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  • human  (11)
  • IN-VITRO  (9)
  • 1
    Keywords: SPECTRA ; CANCER ; CELLS ; CELL ; human ; DNA adducts ; EXPOSURE ; RISK ; GENE ; TISSUE ; PATIENT ; DNA ; MECHANISM ; CARCINOGENESIS ; DNA ADDUCT FORMATION ; RATS ; tumour ; ASSOCIATION ; ACID ; NUMBER ; MUTATION ; p53 ; MUTATIONS ; ADDUCTS ; INDIVIDUALS ; NEPHROPATHY ; mutagenesis ; CONSUMPTION ; aristolochic acid ; CHINESE HERBS NEPHROPATHY ; DNA-ADDUCTS ; RENAL-FAILURE ; molecular ; FEATURES ; ONCOLOGY ; MOLECULAR-MECHANISM ; RE ; PATTERN ; P53 GENE ; RAS GENE ; ADDUCT FORMATION ; development ; analysis ; DNA ADDUCT ; p53 mutation ; RISK-FACTOR ; SPECTRUM ; PREDICT ; aetiology ; COVALENT DNA ADDUCTION ; HUMAN P53 GENE ; OCHRATOXIN-A
    Abstract: Balkan endemic nephropathy (BEN) is found in certain rural areas of the Balkans and affects at least 25 000 inhabitants. Of the many hypotheses on BEN, the Aristolochia hypothesis has recently gained ground substantiated by the investigations on aristolochic acid nephropathy (AAN). On both clinical and morphological grounds, AAN is very similar to BEN. That exposure to aristolochic acid (AA) of individuals living in endemic areas through consumption of bread made with flour contaminated with seeds of Aristolochia clematitis is responsible for BEN is an old hypothesis, but one which is fully consistent with the unique epidemiologic features of BEN. Here, we propose an approach to investigate AA-induced mutagenesis in BEN that can provide molecular clues to the aetiology of its associated urothelial cancer. The molecular mechanism of AA-induced carcinogenesis demonstrates a strong association between DNA adduct formation, mutation pattern and tumour development. A clear link between urothelial tumours, p53 mutations and AA exposure should emerge as more tumour DNA from BEN patients from different endemic areas becomes available for mutation analysis. We predict that the observed p53 mutation spectrum will be dominated by AT -〉 TA transversion mutations as has already been demonstrated in the human p53 gene of immortalized cells after exposure to AAI and urothelial tumours from BEN patients in Croatia. Moreover, the detection of AA-specific DNA adducts in renal tissue of a number of BEN patients and individuals living in areas endemic for BEN in Croatia provides new evidence that chronic exposure to AA is a risk factor for BEN and its associated cancer
    Type of Publication: Journal article published
    PubMed ID: 17434925
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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: 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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  • 5
    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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  • 6
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; CELL ; human ; INHIBITION ; PATHWAY ; PATHWAYS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; ACCUMULATION ; LINES ; RESPONSES ; DNA ; CARCINOGENESIS ; DNA ADDUCT FORMATION ; cell cycle ; CELL-CYCLE ; CELL-LINES ; ACID ; gene expression ; MUTATION ; CELL-LINE ; MODULATION ; CANCER-CELLS ; MUTATIONS ; PARAMETERS ; ONCOGENE ; EPITHELIAL-CELLS ; ADDUCTS ; DNA-REPLICATION ; REPLICATION ; OUTCOMES ; AD ; NEPHROPATHY ; SUBSTRATE-SPECIFICITY ; INJURY ; TP53 ; aristolochic acid ; BALKAN ENDEMIC NEPHROPATHY ; CHINESE HERBS NEPHROPATHY ; AGENT ; UROTHELIAL CARCINOMA ; RE ; P53 GENE ; DEPENDENCE ; ADDUCT FORMATION ; PHASE ; PROFILES ; signalling ; EXPRESSION PROFILES ; pharmacology ; USA ; OXIDATIVE DNA-DAMAGE ; ENGLAND ; aristolochic acid nephropathy ; PROFILE ; outcome ; response ; biological ; expression profile ; CALPAIN INHIBITION ; RENAL FIBROSIS ; Urothelial cancel
    Abstract: Aristolochic acid (AA) is the Causative agent of urothelial tumours associated with aristolochic acid nephropathy. These tumours contain TP53 mutations and over-express TP53. We compared transcriptional and translational responses of two isogenic HCT116 cell lines, one expressing TP53 (p53-WT) and the other with this gene knocked out (p53-null), to treatment with aristolochic acid I (AAI) (50-100 mu M) lor 6-48 h. Modulation of 118 genes was observed in p53-WT cells ad 123 genes in p53-null cells. Some genes, including INSIG1, EGR1, CAV1, LCN2 arid CCNG1, were differentially expressed in the two cell lines. CDKN1A was selectively Up-regulated in p53-WT cells, leading to accumulation of TP53 and CDKN1A. Apoptotic signalling, measured by caspase-3 and -7 activity, was TP53-dependent. Both cell types accumulated in S phase, suggesting that AAI-DNA adducts interfere with DNA replication, independently of TP53 Status. The oncogene MYC, frequently over expressed ill urothelial turnouts, Was Up-regulated by AAI, whereas FOS was down-regulated. Observed modulation of genes involved in endocytosis, e.g. RAB5A, may be relevant to the known inhibition of receptor-mediated endocytosis, an early sign of AA-mediated proximal tubule injury. AAI-DNA adduct Formation was significantly greater in p53-WT cells than in p53-null cells. Collectively, phenotypic anchoring of the AAI-induced expression profiles to DNA adduct formation, cell-cycle parameters, TP53 expression arid apoptosis identified several genes linked to these biological outcomes, some of which are TP53-dependent. These results strengthen the importance of TP53 in AA-induced cancer, arid indicate that other alterations, e.g. to MYC oncogenic pathways, may also contribute. (C) 2008 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18639569
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  • 7
    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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  • 8
    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
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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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