title: The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice.
abstract: The tumour suppressor p53 is one of the most important cancer genes. Previous findings have shown that p53 expression can influence DNA adduct formation of the environmental carcinogen benzo[a]pyrene (BaP) in human cells, indicating a role for p53 in the cytochrome P450 (CYP) 1A1-mediated biotransformation of BaP in vitro. We investigated the potential role of p53 in xenobiotic metabolism in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with BaP. BaP-DNA adduct levels, as measured by (32)P-postlabelling analysis, were significantly higher in liver and kidney of Trp53(-/-) mice than of Trp53(+/+) mice. Complementarily, significantly higher amounts of BaP metabolites were also formed ex vivo in hepatic microsomes from BaP-pretreated Trp53(-/-) mice. Bypass of the need for metabolic activation by treating mice with BaP-7,8-dihydrodiol-9,10-epoxide resulted in similar adduct levels in liver and kidney in all mouse lines, confirming that the influence of p53 is on the biotransformation of the parent compound. Higher BaP-DNA adduct levels in the livers of Trp53(-/-) mice correlated with higher CYP1A protein levels and increased CYP1A enzyme activity in these animals. Our study demonstrates a role for p53 in the metabolism of BaP in vivo, confirming previous in vitro results on a novel role for p53 in CYP1A1-mediated BaP metabolism. However, our results also suggest that the mechanisms involved in the altered expression and activity of the CYP1A1 enzyme by p53 in vitro and in vivo are different.
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Krais
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), 3721 MA, Bilthoven, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Ewoud N
authors.initials: EN
authors.lastname: Speksnijder
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), 3721 MA, Bilthoven, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Joost P M
authors.initials: JP
authors.lastname: Melis
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, 12840, Prague 2, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Indra
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, 12840, Prague 2, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Moserova
authors.affiliation: Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD, Maastricht, The Netherlands.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Godschalk
authors.affiliation: Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD, Maastricht, The Netherlands.
authors.forename: Frederik-J
authors.initials: FJ
authors.lastname: van Schooten
authors.affiliation: Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer-Foundation, 22927, Grosshansdorf, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Seidel
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, 12840, Prague 2, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborova
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), 3721 MA, Bilthoven, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. volker.arlt@kcl.ac.uk.
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000493:pharmacokinetics*; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000493:pharmacokinetics*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D008658:Inactivation, Metabolic; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002274:Carcinogens, Environmental; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse
keywords: Benzo[a]pyrene; Carcinogen metabolism; Cytochrome P450; DNA adducts; Mouse models; Tumour suppressor p53