Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Keywords: BLOOD ; Germany ; LUNG ; DNA adducts ; EXPOSURE ; liver ; TISSUE ; HEART ; DNA ; kidney ; 3-nitrobenzanthrone ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; POSTLABELING ANALYSIS ; RAT ; BIOMARKERS ; CONTAMINANT 3-NITROBENZANTHRONE ; ENRICHMENT ; HPLC ; RATS ; METABOLITES ; HUMANS ; URINARY-BLADDER ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; NUCLEOTIDES ; POLLUTANT 3-NITROBENZANTHRONE ; ADDUCTS ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; DNA-ADDUCTS ; SURFACE SOIL ; V79 CELLS ; SINGLE ; RE ; EMISSIONS ; CARCINOGEN ; ADDUCT ; biomarker ; MUTAGEN 3-NITROBENZANTHRONE ; DNA ADDUCT ; intratracheal instillation ; P-32-postlabeling
    Abstract: 3-Nitrobenzanthrone (3-NBA) is an environmental pollutant and suspected human carcinogen found in emissions from diesel and gasoline engines and on the surface of ambient air particulate matter; human exposure to 3-NBA is likely to occur primarily via the respiratory tract. In our study female Sprague Dawley rats were treated by intratracheal instillation with a single dose of 0.2 or 2 mg/kg body weight of 3-NBA. Using the butanol enrichment version of the P-32-postlabeling method, DNA adduct formation by 3-NBA 48 hr after intratracheal administration in different organs (lung, pancreas, kidney, urinary bladder, heart, small intestine and liver) and in blood was investigated. The same adduct pattern consisting of up to 5 DNA adduct spots was detected by thin layer chromatography in all tissues and blood and at both doses. Highest total adduct levels were found in lung and pancreas (350 +/- 139 and 620 +/- 370 adducts per 10(8) nucleotides for the high dose and 39 +/- 18 and 55 +/- 34 adducts per 10(8) nucleotides for the low dose, respectively) followed by kidney, urinary bladder, heart, small intestine and liver. Adduct levels were dose-dependent in all organs (approximately 10-fold difference between doses). It was demonstrated by high performance liquid chromatography (HPLC) that all 5 3-NBA-derived DNA adducts formed in rats after intratracheal instillation are identical to those formed by other routes of application and are, as previously shown, formed from reductive metabolites bound to purine bases. Although total adduct levels in the blood were much lower (41 +/- 27 and 9.5 +/- 1.9 adducts per 10(8) nucleotides for the high and low dose, respectively) than those found in the lung, they were related to dose and to the levels found in lung. These results show that uptake of 3-NBA by the lung induces high levels of specific DNA adducts in several organs of the rat and an identical adduct pattern in DNA from blood. Therefore, 3-NBA-DNA adducts present in the blood are useful biomarkers for exposure to 3-NBA and may help to assess the effective biological dose in humans exposed to it. (C) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15856450
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: EXPRESSION ; human ; liver ; ENZYMES ; PROTEIN ; TIME ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; AIR-POLLUTION ; INDUCTION ; LIVER-MICROSOMES ; RAT ; SUDAN-I ; CONTAMINANT 3-NITROBENZANTHRONE ; RATS ; RAT-LIVER ; HUMAN ACETYLTRANSFERASES ; BODY ; air pollution ; INCREASE ; WEIGHT ; LEVEL ; ENZYME ; P-32-postlabeling ; reductive activation ; P-32-POSTLABELING ANALYSIS ; BIOTRANSFORMATION ENZYMES ; NAD(P)H-QUINONE OXIDOREDUCTASE ; NITROPOLYCYCLIC AROMATIC-HYDROCARBONS
    Abstract: 3-Nitrobenzanthrone (3-NBA), a suspected human carcinogen occurring in diesel exhaust and air pollution, and its human metabolite 3-aminobenzanthrone (3-ABA) were investigated for their ability to induce biotransformation enzymes in rat liver and the influence of such induction on DNA adduct formation by the compounds. Rats were treated (i.p.) with 0.4, 4, or 40 mg/kg body weight 3-NBA or 3-ABA. When hepatic cytosolic fractions from rats treated with 40 mg/kg body weight 3-NBA or 3-ABA were incubated with 3-NBA, DNA adduct formation, measured by P-32-postlabeling analysis, was 10-fold higher in incubations with cytosols from pretreated rats than with controls. The increase in 3-NBAderived DNA adduct formation corresponded to a dose-dependent increase in protein levels and enzymatic activity of NAD(P) H: quinone oxidoreductase (NQO1). NQO1 is the major enzyme reducing 3-NBA in human and rat livers. Incubations of 3-ABA with hepatic microsomes of rats treated with 3-NBA or 3-ABA (40 mg/ kg body weight) led to as much as a 12-fold increase in 3-ABA-derived DNA adduct formation compared with controls. The observed stimulation of DNA adduct formation by both compounds was attributed to their potential to induce protein expression and enzymatic activity of cytochromes P450 1A1 and/ or -1A2 (CYP1A1/2), the major enzymes responsible for 3-ABA activation in human and rat livers. Collectively, these results demonstrate for the first time, to our knowledge, that by inducing hepatic NQO1 and CYP1A1/2, both 3-NBA and 3-ABA increase the enzymatic activation of these two compounds to reactive DNA adduct-forming species, thereby enhancing their own genotoxic potential
    Type of Publication: Journal article published
    PubMed ID: 16714372
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Keywords: IN-VITRO ; human ; IN-VIVO ; LUNG ; MODEL ; VITRO ; DNA adducts ; liver ; ENZYMES ; METABOLISM ; MICE ; ACTIVATION ; DNA ; kidney ; DNA ADDUCT FORMATION ; LIVER-MICROSOMES ; RAT ; P-32-postlabelling ; BINDING ; MOUSE ; PATTERNS ; DNA-BINDING ; METABOLIC-ACTIVATION ; OXIDATION ; cytochrome P450 ; AGENT ; BODIES ; PATTERN ; WEIGHT ; LEVEL ; pharmacology ; USA ; LOSSES ; PROSTAGLANDIN-H SYNTHASE ; anticancer drug ; ellipticine ; ENVIRONMENTAL-POLLUTANT 3-NITROBENZANTHRONE ; peroxidase ; DETERMINES SUSCEPTIBILITY ; XENOBIOTIC-METABOLISM
    Abstract: Ellipticine is an antineoplastic agent, which forms covalent DNA adducts mediated by cytochromes P450 (CYP) and peroxidases. We evaluated the role of hepatic versus extra-hepatic metabolism of ellipticine, using the HRN (Hepatic Cytochrome P450 Reductase Null) mouse model, in which cytochrome P450 oxidoreductase (POR) is deleted in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated i.p. with 1 and 10 mg/kg body weight of ellipticine. Multiple ellipticine-DNA adducts detected by P-32-postlabelling were observed in organs from both mouse strains. Highest total DNA binding levels were found in liver, followed by lung, kidney, urinary bladder, colon and spleen. Ellipticine-DNA adduct levels in the liver of HRN mice were up to 65% lower relative to WT mice, confirming the importance of CYP enzymes for the activation of ellipticine in livers, recently shown in vitro with human and rat hepatic microsomes. When hepatic microsomes of both mouse strains were incubated with ellipticine, ellipticine-DNA adduct levels with WT microsomes were up to 2.9-fold higher than with those from HRN mice. The ratios of ellipticine-DNA adducts in extra-hepatic organs between HRN and WT mice of up to 4.7 suggest that these organs can activate ellipticine and that more ellipticine is available in the circulation. These results and the DNA adduct patterns found in vitro and in vivo demonstrate that both CYP1A or 3A and peroxidases participate in activation of ellipticine to reactive species forming DNA adducts in the mouse model used in this study. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17976674
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: IN-VIVO ; LUNG-CANCER ; SYSTEM ; TISSUE ; DNA ; CARCINOGENESIS ; DIESEL EXHAUST ; AIR-POLLUTION ; RAT ; CONTAMINANT 3-NITROBENZANTHRONE ; RATS ; LINKAGE ; IDENTIFICATION ; genotoxicity ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; POLLUTANT 3-NITROBENZANTHRONE ; Jun ; ADDUCTS ; rodent ; STANDARD ; V79 CELLS ; RE ; ADDUCT ; MUTAGEN 3-NITROBENZANTHRONE ; SULFOTRANSFERASES ; DNA ADDUCT
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and potential human carcinogen identified in diesel exhaust and ambient air particulate matter. 3-NBA forms DNA adducts in rodent tissues that arise principally through reduction to N-hydroxy-3-aminobenzanthrone (N-OHABA), esterification to its acetate or sulfate ester, and reaction of this activated ester with DNA. We detected 3-NBA-derived DNA adducts in rodent tissues by P-32-postlabeling and generated them chemically by acid-catalyzed reaction of N-OH-ABA with DNA, but their structural identification has not yet been reported. We have now prepared 3-NBA-derived adducts by reaction of a possible reactive metabolite, N-acetoxy-N-acetyl-3-aminobenzanthrone (N-Aco-N-Ac-ABA), with purine nucleosides and nucleotides, characterized them, and have shown that they are present in DNA treated with this 3-NBA derivative. Three of these adducts have been characterized as the C-C adduct N-acetyl-3-amino-2-(2'-deoxyguanosin-8-yl)benzanthrone, the C-N adduct N-acetyl-N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone, and an unusual 3-acetylaminobenzanthrone adduct of deoxyadenosine, which involves a double linkage between adenine and benzanthrone (N1 to C1, N6 to C11b), creating a five-membered imidazo type ring system. According to IUPAC fused ring conventions, we propose the following systematic name for this adduct: (9'-(2"-deoxyribofuranosyl))purino[6',1':2,3]imidazo[5,4-p]-(1,11b-dihyd ro-(N-acetyl-3-amino))benzanthrone. The X-phosphates of these novel adducts could be 5'-postlabeled using [gamma-P-32]ATP, although the efficiency of labeling was found to be low (less than 20%). However, none of these adducts could be detected in DNA from 3-NBA-treated rats by P-32-postlabeling. Two of these synthetic adducts were treated with alkali to generate nonacetylated adducts, and these were also shown by HPLC to differ from those adducts found in rat DNA. Therefore, a different approach to the synthesis of authentic standards is needed for the structural characterization of 3-NBA-derived DNA adducts formed in vivo
    Type of Publication: Journal article published
    PubMed ID: 15962941
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; IN-VIVO ; INHIBITION ; LUNG-CANCER ; DNA adducts ; SAMPLES ; TIME ; ACTIVATION ; DNA ; 3-nitrobenzanthrone ; AIR ; CARCINOGENESIS ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; metabolic activation ; AIR-POLLUTION ; INDUCTION ; LIVER-MICROSOMES ; P-450 REDUCTASE ; RAT ; SUDAN-I
    Abstract: Determining the capability of humans to metabolize the suspected carcinogen 3-nitrobenzanthrone (3-NBA) and understanding which human enzymes are involved in its activation are important in the assessment of individual susceptibility to this environmental contaminant found in diesel exhaust and ambient air pollution. We compared the ability of eight human hepatic microsomal samples to catalyze DNA adduct formation by 3-NBA. Using two enrichment procedures of the P-32-postlabeling method, nuclease P1 digestion and butanol extraction, we found that all hepatic microsomes were competent to activate 3-NBA. DNA adduct patterns with multiple adducts, qualitatively similar to those found recently in vivo in rats, were observed. Additionally one major DNA adduct generated by human microsomes was detected. The role of specific cytochromes P450 (P450) and NADPH:P450 reductase in the human hepatic microsomal samples in 3-NBA activation was investigated by correlating the P450- and NADPH:P450 reductase- linked catalytic activities in each microsomal sample with the level of DNA adducts formed by the same microsomes. On the basis of this analysis, most of the hepatic microsomal activation of 3-NBA was attributed to NADPH:P450 reductase. Inhibition of DNA adduct formation in human liver microsomes by a-lipoic acid, an inhibitor of NADPH:P450 reductase, supported this finding. Using the purified rabbit enzyme and recombinant human NADPH:P450 reductase expressed in Chinese hamster V79 cells, we confirmed the participation of this enzyme in the formation of 3-NBA-derived DNA adducts. Moreover, essentially the same DNA adduct pattern found in microsomes was detected in metabolically competent human lymphoblastoid MCL-5 cells. The role of individual human recombinant P450s 1A1, 1A2, 1B1, 2A6, 2B6, 2D6, 2C9, 2E1, and 3A4 and of NADPH:P450 reductase in the metabolic activation of 3-NBA, catalyzing DNA adduct formation, was also examined using microsomes of baculovirus-transfected insect cells containing the recombinant enzymes (Supersomes). DNA adducts were observed in all Supersomes preparations, essentially similar to those found with human hepatic microsomes and in human cells. Of all of the recombinant human P450s, P450 2B6 and -2D6 were the most efficient to activate 3- NBA, followed by P450 1A1 and -1A2. These results demonstrate for the first time the potential of human NADPH:P450 reductase and recombinant P450s to contribute to the metabolic activation of 3-NBA by nitroreduction
    Type of Publication: Journal article published
    PubMed ID: 12782579
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: CELLS ; IN-VITRO ; human ; IN-VIVO ; LUNG ; PATHWAYS ; VIVO ; DNA adducts ; EXPOSURE ; liver ; ENZYMES ; TISSUE ; HEART ; ACTIVATION ; DNA ; kidney ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; CARCINOGENESIS ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; metabolic activation ; nitro-PAH ; RAT ; animals ; AROMATIC-AMINES ; BASE ; BIOMARKERS ; BODY-WEIGHT ; colon ; CONTAMINANT 3-NITROBENZANTHRONE ; ENRICHMENT ; HPLC ; P-32-postlabelling ; RATS ; TISSUES ; tumour
    Abstract: Diesel exhaust is known to induce tumours in animals and is suspected of being carcinogenic in humans. Of the compounds found in diesel exhaust, 3-nitrobenzanthrone (3-NBA) is an extremely potent mutagen and suspected human carcinogen forming multiple DNA adducts in vitro. 3-Aminobenzanthrone (3-ABA). 3- acetylaminobenzanthrone (3-Ac-ABA), and N-acetyl-N-hydroxy-3- aminobenzanthrone (N-Ac-N-OH-ABA) were identified as 3-NBA metabolites. In order to gain insight into the pathways of metabolic activation leading to 3-NBA-derived DNA adducts we treated Wistar rats intraperitoneally with 2 mg/kg body weight of 3-NBA, 3-ABA. 3-Ac-ABA, or N-Ac-N-OH-ABA and compared DNA adducts present in different organs, With each compound either four or five DNA adduct spots were detected by TLC in all tissues examined (lung, liver. kidney, heart, pancreas, and colon) using the nuclease P1 or butanol enrichment version of the P-32-postlabelling method, respectively. Using HPLC co- chromatographic analysis we showed that all major 3-NBA-DNA adducts produced in vivo in rats are derived from reductive metabolites bound to purine bases and lack an N-acetyl group. Our results indicate that 3-NBA metabolites (3-ABA, 3-Ac-ABA and AT-Ac-N-OH-ABA) undergo several biotransformations and that N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to be the common intermediate in 3-NBA-derived DNA adduct formation. Therefore, 3-NBA-DNA adducts are useful biomarkers for exposure to 3-NBA and its metabolites and may help to identify enzymes involved in their metabolic activation. (C) 2002 Elsevier Science (USA). All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12480528
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: BLOOD ; Germany ; human ; LUNG ; LUNG-CANCER ; DNA adducts ; EXPOSURE ; liver ; LONG-TERM ; TISSUE ; HEART ; TIME ; DNA ; kidney ; 3-nitrobenzanthrone ; CARCINOGENESIS ; DIESEL EXHAUST ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; RAT ; animals ; BIOMARKERS ; RATS ; TISSUES ; treatment ; TARGET ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; POLYCYCLIC AROMATIC-HYDROCARBONS ; ADDUCTS ; BODY ; SMALL-INTESTINE ; DECLINE ; HIGH-LEVEL ; DNA-ADDUCTS ; V79 CELLS ; SINGLE ; ONCOLOGY ; LEVEL ; biomarker ; DNA ADDUCT ; PERSISTENCE ; LOSSES ; uptake ; correlation ; P-32-POSTLABELING ANALYSIS ; carcinogenic ; lungs ; animal ; LONG-TERM PERSISTENCE ; WHOLE-BLOOD ; CD-1 MICE
    Abstract: Sprague-Dawley rats were treated by intratracheal instillation with a single dose of 0.2 mg/kg body wt of 3-nitrobenzanthrone (3-NBA), and whole blood, lungs, pancreases, kidneys, urinary bladders, hearts, small intestines and livers were removed at various times after administration. At five posttreatment times (2 days, 2, 10, 20 and 36 weeks), DNA adducts were analysed in each tissue by P-32-postlabelling to study their long-term persistence. 3-NBA-derived DNA adducts consisting of the same adduct pattern were observed in all tissues from animals killed between 2 days and 36 weeks and between 2 days and 20 weeks in blood. DNA isolated from whole blood contained the same 3-NBA-specific adduct pattern as that found in tissues. Although total adduct levels in the blood were much lower than those found in the lung, the target organ of 3-NBA tumourigenicity, they were related (20-25%, R-2 = 0.98) to the levels found in lung. In all organs, total adduct levels decreased over time to 20-30% of the initial levels till the latest time point (36 weeks) and showed a biphasic profile, with a rapid loss during the first 2 weeks followed by a much slower decline that reached a stable plateau at 20 weeks after treatment. These results show that uptake of 3-NBA by the lung induces high levels of specific DNA adducts in target and non-target organs of the rat. The correlation between DNA adducts in lung and blood suggests that persistent 3-NBA-DNA adducts in the blood may be useful biomarkers for human respiratory exposure to 3-NBA
    Type of Publication: Journal article published
    PubMed ID: 17114646
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: EXPRESSION ; human ; LUNG ; DNA adducts ; PROTEIN ; ACTIVATION ; DNA ; kidney ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; AIR ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; GENETIC POLYMORPHISMS ; PHENOL SULFOTRANSFERASES ; INDUCTION ; RAT ; animals ; CONTAMINANT 3-NITROBENZANTHRONE ; P-32-postlabelling ; RATS ; STIMULATION ; TARGET ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; ADDUCTS ; protein expression ; cytochrome P450 ; DNA-ADDUCTS ; air pollution ; INCREASE ; LEVEL ; pharmacology ; cyclooxygenase ; PROSTAGLANDIN-H SYNTHASE ; animal ; enzymatic ; QUINONE OXIDOREDUCTASE ; ANTIOXIDANT-RESPONSE-ELEMENT ; NAD(P)H : quinone oxidoreductase ; cytochrome p450 1A1
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a carcinogen occurring in diesel exhaust and air pollution. Using the P-32-postlabelling method, we found that 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), are activated to species forming DNA adducts by cytosols and/or microsomes isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney. Each compound generated identical five DNA adducts. We have demonstrated the importance of pulmonary and renal NAD(P)H:quinone oxidoreductase (NQO1) to reduce 3-NBA to species that are further activated by N,O-acetyltransferases and sulfotransferases. Cytochrome P450 (CYP) 1A1 is the essential enzyme for oxidative activation of 3-ABA in microsomes of both organs, while cyclooxygenase plays a minor role. 3-NBA was also investigated for its ability to induce NQO1 and CYP1A1 in lungs and kidneys, and for the influence of such induction on DNA adduct formation by 3-NBA and 3-ABA. When cytosols from rats treated i.p. with 40 mg/kg bw of 3-NBA were incubated with 3-NBA, DNA adduct formation was up to 2.1-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. Incubations of 3-ABA with microsomes of 3-NBA-treated rats led to up to a fivefold increase in DNA adduct formation relative to controls. The stimulation of DNA adduct formation correlated with the potential of 3-NBA to induce protein expression and activity of CYP1A1. These results demonstrate that 3-NBA is capable to induce NQO1 and CYP1A1 in lungs and kidney of rats thereby enhancing its own genotoxic and carcinogenic potential. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18329153
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Keywords: IN-VITRO ; human ; IN-VIVO ; LUNG ; VITRO ; VIVO ; DNA adducts ; liver ; NEW-YORK ; GENE ; TISSUE ; MICE ; ACTIVATION ; DNA ; kidney ; 3-nitrobenzanthrone ; DIESEL EXHAUST ; HETEROCYCLIC AMINES ; INDUCTION ; RAT ; BODY-WEIGHT ; CONTAMINANT 3-NITROBENZANTHRONE ; RATS ; TISSUES ; BINDING ; SEQUENCE ; treatment ; FREQUENCY ; METABOLITES ; MOUSE ; MUTANT ; TRANSGENIC MICE ; PATTERNS ; ASSAY ; MUTATION ; BLADDER ; DNA-BINDING ; NUCLEOTIDES ; POLLUTANT 3-NITROBENZANTHRONE ; MUTATIONS ; ADDUCTS ; TESTIS ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; 3-nitrobenzanthrone,Muta Mouse,mutation spectra,cll,DNA adducts,P-32-post-labeling,diesel exhaust,ai ; CII GENE ; DEOXYADENOSINE ; DNA-ADDUCTS ; LAMBDA/LACZ TRANSGENIC MICE ; micronuclei ; POTENT ; SURFACE SOIL ; V79 CELLS
    Abstract: 3-nitrobenzanthrone (3-NBA) is an extremely potent mutagen in the Salmonella reversion assay and a suspected human carcinogen identified in diesel exhaust and in ambient airborne particulate matter. To evaluate the in vivo mutagenicity of 3-NBA, we analyzed the mutant frequency (MF) in the cll gene of various organs (lung, liver, kidney, bladder, colon, spleen, and testis) in lambda/lacZ transgenic mice (Muta Mouse) after intraperitoneal treatment with 3-NBA (25 mg/kg body weight injected once a week for 4 weeks). Increases in MF were found in colon, liver, and bladder, with 7.0-, 4.8-, and 4.1-fold increases above the control value, respectively, whereas no increase in MF was found in lung, kidney, spleen, and testis. Simultaneously, induction of micronuclei in peripheral blood reticulocytes was observed. The sequence alterations in the cll gene recovered from 41 liver mutants from 3-NBA-treated mice were compared with 32 spontaneous mutants from untreated mice. Base substitution mutations predominated for both the 3-NBA-treated (80%) and the untreated (81%) groups. However, the proportion of G:C--〉T:A transversions in the mutants from 3-NBA-treated mice was higher (49% vs. 6%) and the proportion of G:C--〉A:T transitions was lower than those from untreated mice (10% vs. 66%). The increase in MF in the liver was associated with strong DNA binding by 3-NBA, whereas in lung, in which there was no increase in MF, a low level of DNA binding was observed (268.0-282.7 vs. 8.8-15.9 adducts per 10(8) nucleotides). DNA adduct patterns with multiple adduct spots, qualitatively similar to those formed in vitro after activation of 3-NBA with nitroreductases and in vivo in rats, were observed in all tissues examined. Using high-pressure liquid cochromatographic analysis, we confirmed that all major 3-NBA-DNA adducts produced in vivo in mice are derived from reductive metabolites bound to purine bases (70-80% with deoxyguanosine and 20-30% with deoxyadenosine in liver). These results suggest that G:C--〉T:A transversions induced by 3-NBA are caused by misreplication of adducted guanine residues through incorporation of adenine opposite the adduct (A-rule)
    Type of Publication: Journal article published
    PubMed ID: 15065206
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Keywords: IN-VITRO ; human ; IN-VIVO ; LUNG ; VITRO ; SYSTEM ; DNA adducts ; TISSUE ; MICE ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; CARCINOGENESIS ; DIESEL EXHAUST ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; POSTLABELING ANALYSIS ; RAT ; RATS ; TISSUES ; METABOLITES ; IDENTIFICATION ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; MUTAGENICITY ; rodent ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; SURFACE SOIL ; V79 CELLS ; RE ; air pollution ; ENZYME ; P-32-postlabeling ; in vivo ; DEOXYGUANOSINE ; LIQUID ; P-32-POSTLABELING ANALYSIS ; xanthine oxidase
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and potential human carcinogen identified in diesel exhaust and ambient air particulate matter. Previously, we detected the formation of 3-NBA-derived DNA adducts in rodent tissues by P-32-postlabeling, all of which are derived from reductive metabolites of 3-NBA bound to purine bases, but structural identification of these adducts has not yet been reported. We have now prepared 3-NBA-derived DNA adduct standards for P-32-postlabeling by reacting N-acetoxy-3-aminobenzanthrone (N-Aco-ABA) with purine nucleotides. Three deoxyguanosine (dG) adducts have been characterised as N-(2'-deoxy-guanosin-8-yl)-3-aminobenzanthrone-3'-phosphate (dG3'p-C8-N-ABA), 2-(2'-deoxyguanosin-N-2 -yl)-3-aminobenzanthrone-3'-phosphate (dG3'p-N-2-ABA) and 2-2'-(deoxygtianosin-8-yl)-3-aminobenzanthrone-3'-phosphate (dG3'p-C8-C2-ABA), and a deoxyadenosine (dA) adduct was characterised as 2-(2'-deoxyadenosm-N-6-yl)-3-aminobenzanthrone-3'-phosphate (dA3'p-N-6-ABA). 3-NBA-derived DNA adducts formed experimentally in vivo and in vitro were compared with the chemically synthesised adducts. The major 3-NBA-derived DNA adduct formed in rat lung cochromatographed with dG3'p-N-2-ABA in two independent systems (thin layer and high-performance liquid chromatography). This is also the major adduct formed in tissue of rats or mice treated with 3-aminobenzanthrone (3-ABA), the major human metabolite of 3-NBA. Similarly, dG3'p-C8-N-ABA and dA3'p-N-6-ABA cochromatographed with two other adducts formed in various organs of rats or mice treated either with 3-NBA or 3-ABA, whereas dG3'p-C8-C2-ABA did not cochromatograph with my of the adducts found in vivo. Utilizing different enzymatic systems in vitro, including human hepatic microsomes and cytosols, and purified and recombinant enzymes, we found that a variety of enzymes [NAD(P)H:quinone oxidoreductase, xanthine oxidase, NADPH:cytochrome P450 oxidoreductase, cytochrome P450s 1A1 and 1A2, N,O-acetyltransferases 1 and 2, sulfotransferases 1A1 and 1A2, and myeloperoxidase] are able to catalyse the formation of 2-(2-deoxyguanosin-N-2-yl)3-aminobenzanthrone, N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone and 2-(2'-deoxyadenosin-N-6-yl)-3-aminobenzanthrone in DNA, after incubation with 3-NBA and/or 3-ABA. (c) 2005Wiley-Liss, Inc
    Type of Publication: Journal article published
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...