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  • 1
    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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  • 2
    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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  • 3
    Keywords: TOXICOLOGY ; EXPOSURE ; ACTIVATION ; metabolic activation ; MOUSE ; genetics ; METABOLIC-ACTIVATION ; mutagenesis ; heredity ; cytochrome P450
    Type of Publication: Meeting abstract published
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