The DNA repair enzyme TDP2 resolves 5'-phosphotyrosyl-DNA adducts, and is responsible for resistance to anti-cancer drugs that target covalent topoisomerase-DNA complexes. TDP2 also participates in key signaling pathways during development and tumorigenesis, and cleaves a protein-RNA linkage during picornavirus replication. The crystal structure of zebrafish TDP2 bound to DNA reveals a deep and narrow basic groove that selectively accommodates the 5'-end of single-stranded DNA in a stretched conformation. The crystal structure of the full-length C. elegans TDP2 shows that this groove can also accommodate an acidic peptide stretch in vitro, with Glu and Asp sidechains occupying the DNA backbone phosphate binding sites. This extensive molecular mimicry suggests a potential mechanism for auto-regulation and how TDP2 may interact with phosphorylated proteins in signaling. Our study provides a framework to interrogate functions of TDP2 and develop inhibitors for chemotherapeutic and antiviral applications.

  4. SYNTHESIS AND PHARMACOLOGICAL EFFECTS OF BUTADIENE AND CYCLOPENTADIENE ADDUCTS OF METHANDROSTENOLONE IN RATS

    Directory of Open Access Journals (Sweden)

    FAZEL SHAMSA

    2006-06-01

    Full Text Available In this study the reactivity of methandrostenolone or [(17b-17-hydroxy-17-methylandrosta-1, 4-diene-3-one], as a dienophil in a Diels-Alder type cycloaddition reaction was investigated. The purpose of this approach was to investigate whether the 1-dehydro position of methandrostenolone 1 undergoes a cycloaddition reaction with dienes, such as 1, 3 butadiene or cyclopentadiene, and to investigate the biological behavior of the reaction adducts, i.e, compound 3 {(17b-17-hydroxy-17-methyl androsta [1a, 2a] cyclohex 3’, 4-diene-3-one} and compound 4 {(17b-17-hydroxy-17-methyl androsta [1a, 2a] cyclohex (2’,5’ methylene 3’, 4-diene-3-one}, relative to compound 1. The results indicated that thedDiels-Alder reactionddid notpproceed under the usual circumstances of high pressure and temperature, but could proceed in the presence of a Lewis acid (AlCl3. The structures of compounds 3 and 4 were confirmed by spectroscopic methods. The androgenic behavior of compounds 3 and 4 in comparison to compound 1 in the apomorphine test indicated that both compounds were almost devoid of androgenic activity, but prevented apomorphine mediated penile erection in male rats in a similar manner as cyproterone acetate.

  5. Zwitterionic pyrimidinium adducts as antioxidants with therapeutic potential as nitric oxide scavenger.

    Science.gov (United States)

    Barakat, Assem; Al-Majid, Abdullah Mohammed; Al-Najjar, Hany J; Mabkhot, Yahia Nasser; Javaid, Sumaira; Yousuf, Sammer; Choudhary, M Iqbal

    2014-09-12

    A variety of zwitterionic adducts were synthesized by using means green chemistry method. The products contain the biologically active barbituric acid moiety embedded in zwitterion products. Both features are pharmaceutically relevant. The chemical structures were deduced by (1)H-, (13)C-, NMR and HRMS spectral analysis, and X-ray diffraction techniques. In vitro evaluation for the antioxidant activities were carried out towards the inhibition of nitric oxide (NO) radical, known to regulate a mechanism of signals for various cellular functions. NO also play an important role as a mediator of various pathological conditions responsible for cellular damages such as strokes, cancers, diabetes, chronic heart failure and inflammatory disease and various neurodegenerative disorders. All tested compounds were found to be more potent nitric oxide scavengers as compared to standard drug ascorbic acid (IC50 = 618 ± 2.0 μM). Compounds 4c and e exhibiting several hundred fold more activity against nitric oxide radical with IC50 values of 69 ± 1.66 and 70.1 ± 0.89 μM respectively, as compared to standard drug ascorbic acid (IC50 = 618 ± 2.0 μM). PMID:25016372

  6. Differential immune responses to albumin adducts of reactive intermediates of trichloroethene in MRL+/+ mice

    International Nuclear Information System (INIS)

    Trichloroethene (TCE) is an industrial degreasing solvent and widespread environmental contaminant. Exposure to TCE is associated with autoimmunity. The mode of action of TCE is via its oxidative metabolism, and most likely, immunotoxicity is mediated via haptenization of macromolecules and subsequent induction of immune responses. To better understand the role of protein haptenization through TCE metabolism, we immunized MRL+/+ mice with albumin adducts of various TCE reactive intermediates. Serum immunoglobulins and cytokine levels were measured to determine immune responses against haptenized albumin. We found antigen-specific IgG responses of the IgG subtypes IgG1, IgG2a, and IgG2b, with IgG1 predominating. Serum levels of G-CSF were increased in immunized mice, suggesting macrophage activation. Liver histology revealed lymphocyte infiltration in the lobules and the portal area following immunization with formyl-albumin. Our findings suggest that proteins haptenized by metabolites of TCE may act as neo-antigens that can induce humoral immune responses and T cell-mediated hepatitis

  7. Hypervalent Compounds as Ligands: I 3 -Anion Adducts with Transition Metal Pentacarbonyls

    KAUST Repository

    Rogachev, Andrey Yu.

    2013-06-17

    Just a couple of transition metal complexes of the familiar triiodide anion are known. To investigate the bonding in these, as well as isomeric possibilities, we examined theoretically adducts of I3 - with model organometallic fragments, [Cr(CO)5] and [Mn(CO) 5]+. Bonding energy computations were augmented by a Natural Bond Orbital (NBO) perturbation theory analysis and Energy Decomposition Analysis (EDA). The bonding between I3 - and the organometallic fragment is substantial, especially for the electrostatically driven anion-cation case. "End-on" coordination is favored by 5-13 kcal/mol over "side-on" (to the central I of I3 -), with a ∼10 kcal/mol barrier for isomerization. A developing asymmetry in the I-I bonding of "end-on" coordinated I 3 - led us to consider in some detail the obvious fragmentation to a coordinated I- and free I2. While the signs of incipient fragmentation in that direction are there, these is a definite advantage to maintaining some I- to I2 bonding in triiodide complexes. © 2013 American Chemical Society.

  8. Theoretical Investigation of Detailed Thermodynamic Character of Possible Difunctional Adducts Model

    Institute of Scientific and Technical Information of China (English)

    CHANG Guan-Ru; ZHOU Li-Xin; CHEN Dong

    2006-01-01

    The B3LYP/6-31G* level of theory was used to optimize trans-[Pt(NH3)(Am)G-L], where Am = quinoline or thiazole and L is chosen as the model for functional groups of peptide side chains, and for adenine and guanine sites of DNA as the ultimate target of platinum anticancer drugs. Bond dissociating energy and stability energy of complexes are chosen to study detailedly ther- modynamic character of possible difunctional adducts model. In order to investigate the influence of a polarizable environment on the energy of the Pt-L bond formation, we adopt a new bonding energy formula brought forward by Lippard and his coworkers: ΔH(Sol) = ΔH(SCF) + ΔG(Solv), which is quite appropriate to compare with what is found in experimental studies. Our calculated results demonstrate that N-containing ligands are more favored in view of thermodynamics both in gas phrase and in solution. However, it is worthly to be noted that addition of solvation free energies result in moderate correction of bonding energy in relative ordering, and the largest ones both present in imidazole ligand, not in guanine ligand. Finally, the nature of bond is analyzed in terms of partial charges distribution based on NBO population.

  9. Serendipitous compositional and structural diversity in urotropine adducts of binary cadmium xanthates

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Yee Seng; Azizuddin, Aliaa Diyana [Malaya Univ., Kuala Lumpur (Malaysia). Dept. of Chemistry; Campian, Marius V.; Haiduc, Ionel [Babes-Bolyai Univ., Cluj-Napoca (Romania). Dept. of Chemistry; Tiekink, Edward R.T. [Sunway Univ., Bandar Sunway (Malaysia). Centre for Crystalline Material

    2016-05-01

    Three new compounds, Cd(S{sub 2}COMe){sub 2}(hmta) (1), Cd(S{sub 2}COEt){sub 2}(hmta)0.5 (2) and Cd(S{sub 2}COiPr){sub 2}(hmta) (3), have been isolated from a systematic study of adduct formation between Cd(S{sub 2}COR){sub 2}, R = Me, Et and iPr, precursors and potentially polydentate hmta; hmta is urotropine (hexamethylenetetramine). The compounds have been characterised by a variety of spectroscopic techniques including a photoluminescence study in both solution and the solid-state, as well as by thermal methods. Crystallography shows 1 to have μ{sub 2}-bridging hmta leading to a one-dimensional coordination polymer. This framework is essentially repeated in 2 but with a μ{sub 3}-bridging hmta so that Cd(S{sub 2}COEt){sub 2} entities decorate the chain. By contrast, a binuclear zero-dimensional aggregate with terminally bound hmta is found in 3. The influence of steric bulk of the alkyl substituents in Cd(S{sub 2}COR){sub 2} is pivotal in determining the ultimate structural outcome.

  10. Real-Time Knee Adduction Moment Feedback for Gait Retraining Through Visual and Tactile Displays

    KAUST Repository

    Wheeler, Jason W.

    2011-01-01

    The external knee adduction moment (KAM) measured during gait is an indicator of tibiofemoral joint osteoarthritis progression and various strategies have been proposed to lower it. Gait retraining has been shown to be an effective, noninvasive approach for lowering the KAM. We present a new gait retraining approach in which the KAM is fed back to subjects in real-time during ambulation. A study was conducted in which 16 healthy subjects learned to alter gait patterns to lower the KAM through visual or tactile (vibration) feedback. Participants converged on a comfortable gait in just a few minutes by using the feedback to iterate on various kinematic modifications. All subjects adopted altered gait patterns with lower KAM compared with normal ambulation (average reduction of 20.7%). Tactile and visual feedbacks were equally effective for real-time training, although subjects using tactile feedback took longer to converge on an acceptable gait. This study shows that real-time feedback of the KAM can greatly increase the effectiveness and efficiency of subject-specific gait retraining compared with conventional methods. © 2011 American Society of Mechanical Engineers.

  11. Long-term indwelling double-J stents: Bulky kidney and urinary bladder calculosis, spontaneous intraperitoneal perforation of the kidney and peritonitis as a result of 'forgotten' double-J stent

    Directory of Open Access Journals (Sweden)

    Stojković Ivica

    2009-01-01

    Full Text Available Background. The first double-J (DJ stents were manufactured in 1978. Their J-shaped tips efficiently prevent their migration from kidneys and from the urinary bladder. Nowadays, DJ stents are in common use because they provide efficient and relatively safe urinary derivation between the kidney and the urinary bladder. We report this case with the aim to point out possible serious complications with long-term indwelling stents. Case report. The patient was admitted to hospital five years after the placement of DJ in a bad general condition, with symptoms of peritonitis. Radiological examination (plain abdominal film, computerized tomography, excretory urogram and cystography showed bulky calculosis at each tip of the stent, affunctional right kidney, vesicoureteral reflux through the DJ stent and ureter all the way to the right kidney, as well as a large amount of turbid liquid in the abdomen. In the course of the operation, the bulky stone with the DJ stent was removed form the urinary bladder, followed by a large amount of turbid liquid extracted from the abdomen. During adhesiolysis, a small intraperitoneal perforation through which a tip of the stent prolapsed, was found on the upper pole of the kidney. After that, nefrectomy was performed. The patient was discharged 18 days after the surgery. Conclusion. There are usually no complications with shortterm DJ stent urinary drainage. However, indwelling DJ stents can cause serious complications, such as migration, incrustration and fragmentation. DJ indwelling should be as short as possible. If indwelling stenting is necessary, the DJ stent should be replaced with a new one in due time, or another kind of derivation should be performed. Careful monitoring of patients could exclude any possibility of a stent being forgotten at all.

  12. Non-covalent C-Cl…π interaction in acetylene-carbon tetrachloride adducts: Matrix isolation infrared and ab initio computational studies.

    Science.gov (United States)

    Ramanathan, N; Sundararajan, K; Vidya, K; Jemmis, Eluvathingal D

    2016-03-15

    Non-covalent halogen-bonding interactions between π cloud of acetylene (C2H2) and chlorine atom of carbon tetrachloride (CCl4) have been investigated using matrix isolation infrared spectroscopy and quantum chemical computations. The structure and the energies of the 1:1 C2H2-CCl4 adducts were computed at the B3LYP, MP2 and M05-2X levels of theory using 6-311++G(d,p) basis set. The computations indicated two minima for the 1:1 C2H2-CCl4 adducts; with the C-Cl…π adduct being the global minimum, where π cloud of C2H2 is the electron donor. The second minimum corresponded to a C-H…Cl adduct, in which C2H2 is the proton donor. The interaction energies for the adducts A and B were found to be nearly identical. Experimentally, both C-Cl…π and C-H…Cl adducts were generated in Ar and N2 matrixes and characterized using infrared spectroscopy. This is the first report on halogen bonded adduct, stabilized through C-Cl…π interaction being identified at low temperatures using matrix isolation infrared spectroscopy. Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) analyses were performed to support the experimental results. The structures of 2:1 ((C2H2)2-CCl4) and 1:2 (C2H2-(CCl4)2) multimers and their identification in the low temperature matrixes were also discussed. PMID:26722673

  13. Influence of a ring substituent on the tendency to form H(2)O adducts to Ag(+) complexes with phenylalanine analogues in an ion trap mass spectrometer.

    Science.gov (United States)

    Perera, B A; Gallardo, A L; Barr, J M; Tekarli, S M; Anbalagan, V; Talaty, E R; Van Stipdonk, M J

    2002-04-01

    In a previous report we showed that certain binary Ag(+)-amino acid complexes formed adduct ions by the attachment of a single water and methanol molecule when stored in an ion trap mass spectrometer: complexes with aliphatic amino acids and with 4-fluorophenylalanine formed the adduct ions whereas complexes with phenylalanine and tryptophan did not. In this study we compared the tendency of the Ag(+) complexes derived from phenylalanine, 4-fluorophenylalanine, 4-hydroxyphenylalanine (tyrosine), 4-bromophenylalanine, 4-nitrophenylalanine and aminocyclohexanepropionic acid to form water adducts when stored, without further activation, in the ion trap for times ranging from 1 to 500 ms. Because the donation of pi electron density to the Ag(+) ion is a likely determining factor in complex reactivity, our aim in the present study was to determine qualitatively the influence of para-position substituents on the aromatic ring on the formation of the water adducts. Our results show that the reactivity of the complexes is influenced significantly by the presence of the various substituents. Decreases in [M + Ag](+) ion abundance, and increases in adduct ion abundance, both measured as a function of storage time, follow the trend -NO(2) > -Br > -F > -OH > -H. The complex of Ag(+) with 4-nitrophenylalanine was nearly as reactive towards water as the Ag(+) complex with aminocyclohexanepropionic acid, the last being an amino acid devoid of pi character in the ring system. Collision induced dissociation of the [M + Ag](+) species derived from the amino acids produces, among other products, Ag(+) complexes with a para-substituted phenylacetaldehyde: complexes that also form adduct species when stored in the ion trap. The trends in adduct ion formation exhibited by the aldehyde-Ag(+) complex ions were similar to those observed for the precursor complexes of Ag(+) and the amino acids, confirming the influence of the ring substituent. PMID:11948847

  14. Non-covalent C-Cl…π interaction in acetylene-carbon tetrachloride adducts: Matrix isolation infrared and ab initio computational studies

    Science.gov (United States)

    Ramanathan, N.; Sundararajan, K.; Vidya, K.; Jemmis, Eluvathingal D.

    2016-03-01

    Non-covalent halogen-bonding interactions between π cloud of acetylene (C2H2) and chlorine atom of carbon tetrachloride (CCl4) have been investigated using matrix isolation infrared spectroscopy and quantum chemical computations. The structure and the energies of the 1:1 C2H2-CCl4 adducts were computed at the B3LYP, MP2 and M05-2X levels of theory using 6-311 ++G(d,p) basis set. The computations indicated two minima for the 1:1 C2H2-CCl4 adducts; with the C-Cl…π adduct being the global minimum, where π cloud of C2H2 is the electron donor. The second minimum corresponded to a C-H…Cl adduct, in which C2H2 is the proton donor. The interaction energies for the adducts A and B were found to be nearly identical. Experimentally, both C-Cl…π and C-H…Cl adducts were generated in Ar and N2 matrixes and characterized using infrared spectroscopy. This is the first report on halogen bonded adduct, stabilized through C-Cl…π interaction being identified at low temperatures using matrix isolation infrared spectroscopy. Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) analyses were performed to support the experimental results. The structures of 2:1 ((C2H2)2-CCl4) and 1:2 (C2H2-(CCl4)2) multimers and their identification in the low temperature matrixes were also discussed.

  15. Dose-dependent reduction of 3,2'-dimethyl-4-aminobiphenyl-derived DNA adducts in colon and liver of rats administered celecoxib

    International Nuclear Information System (INIS)

    Colon cancer is second leading cause of cancer-related deaths in Western countries. Diet and smoking, which contain aromatic and heterocyclic amines, are major risk factors for colon cancer. Colorectal cancers have a natural history of long latency and therefore provide ample opportunities for effective chemoprevention. 3,2'-Dimethyl-4-aminobiphenyl (DMABP) is an experimental aromatic amine that causes cancer in rat colon and serves as an experimental model for arylamine and heterocyclic amine mutagens derived from diet and smoking. In this study, we investigated the effects of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor on DMABP-induced DNA adduct formation in rat liver and colon. Male F-344 rats (5-week old) were provided free access to modified AIN-76A rat chow containing 0 (control), 500, 1000, or 1500 ppm celecoxib. Two weeks later, the rats received a subcutaneous injection of 100 mg/kg DMABP in peanut oil. Two days after DMABP treatment, the rats were killed and DMABP-derived adducts were analyzed in colon and liver DNA by butanol extraction-mediated 32P-postlabeling. Two major DNA adducts, identified as dG-C8-DMABP and dG-N2-DMABP, were detected in liver and colon of rats treated with DMABP. These DNA adducts were diminished approximately 35-40% with 500 ppm and 65-70% with 1,000 ppm celecoxib. In the colon, no further decline in DNA adducts was observed at 1500 ppm. The same DMABP-DNA adducts also were detected in the liver and were also diminished by celecoxib treatment. The reduction in DMABP-DNA adduct levels in celecoxib-treated animals provides further support for celecoxib as a chemopreventive agent for colorectal cancer

  16. Acetylator genotype-dependent formation of 2-aminofluorene-hemoglobin adducts in rapid and slow acetylator Syrian hamsters congenic at the NAT2 locus.

    Science.gov (United States)

    Feng, Y; Rustan, T D; Ferguson, R J; Doll, M A; Hein, D W

    1994-01-01

    Arylamine-hemoglobin adducts are a valuable dosimeter for assessing arylamine exposures and carcinogenic risk. The effects of age, sex, time-course, dose, and acetylator genotype on levels of 2-aminofluorene-hemoglobin adducts were investigated in homozygous rapid (Bio. 82.73/H-Patr) and slow (Bio. 82.73/H-Pats) acetylator hamsters congenic at the polymorphic (NAT2) acetylator locus. Following administration of a single ip dose of [3H]2-aminofluorene, peak 2-aminofluorene-hemoglobin adduct levels were achieved at 12-18 hr and retained a plateau up to 72 hr postinjection in both rapid and slow acetylator congenic hamsters. 2-Aminofluorene-hemoglobin adduct levels did not differ significantly between young (5-6 weeks) and old (32-49 weeks) hamsters or between male and female hamsters within either acetylator genotype. 2-Aminofluorene-hemoglobin adduct levels increased in a dose-dependent manner (r = 0.95, p = 0.0001) and were consistently higher in slow versus rapid acetylator congenic hamsters in studies of both time-course and dose-effect. The magnitude of the acetylator genotype-dependent difference was a function of dose; 2-aminofluorene-hemoglobin adduct levels were 1.5-fold higher in slow acetylator congenic hamsters following a 60 mg/kg 2-aminofluorene dose (p = 0.0013) but 2-fold higher following a 100 mg/kg 2-aminofluorene dose (p < 0.0001). These results show a specific and significant role for NAT2 acetylator genotype in formation of arylamine-hemoglobin adducts, which may reflect the relationship between acetylator genotype and the incidence of different cancers from arylamine exposures. PMID:8291051

  17. A physiologically based biodynamic (PBBD) model for estragole DNA binding in rat liver based on in vitro kinetic data and estragole DNA adduct formation in primary hepatocytes

    International Nuclear Information System (INIS)

    Estragole has been shown to be hepatocarcinogenic in rodent species at high-dose levels. Translation of these results into the likelihood of formation of DNA adducts, mutation, and ultimately cancer upon more realistic low-dose exposures remains a challenge. Recently we have developed physiologically based biokinetic (PBBK) models for rat and human predicting bioactivation of estragole. These PBBK models, however, predict only kinetic characteristics. The present study describes the extension of the PBBK model to a so-called physiologically based biodynamic (PBBD) model predicting in vivo DNA adduct formation of estragole in rat liver. This PBBD model was developed using in vitro data on DNA adduct formation in rat primary hepatocytes exposed to 1'-hydroxyestragole. The model was extended by linking the area under the curve for 1'-hydroxyestragole formation predicted by the PBBK model to the area under the curve for 1'-hydroxyestragole in the in vitro experiments. The outcome of the PBBD model revealed a linear increase in DNA adduct formation with increasing estragole doses up to 100 mg/kg bw. Although DNA adduct formation of genotoxic carcinogens is generally seen as a biomarker of exposure rather than a biomarker of response, the PBBD model now developed is one step closer to the ultimate toxic effect of estragole than the PBBK model described previously. Comparison of the PBBD model outcome to available data showed that the model adequately predicts the dose-dependent level of DNA adduct formation. The PBBD model predicts DNA adduct formation at low levels of exposure up to a dose level showing to cause cancer in rodent bioassays, providing a proof of principle for modeling a toxicodynamic in vivo endpoint on the basis of solely in vitro experimental data.

  18. Specificity and affinity of phenosafranine protein adduct: Insights from biophysical aspects

    Energy Technology Data Exchange (ETDEWEB)

    Ding Fei [Department of Chemistry, China Agricultural University, Beijing 100193 (China); Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States); Zhang Li; Sun Ye [Department of Chemistry, China Agricultural University, Beijing 100193 (China); Diao Jianxiong [College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193 (China); Yang Xinling [Department of Chemistry, China Agricultural University, Beijing 100193 (China); Sun Ying, E-mail: sunying@cau.edu.cn [College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193 (China); Zhang Li, E-mail: zhli.work@gmail.com [Key Laboratory of Pesticide Chemistry and Application Technology, Ministry of Agriculture, Department of Applied Chemistry, China Agricultural University, Beijing 100193 (China)

    2012-03-15

    Phenosafranine is a toxic and recalcitrant compound, whose capacity to intercalate with double stranded DNA has been shown. In this contribution, a biophysical discuss on the conjugation of phenosafranine with two model proteins human serum albumin (HSA) and lysozyme (Lys) has been identified utilizing a combination of molecular modeling, steady state and time-resolved fluorescence and circular dichroism (CD) approaches. The accurate binding domain of phenosafranine in protein has been characterized from molecular modeling, subdomain IIIA of HSA and Trp-62, Trp-63 and Trp-108 residues of Lys was designated to possess high-affinity for this compound, the dominant forces in the protein-phenosafranine adduct are hydrogen bonds and {pi}-{pi} interactions, but hydrophobic interactions between dye and Lys are also not exclude. The data of fluorescence displayed that the complex of phenosafranine with protein produces quenching through static property, this corroborates the time-resolved fluorescence results that the ground state complex formation with a moderate affinity of 10{sup 4} M{sup -1}. Moreover, via synchronous fluorescence, CD and three-dimensional fluorescence we indicated some extent of polypeptide chain of protein partially unfolding upon conjugation with phenosafranine. Through this work, we anticipate it can supply salient clues on the toxicological action of phenosafranine and other azines, which have analogous configuration with phenosafranine. - Highlights: Black-Right-Pointing-Pointer Our study supply salient clues on the toxicological action of toxic phenosafranine. Black-Right-Pointing-Pointer Phenosafranine is situated within subdomain IIIA, Sudlow's site II on HSA. Black-Right-Pointing-Pointer Trp-62, Trp-63 and Trp-108 residues on the Lys molecule are all close to dye. Black-Right-Pointing-Pointer Static property of the phenosafranine induced quenching of protein Trp fluorescence. Black-Right-Pointing-Pointer Protein spatial structure proved

  19. gamma-Diketone neuropathy: axon atrophy and the role of cytoskeletal protein adduction.

    Science.gov (United States)

    LoPachin, Richard M; DeCaprio, Anthony P

    2004-08-15

    Multifocal giant neurofilamentous axonal swellings and secondary distal degeneration have been historically considered the hallmark features of gamma-diketone neuropathy. Accordingly, research conducted over the past 25 years has been directed toward discerning mechanisms of axonal swelling. However, this neuropathological convention has been challenged by recent observations that swollen axons were an exclusive product of long-term 2.5-hexanedione (HD) intoxication at lower daily dose-rates (e.g., 175 mg/kg/day); that is, higher HD dose-rates (e.g., 400 mg/kg/day) produced neurological deficits in the absence of axonal swellings. The observation that neurological toxicity can be expressed without axonal swelling suggests that this lesion is not an important pathophysiological event. Instead, several research groups have now shown that axon atrophy is prevalent in nervous tissues of laboratory animals intoxicated over a wide range of HD dose-rates. The well-documented nerve conduction defects associated with axon atrophy, in conjunction with the temporal correspondence between this lesion and the onset of neurological deficits, strongly suggest that atrophy has pathophysiological significance. In this commentary, we present evidence that supports a pathognomonic role for axon atrophy in gamma-diketone neuropathy and suggests that the functional consequences of this lesion mediate the corresponding neurological toxicity. Previous research has demonstrated that HD interacts with proteins via formation of pyrrole adducts. We therefore discuss the possibility that this chemical process is essential to the mechanism of atrophy. Evidence presented in this review suggests that "distal axonopathy" is an inaccurate classification and future nosological schemes should be based on the apparent primacy of axon atrophy. PMID:15289087

  20. Quantifying tetrahedral adduct formation and stabilization in the cysteine and the serine proteases.

    Science.gov (United States)

    Cleary, Jennifer A; Doherty, William; Evans, Paul; Malthouse, J Paul G

    2015-10-01

    Two new papain inhibitors have been synthesized where the terminal α-carboxyl groups of Z-Phe-Ala-COOH and Ac-Phe-Gly-COOH have been replaced by a proton to give Z-Phe-Ala-H and Ac-Phe-Gly-H. We show that for papain, replacing the terminal carboxylate group of a peptide inhibitor with a hydrogen atom decreases binding 3-4 fold while replacing an aldehyde or glyoxal group with a hydrogen atom decreases binding by 300,000-1,000,000 fold. Thiohemiacetal formation by papain with aldehyde or glyoxal inhibitors is shown to be ~10,000 times more effective than hemiacetal or hemiketal formation with chymotrypsin. It is shown using effective molarities, that for papain, thiohemiacetal stabilization is more effective with aldehyde inhibitors than with glyoxal inhibitors. The effective molarity obtained when papain is inhibited by an aldehyde inhibitor is similar to the effective molarity obtained when chymotrypsin is inhibited by glyoxal inhibitors showing that both enzymes can stabilize tetrahedral adducts by similar amounts. Therefore the greater potency of aldehyde and glyoxal inhibitors with papain is not due to greater thiohemiacetal stabilization by papain compared to the hemiketal and hemiacetal stabilization by chymotrypsin, instead it reflects the greater intrinsic reactivity of the catalytic thiol group of papain compared to the catalytic hydroxyl group of chymotrypsin. It is argued that while the hemiacetals and thiohemiacetals formed with the serine and cysteine proteases respectively can mimic the catalytic tetrahedral intermediate they are also analogues of the productive and non-productive acyl intermediates that can be formed with the cysteine and serine proteases. PMID:26169698

  1. Environmental carcinogens in human target tissues in culture: Progress report

    International Nuclear Information System (INIS)

    We have accumulated more experimental evidences that demonstrated the comparative approaches with human cells will allow us to predict human risk with good accuracy following exposure to toxic chemicals. We also synthesized several carcinogenic DNA adducts, i.e., the major benzo[a]pyrene DNA adduct, 06-methyldeoxyguanosine, 7-methyl- deoxyguanosine and 2-methyl-deoxyguanosine to be used as standards for quantitating DNA adduct formation in carcinogen exposed cells. A simple synthetic method was developed for preparation of the major B[a]p DNA adduct with yields better than those reported. The main accomplishments related to the originally stated objectives are summarized. 8 refs., 2 figs., 1 tab

  2. Characterization of hemoglobin adduct formation in mice and rats after administration of [14C]butadiene or [14C]isoprene

    International Nuclear Information System (INIS)

    Occupational exposures to 1,3-butadiene or isoprene occur through their use in the manufacture of rubber and other related polymer products. The purpose of this study was to determine if butadiene or isoprene administration would result in the formation of adducts with blood hemoglobin (Hb), and if such adducts can be used as a measure of previous exposure(s). Male B6C3F1 mice and male Sprague-Dawley rats were injected intraperitoneally with 1, 10, 100, or 1000 mumol [14C]butadiene or 0.3, 3.0, 300, 1000, or 3000 mumol [14C]isoprene per kilogram body weight. Animals were killed 24 hr later. Globin was isolated from blood samples and was analyzed for 14C by liquid scintillation spectroscopy. Hb adduct formation was linearly related to administered doses up to 100 mumol [14C]butadiene or 500 mumol [14C]isoprene per kilogram body weight for mice and rats, respectively. For [14C]butadiene, the efficiency of Hb adduct formation in mice and rats within the linear response range was 0.177 +/- 0.003 and 0.407 +/- 0.019 (pmol of 14C-adducts/mg globin)/(mumol of retained [14C]butadiene/kg body wt), respectively (mean +/- SE; n = 18). For [14C]isoprene, these values for mice and rats were 0.158 +/- 0.035 and 0.079 +/- 0.016 (pmol of 14C-adducts/mg globin)/(mumol of retained [14C]isoprene/kg body wt), respectively (mean +/- SE; n = 12). Hb adducts also accumulated linearly after repeated daily administration of 100 mumol [14C]butadiene or 500 mumol [14C]isoprene per kilogram body wt to mice and rats, respectively, for 3 days. [14C]Butadiene-derived Hb adducts in blood showed lifetimes of approximately 24 and approximately 65 days for mice and rats, respectively, which correlate with the reported lifetimes for red blood cells in these rodent species. Thus, levels of butadiene- or isoprene-derived adducts on Hb in circulating blood may be a useful measure of prior repeated exposures to these compounds

  3. Estimating the value of the metal-ligand bond dissociation enthalpy (M-L for adducts using empirical equations supported by TG data

    Directory of Open Access Journals (Sweden)

    Farias Robson Fernandes

    1999-01-01

    Full Text Available In this work is presented and tested (for 106 adducts, mainly of the zinc group halides two empirical equations supported in TG data to estimate the value of the metal-ligand bond dissociation enthalpy for adducts: (M-O = t i / g if t i < 420 K and (M-O = (t i / g - 7,75 . 10-2 . t i if t i > 420 K. In this empirical equations, t i is the thermodynamic temperature of the beginning of the thermal decomposition of the adduct, as determined by thermogravimetry, andg is a constant factor that is function of the metal halide considered and of the number of ligands, but is not dependant of the ligand itself. To half of the tested adducts the difference between experimental and calculated values was less than 5%. To about 80% of the tested adducts, the difference between the experimental (calorimetric and the calculated (using the proposed equations values are less than 15%.

  4. The role of reactive oxygen species (ROS and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts

    Directory of Open Access Journals (Sweden)

    Kirsten Linhart

    2014-01-01

    Full Text Available Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1. In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1.

  5. Variation in PAH-related DNA adduct levels among non-smokers: the role of multiple genetic polymorphisms and nucleotide excision repair phenotype.

    Science.gov (United States)

    Etemadi, Arash; Islami, Farhad; Phillips, David H; Godschalk, Roger; Golozar, Asieh; Kamangar, Farin; Malekshah, Akbar Fazel-Tabar; Pourshams, Akram; Elahi, Seerat; Ghojaghi, Farhad; Strickland, Paul T; Taylor, Philip R; Boffetta, Paolo; Abnet, Christian C; Dawsey, Sanford M; Malekzadeh, Reza; van Schooten, Frederik J

    2013-06-15

    Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P-postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r = 0.4, p studies, with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity. PMID:23175176

  6. The solid-matrix phosphorescence of (±)-anti-dibenzo[a,l]pyrene diol epoxide-DNA adducts and benzo[e]pyrene

    International Nuclear Information System (INIS)

    New solid-matrix phosphorescence (SMP) methods for (±)-anti-DB[a,l]PDE-DNA adducts and B[e]P were developed. The methods can be used to detect and characterize (±)-anti-DB[a,l]PDE-DNA adducts and B[e]P by employing SMP spectra, intensities, and lifetimes acquired with the heavy-atom salt, TlNO3, on Whatman 1PS paper. With the SMP data, a number of photophysical parameters were calculated such as biexponential SMP decay curves, pre-exponential factors, and fractional contribution to SMP decay curves. The SMP results were compared with earlier SMP data for (±)-anti-BPDE-DNA adducts and tetrol I-1. The SMP results show that small molecular-weight compounds like B[e]P can be readily detected and characterized by SMP. For example, the limit of detection for B[e]P was 0.60 pmol. Comparison of the SMP properties of the (±)-anti-DB[a,l]PDE-DNA adducts with earlier SMP data for the (±)-anti-BPDE-DNA adducts showed major differences in the SMP spectra, intensities, and lifetimes. The methods developed are important for the comparison of the SMP properties of different diol epoxides of PAH bonded to DNA

  7. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    Energy Technology Data Exchange (ETDEWEB)

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H

    2007-05-23

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  8. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single (14C)-Labeled Therapeutic Dose

    International Nuclear Information System (INIS)

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single (14C)-labeled therapeutic (20 mg) dose, ∼18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N2-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/109 nucleotides. No (14C)-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to α-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was ∼10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  9. Histone-DNA interactions within chromatin. Isolation of histones from DNA adducts induced in nuclei by UV light

    International Nuclear Information System (INIS)

    A method has been developed by which to isolate histones that have been crosslinked to DNA following irradiation of calf thymus nuclei by UV light. The procedure involves separation of protein-DNA adducts from uncrosslinked protein by Sepharose 4B chromatography under dissociating conditions. Histones which are crosslinked to DNA are released by chemical hydrolysis of the DNA and identified by SDS gel electrophoresis. The results indicate that, of the histones, H1 and H3 become crosslinked to the DNA most readily under our irradiation conditions. (author)

  10. PAH-DNA adducts in environmentally exposed population in relation to metabolic and DNA repair genes polymorphisms

    Czech Academy of Sciences Publication Activity Database

    Binková, Blanka; Chvátalová, Irena; Lněničková, Zdena; Milcová, Alena; Tulupová, Elena; Farmer, P. B.; Šrám, Radim

    2007-01-01

    Roč. 620, - (2007), s. 49-61. ISSN 0027-5107 R&D Projects: GA MŽP SI/340/2/00; GA MŽP SL/740/5/03 Grant ostatní: EU(GB) 2000-00091 Institutional research plan: CEZ:AV0Z50390512 Source of funding: R - rámcový projekt EK Keywords : DNA adducts * genetic polymorphisms * metabolic genes Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.159, year: 2007

  11. Interfacial molecular recognition of adenine, adenosine and ATP by a C60-uracil adduct via complementary base pairing

    Science.gov (United States)

    Marczak, Renata; Hoang, Vu T.; Noworyta, Krzysztof; Zandler, Melvin E.; Kutner, Wlodzimierz; D'Souza, Francis

    2002-10-01

    A new C60-uracil adduct was demonstrated to recognize adenine, adenosine, or adenosine 5'-triphosphate (ATP) via complementary base pairing which led to complex formation. The base-pairing mechanism was modeled by ab initio B3LYP/3-21G(*) calculations which revealed the Watson-Crick (A-T) interactions. Stable "expanded liquid" Langmuir films of the complexes were prepared with the limiting area per molecule increasing for different subphase composition in the order: water < adenine < adenosine < ATP solution. Comparison of experimental and calculated areas per molecule and dipole moments suggest both prevailing horizontal orientation of the complexes in films.

  12. Hyphenating the curtius rearrangement with Morita-Baylis-Hillman adducts: synthesis of biologically active acyloins and vicinal aminoalcohols

    Energy Technology Data Exchange (ETDEWEB)

    Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando, E-mail: coelho@iqm.unicamp.b [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Inst. de Quimica. Lab. de Sintese de Produtos Naturais e Farmacos

    2011-07-01

    Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (+-)-bupropion, a drug used to treat the abstinence syndrome of smoker and (+-)-spisulosine, a potent anti-tumoral compound originally isolated from a marine source. (author)

  13. Hyphenating the curtius rearrangement with Morita-Baylis-Hillman adducts: synthesis of biologically active acyloins and vicinal aminoalcohols

    International Nuclear Information System (INIS)

    Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (+-)-bupropion, a drug used to treat the abstinence syndrome of smoker and (+-)-spisulosine, a potent anti-tumoral compound originally isolated from a marine source. (author)

  14. SYNTHESIS AND INFRARED STUDY OF POLYNUCLEAR DABCO ADDUCTS WITH NiCl2 AND CuCl2

    Directory of Open Access Journals (Sweden)

    MAMADOU NDIAYE

    2015-02-01

    Full Text Available The proposed structures for the studied adducts - DABCO.3[NiCl2·2H2O].EtOH and 2DABCO.3CuCl2.4EtOH or 3DABCO. 4CuCl2.5EtOH are discrete with two or three metallic components, the environments around the Nickel centres being octahedral or square planar, while being octahedral , linear or a square based prism around the Copper centres, the DABCO behaving as a monodentate or bridging bidentate ligand or being lattice. Extra intermolecular interactions via hydrogen bonds when considered, may lead to supramolecular architectures.

  15. Mechanism of Translesion Synthesis Past an Equine Estrogen-DNA Adduct by Y-Family DNA Polymerases

    OpenAIRE

    Yasui, Manabu; Suzuki, Naomi; Liu, Xiaoping; Kim, Yoshinori Okamoto Sung Yeon; Laxmi, Y. R. Santosh; Shibutani, Shinya

    2007-01-01

    4-Hydroxyequilenin (4-OHEN)-dC is a major, potentially mutagenic DNA adduct induced by equine estrogens used for hormone replacement therapy. To study the miscoding property of 4-OHEN-dC and the involvement of Y-family human DNA polymerases (pols) η, κ and ι in that process, we incorporated 4-OHEN-dC into oligodeoxynucleotides and used them as templates in primer extension reactions catalyzed by pol η, κ and ι. Pol η inserted dAMP opposite 4-OHEN-dC, accompanied by lesser amounts of dCMP and ...

  16. Triphenyl phosphine adducts of platinum(IV) and palladium(II) dithiocarbamates complexes: a spectral and in vitro study

    Science.gov (United States)

    Manav, N.; Mishra, A. K.; Kaushik, N. K.

    2004-11-01

    Triphenyl phosphine adducts of dithiocarbamate complexes of platinum(IV) and palladium(II) of the type [Pt(L) 2PPh 3Cl 2] and [Pd(L) 2PPh 3] [L: morpholine dithiocarbamate (L 1), aniline dithiocarbamate (L 2) and N-(methyl, cyclohexyl) dithiocarbamate (L 3)] were prepared and characterized by elemental analysis, electronic, IR, 1H NMR and 13C NMR spectral studies. Thermal studies of the complexes were carried out. In vitro antitumor activity has been screened towards human adenocarcinoma cell lines and showed significant inhibition even at very low concentration.

  17. DNA adduct formation by 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) in rat colon

    OpenAIRE

    Lin, Chun-xing; Mondan, Yasumasa; Umemoto, Atsushi

    2001-01-01

    A food-born carcinogen, 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) induces cancer in the rat colon. The mechanism for colonic DNA adduct formation leading to cancer by IQ was studied using a colostomized F344 rat model. In this model, the transverse colon of the rat was colostomized, which produced a fecal stream-positive proximal colon and a negative distal colon were produced. When IQ (50 mg/kg) was administered into the distal colon of the colostomized rats (n=5), the ratio of the DNA ...

  18. ()-Garner aldehyde derived Baylis-Hillman adduct: A potential substrate for the synthesis of D- phytosphinosine analogue

    Indian Academy of Sciences (India)

    Gulshan Kumar; Amanpreet Kaur; Vasundhara Singh

    2014-11-01

    A short, facile and efficient synthesis of D-lyxo-phytosphingosine analogue has been achieved. The key steps involved are the Baylis-Hillman reaction of (S)-Garner aldehyde with methyl acrylate to obtain the corresponding adduct as the potential substrate, to which was added decylmagnesium bromide to obtain the E-trisubstituted alkene followed by OsO4/NMO mediated dihydroxylation gave the desired D-lyxophytosphingosine analogue intermediate diol which on acid hydrolysis resulted in the formation of the target molecule in good yield.

  19. SYNTHESIS OF THE FULLY PROTECTED PHOSPHORAMIDITE OF THE BENZENE-DNA ADDUCT, N2- (4-HYDROXYPHENYL)-2'-DEOXYGUANOSINE AND INCORPORATION OF THE LATER INTO DNA OLIGOMERS

    Energy Technology Data Exchange (ETDEWEB)

    Chenna, Ahmed; Gupta, Ramesh C.; Bonala, Radha R.; Johnson, Francis; Huang, Bo

    2008-06-09

    N2-(4-Hydroxyphenyl)-2'-deoxyguanosine-5'-O-DMT-3'-phosphoramidite has been synthesized and used to incorporate the N2-(4-hydroxyphenyl)-2'-dG (N2-4-HOPh-dG) into DNA, using solid-state synthesis technology. The key step to obtaining the xenonucleoside is a palladium (Xantphos-chelated) catalyzed N2-arylation (Buchwald-Hartwig reaction) of a fully protected 2'-deoxyguanosine derivative by 4-isobutyryloxybromobenzene. The reaction proceeded in good yield and the adduct was converted to the required 5'-O-DMT-3'-O-phosphoramidite by standard methods. The latter was used to synthesize oligodeoxynucleotides in which the N2-4-HOPh-dG adduct was incorporated site-specifically. The oligomers were purified by reverse-phase HPLC. Enzymatic hydrolysis and HPLC analysis confirmed the presence of this adduct in the oligomers.

  20. Typical signature of DNA damage in white blood cells: a pilot study on etheno adducts in Danish mother-newborn child pairs

    DEFF Research Database (Denmark)

    Arab, K; Pedersen, Marie; Nair, J;

    2009-01-01

    The impact of DNA damage commonly thought to be involved in chronic degenerative disease causation is particularly detrimental during fetal development. Within a multicenter study, we analyzed 77 white blood cell (WBC) samples from mother-newborn child pairs to see if imprinting of DNA damage in...... mother and newborn shows a similar pattern. Two adducts 1,N(6)-ethenodeoxyadenosine (epsilondA) and 3,N(4)-ethenodeoxycytidine (epsilondC) were measured by our ultrasensitive immunoaffinity (32)P-post-labeling method. These miscoding etheno-DNA adducts are generated by the reaction of lipid peroxidation...... arising from endogenous reactive aldehydes in WBC of both mother and newborn can be reliably assessed by epsilondA and epsilondC as biomarkers. The high correlation of etheno adduct levels in mother and child WBC suggests that a typical signature of DNA damage is induced similarly in fetus and mother...