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  • ACTIVATION  (15)
  • IN-VITRO  (9)
  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VIVO ; LUNG-CANCER ; DNA adducts ; RISK ; GENE ; LINES ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; AIR ; CARCINOGENESIS ; CYP1A2 ; CYTO-TOXIC METABOLITES ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; GENETIC POLYMORPHISMS ; HETEROCYCLIC AMINES ; HETEROLOGOUS EXPRESSION ; HUMAN CYTOSOLIC SULFOTRANSFERASES ; IONS ; metabolic activation ; NAT : SULT ; nitro-PAH ; P-32- postlabeling ; PHENOL SULFOTRANSFERASES ; POSTLABELING ANALYSIS
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and ambient air pollution. 3-Aminobenzanthrone (3-ABA), 3- acetylaminobenzanthrone (3-Ac-ABA) and N-acetyl-N-hydroxy-3- aminobenzanthrone (N-Ac-N-OH-ABA) have been identified as 3-NBA metabolites. Recently we found that 3-NBA and its metabolites (3-ABA, 3-Ac-ABA and N-Ac-N-OH-ABA) form the same DNA adducts in vivo in rats. In order to investigate whether human cytochrome P450 (CYP) enzymes (i.e., CYPIA2), human N,O- acetyltransferases (NATs) and sulfotransferases (SULTs) contribute to the metabolic activation of 3-NBA and its metabolites we developed a panel of Chinese hamster V79MZ-hIA2 derived cell lines expressing human CYPIA2 in conjunction with human NATI, NAT2, SULTIAI or SULTIA2, respectively. Cells were treated with 0.01, 0.1 or I muM 3-NBA, or its metabolites (3- ABA, 3-Ac-ABA and N-Ac-N-OH-ABA). Using both enrichment versions of the P-32-postlabeling assay, nuclease P I digestion and butanol extraction, essentially 4 major and 2 minor DNA adducts were detected in the appropriate cell lines with all 4 compounds. The major ones were identical to those detected in rat tissue; the adducts lack an N-acetyl group. Human CYPIA2 was required for the metabolic activation of 3-ABA and 3-Ac-ABA (probably via N-oxidation) and enhanced the activity of 3-NBA (probably via nitroreduction). The lack of acetylated adducts suggests N-deacetylation of 3-Ac-ABA and N-Ac-N-OH-ABA. Thus, N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to be a common intermediate for the formation of the electrophilic arylnitrenium ions capable of reacting with DNA. Human NAT I and NAT2 as well as human SULTIAI and SULTIA2 strongly contributed to the high genotoxicity of 3-NBA and its metabolites. Moreover, N,O-acetyltransfer reactions catalyzed by human NATs leading to the corresponding N-acetoxyester may be important in the bioactivation of N-Ac-N-OH-ABA. As human exposure to 3-NBA is likely to occur primarily via the respiratory tract, expression of CYPs, NATs and SULTs in respiratory tissues may contribute significantly and specifically to the metabolic activation of 3-NBA and its metabolites. Consequently, polymorphisms in these genes could be important determinants of lung cancer risk from 3-NBA
    Type of Publication: Journal article published
    PubMed ID: 12740904
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  • 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
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  • 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
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  • 4
    Keywords: INHIBITOR ; IN-VIVO ; INHIBITION ; LUNG ; LUNG-CANCER ; DNA adducts ; liver ; ENZYMES ; TISSUE ; MICE ; ACTIVATION ; DNA ; kidney ; 3-nitrobenzanthrone ; CARCINOGENESIS ; DIESEL EXHAUST ; AIR-POLLUTION ; CONTAMINANT 3-NITROBENZANTHRONE ; BINDING ; DNA-BINDING ; METABOLIC-ACTIVATION ; ADDUCTS ; rodent ; DT-DIAPHORASE ; RAT-LIVER CYTOSOL ; XANTHINE-OXIDASE ; DNA-ADDUCTS ; V79 CELLS ; ACETYLTRANSFERASE ; ADDUCT ; COFACTOR ; CARCINOGENIC ARISTOLOCHIC ACIDS ; CYTOCHROME-P450 1A1 ; MUTAGEN 3-NITROBENZANTHRONE ; SULFOTRANSFERASES ; DNA ADDUCT ; sulfotransferase
    Abstract: 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and air pollution. We compared the ability of human hepatic cytosolic samples to catalyze DNA adduct formation by 3-NBA. Using the (32)p-postlabeling method, we found that 12/12 hepatic cytosols activated 3-NBA to form multiple DNA adducts similar to those formed in vivo in rodents. By comparing 3-NBA-DNA adduct formation in the presence of cofactors of NAD(P)H:quinone oxidoreductase (NQO1) and xanthine oxidase, most of the reductive activation of 3-NBA in human hepatic cytosols was attributed to NQO1. Inhibition of adduct formation by dicoumarol, an NQO1 inhibitor, supported this finding and was confirmed with human recombinant NQO1. When cofactors of N,O-acetyltransferases (NAT) and sulfotransferases (SUIT) were added to cytosolic samples, 3-NBA-DNA adduct formation increased 10- to 35-fold. Using human recombinant NQO1 and NATs or SULTs, we found that mainly NAT2, followed by SULT1A2, NAT1, and, to a lesser extent, SULT1A1 activate 3-NBA. We also evaluated the role of hepatic NADPH:cytochrome P450 oxidoreductase (POR) in the activation of 3-NBA in vivo by treating hepatic POR-null mice and wild-type littermates i.p. with 0.2 or 2 mg/kg body weight of 3-NBA. No difference in DNA binding was found in any tissue examined (liver, lung, kidney, bladder, and colon) between null and wild-type mice, indicating that 3-NBA is predominantly activated by cytosolic nitroreductases rather than microsomal POR. Collectively, these results show the role of human hepatic NQO1 to reduce 3-NBA to species being further activated by NATs and SULTs
    Type of Publication: Journal article published
    PubMed ID: 15805261
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  • 5
    Keywords: IN-VITRO ; BLOOD ; IN-VIVO ; MODEL ; VITRO ; SYSTEM ; SYSTEMS ; liver ; ENZYMES ; GENE-EXPRESSION ; METABOLISM ; TISSUE ; MICE ; ACTIVATION ; DNA ; CARCINOGENESIS ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; TISSUES ; MOUSE ; NO ; DIFFERENCE ; mass spectrometry ; METABOLIC-ACTIVATION ; POLLUTANT 3-NITROBENZANTHRONE ; POLYCYCLIC AROMATIC-HYDROCARBONS ; MASS-SPECTROMETRY ; CHROMATOGRAPHY ; LIQUID-CHROMATOGRAPHY ; CLEARANCE ; MOUSE MODEL ; PHARMACOKINETICS ; cytochrome P450 ; ORDER ; BODIES ; ONCOLOGY ; RE ; KNOCKOUT MICE ; LEVEL ; analysis ; MASS ; LOSSES ; PROSTAGLANDIN-H SYNTHASE ; ENGLAND ; ANTICANCER DRUG ELLIPTICINE ; CONDITIONAL DELETION ; DETERMINES SUSCEPTIBILITY
    Abstract: Many studies using mammalian cellular and subcellular systems have demonstrated that polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are metabolically activated by cytochrome P450s (CYPs). In order to evaluate the role of hepatic versus extra-hepatic metabolism of BaP and its pharmacokinetics, we used the hepatic cytochrome P450 reductase null (HRN) mouse model, in which cytochrome P450 oxidoreductase, the unique electron donor to CYPs, is deleted specifically in hepatocytes, resulting in the loss of essentially all hepatic CYP function. HRN and wild-type (WT) mice were treated intraperitoneally (i.p.) with 125 mg/kg body wt BaP daily for up to 5 days. Clearance of BaP from blood was analysed by high-performance liquid chromatography with fluorescence detection. DNA adduct levels were measured by P-32-post-labelling analysis with structural confirmation of the formation of 10-(deoxyguanosin-N-2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]py rene by liquid chromatography-tandem mass spectrometry analysis. Hepatic microsomes isolated from BaP-treated and untreated mice were also incubated with BaP and DNA in vitro. BaP-DNA adduct formation was up to 7-fold lower with the microsomes from HRN mice than with that from WT mice. Most of the hepatic microsomal activation of BaP in vitro was attributable to CYP1A. Pharmacokinetic analysis of BaP in blood revealed no significant differences between HRN and WT mice. BaP-DNA adduct levels were higher in the livers (up to 13-fold) and elevated in several extra-hepatic tissues of HRN mice (by 1.7- to 2.6-fold) relative to WT mice. These data reveal an apparent paradox, whereby hepatic CYP enzymes appear to be more important for detoxification of BaP in vivo, despite being involved in its metabolic activation in vitro
    Type of Publication: Journal article published
    PubMed ID: 18204078
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  • 6
    Keywords: CELLS ; IN-VITRO ; CELL ; human ; IN-VIVO ; LUNG ; MODEL ; PATHWAY ; PATHWAYS ; VITRO ; VIVO ; SYSTEM ; liver ; MICE ; TIME ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; AIR ; CARCINOGENESIS ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; CONTAMINANT 3-NITROBENZANTHRONE ; BINDING ; bone marrow ; BONE-MARROW ; MOUSE ; MUTANT ; TRANSGENIC MICE ; ASSAY ; genetics ; genotoxicity ; DNA-BINDING ; METABOLIC-ACTIVATION ; NUCLEOTIDES ; POLYCYCLIC AROMATIC-HYDROCARBONS ; EPITHELIAL-CELLS ; ADDUCTS ; heredity ; BODIES ; RE ; air pollution ; INCREASE ; ADDUCT FORMATION ; LEVEL ; BONE ; ENGLAND ; PREDICT ; INCREASES ; ENVIRONMENTAL-POLLUTANT 3-NITROBENZANTHRONE ; NOV ; outcome ; MARROW ; NUCLEOTIDE ; CARCINOGEN 3-NITROBENZANTHRONE ; HUMAN METABOLITE ; URBAN AIR-POLLUTION
    Abstract: FE1 lung epithelial cells derived from Muta (TM) Mouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo Muta (TM) Mouse test. 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and urban air pollution. We investigated the mutagenicity and DNA binding of 3-NBA and its main metabolite 3-aminobenzanthrone (3-ABA) in vitro and in vivo in the Muta (TM) Mouse assay. Mice were treated with 3-NBA or 3-ABA (0, 2 or 5 mg/kg body weight/day) by gavage for 28 days and 28 days later lacZ mutant frequency (MF) was determined in liver, lung and bone marrow. For both compounds, dose-related increases in MF were seen in liver and bone marrow, but not in lung; mutagenic activity was similar to 2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by P-32-post-labelling) were found in liver (similar to 230 adducts per 10(8) nucleotides) with levels 20- to 40-fold lower in bone marrow and lung. With 3-ABA, DNA adduct levels were again highest in the liver, but similar to 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 mu g/ml 3-NBA or 3-ABA for 6 h with or without exogenous activation (S9) and harvested after 3 days. For 3-NBA, there was a dose-related increase in MF both with and without S9 mix, which was 〉 10 times higher than observed in vivo. At the highest concentration of 3-ABA (10 mu g/ml), we found only around a 2-fold increase in MF relative to controls. DNA adduct formation in FE1 cells was dose-dependent for both compounds, but 10- to 20-fold higher for 3-NBA compared to 3-ABA. Collectively, our data indicate that Muta (TM) Mouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo Muta (TM) Mouse testing
    Type of Publication: Journal article published
    PubMed ID: 18635558
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  • 7
    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
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  • 8
    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
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  • 9
    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
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  • 10
    Keywords: CANCER ; CELLS ; IN-VITRO ; CELL ; EXPOSURE ; GENE ; SAMPLES ; MICE ; PATIENT ; DNA ; CARCINOGENESIS ; ACID ; DATABASE ; MUTATIONS ; mutagenesis ; P53 MUTATIONS ; immortalization ; INVESTIGATE ; TP53 mutation ; cancer aetiology
    Abstract: The proposal has been put forward that the primary cause of Balkan endemic nephropathy (BEN) is exposure to food crops contaminated with seeds of Aristolochia spp, which contain high levels of aristolochic acids (AA). Recently. tumour DNA samples from patients with BEN were found to harbour principally A to T mutations in the TP53 tumour suppressor gene (Grollman et al., Proc Natl Acad Sci USA 2007;104:12129-34). Using a novel mutation assay in which we can induce and select mutations in human TP53 sequences in vitro by exposure of cultured cells to a mutagen, we found that A to T mutations were elicited by aristolochic acid at sites in TP53 rarely mutated in human cancers in general, but which were observed in the BEN patients. This concordance of specific mutations in patient tumours and aristolochic acid exposed cultures supports the argument that AA has a direct role in the aetiology of BEN-associated cancer. (C) 2008 Wiley-Liss. Inc
    Type of Publication: Journal article published
    PubMed ID: 19030178
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