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dc.date.accessioned2018-07-05T09:35:09Z
dc.date.issued2016
dc.identifierhttp://link.springer.com/article/10.1007/s00204-014-1409-1
dc.identifier.citationARCHIVES OF TOXICOLOGY, 2016, 90 (2), pp. 291 - 304
dc.identifier.issn0340-5761
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1988
dc.description.abstractThe tumour suppressor gene TP53 is mutated in more than 50 % of human tumours, making it one of the most important cancer genes. We have investigated the role of TP53 in cytochrome P450 (CYP)-mediated metabolic activation of three polycyclic aromatic hydrocarbons (PAHs) in a panel of isogenic colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/-), TP53(-/-), TP53(R248W/+) or TP53(R248W/-) were treated with benzo[a]pyrene (BaP), dibenz[a,h]anthracene and dibenzo[a,l]pyrene, and the formation of DNA adducts was measured by P-32-postlabelling analysis. Each PAH formed significantly higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. There were also significantly lower levels of PAH metabolites in the culture media of these other cell lines. Bypass of the need for metabolic activation by treating cells with the corresponding reactive PAH-diol-epoxide metabolites resulted in similar adduct levels in all cell lines, which confirms that the influence of p53 is on the metabolism of the parent PAHs. Western blotting showed that CYP1A1 protein expression was induced to much greater extent in TP53(+/+) cells than in the other cell lines. CYP1A1 is inducible via the aryl hydrocarbon receptor (AHR), but we did not find that expression of AHR was dependent on p53; rather, we found that BaP-induced CYP1A1 expression was regulated through p53 binding to a p53 response element in the CYP1A1 promoter region, thereby enhancing its transcription. This study demonstrates a new pathway for CYP1A1 induction by environmental PAHs and reveals an emerging role for p53 in xenobiotic metabolism.
dc.format.extent291 - 304
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectBenzo[a]pyrene Tumour suppressor p53 Cytochrome P450 Carcinogen metabolism DNA adducts human cancer-cells aristolochic acid nephropathy nucleotide excision-repair dna-adducts in-vivo metabolic-activation messenger-rna p53 expression responses Toxicology
dc.titleCarcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism
dc.typeJournal Article
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfARCHIVES OF TOXICOLOGY
pubs.issue2
pubs.notesISI Document Delivery No.: DD8SD Times Cited: 3 Cited Reference Count: 60 Wohak, Laura E. Krais, Annette M. Kucab, Jill E. Stertmann, Julia Ovrebo, Steinar Seidel, Albrecht Phillips, David H. Arlt, Volker M. Cancer Research UK [C313/A14329]; Wellcome Trust [101126/Z/13/Z, 101126/B/13/Z]; Institute of Cancer Research, London, United Kingdom; German Research Foundation (DFG); United Kingdom Environmental Mutagen Society (UKEMS) The study was funded, in part, by Cancer Research UK (Grant C313/A14329) and the Wellcome Trust (Grants 101126/Z/13/Z and 101126/B/13/Z). Laura Wohak was supported by a PhD studentship from the Institute of Cancer Research, London, United Kingdom. Annette Krais was supported by a fellowship from the German Research Foundation (DFG). Julia Stertmann received a Summer Student Placement Award from the United Kingdom Environmental Mutagen Society (UKEMS). We thank Dr. Phil Cunningham from King's College London for advice and help with the bioinformatic analysis for the primer design. 3 0 Springer heidelberg Heidelberg 1432-0738 public The tumour suppressor gene TP53 is mutated in more than 50 % of human tumours, making it one of the most important cancer genes. We have investigated the role of TP53 in cytochrome P450 (CYP)-mediated metabolic activation of three polycyclic aromatic hydrocarbons (PAHs) in a panel of isogenic colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/-), TP53(-/-), TP53(R248W/+) or TP53(R248W/-) were treated with benzo[a]pyrene (BaP), dibenz[a,h]anthracene and dibenzo[a,l]pyrene, and the formation of DNA adducts was measured by P-32-postlabelling analysis. Each PAH formed significantly higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. There were also significantly lower levels of PAH metabolites in the culture media of these other cell lines. Bypass of the need for metabolic activation by treating cells with the corresponding reactive PAH-diol-epoxide metabolites resulted in similar adduct levels in all cell lines, which confirms that the influence of p53 is on the metabolism of the parent PAHs. Western blotting showed that CYP1A1 protein expression was induced to much greater extent in TP53(+/+) cells than in the other cell lines. CYP1A1 is inducible via the aryl hydrocarbon receptor (AHR), but we did not find that expression of AHR was dependent on p53; rather, we found that BaP-induced CYP1A1 expression was regulated through p53 binding to a p53 response element in the CYP1A1 promoter region, thereby enhancing its transcription. This study demonstrates a new pathway for CYP1A1 induction by environmental PAHs and reveals an emerging role for p53 in xenobiotic metabolism.
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.volume90
pubs.embargo.termsNot known
icr.researchteamSarcoma Molecular Pathologyen_US
dc.contributor.icrauthorWohak, Lauraen


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