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.

Analytical and Environmental Sciences Division MRC PHE Centre for Environment and Health King's College London Franklin Wilkins Building 150 Stamford Street London SE1 9NH UK

Biochemical Institute for Environmental Carcinogens Prof Dr Gernot Grimmer Foundation 22927 Grosshansdorf Germany

Center for Health Protection National Institute for Public Health and the Environment 3721 MA Bilthoven The Netherlands Department of Human Genetics Leiden University Medical Center 2300 RC Leiden The Netherlands

Department of Biochemistry Faculty of Science Charles University 12840 Prague 2 Czech Republic

Department of Toxicology School for Nutrition Toxicology and Metabolism Maastricht University Medical Centre 6200 MD Maastricht The Netherlands

Division of Radiopharmaceutical Chemistry German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

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$a Krais, Annette M $u 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.

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$a The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice / $c AM. Krais, EN. Speksnijder, JP. Melis, R. Indra, M. Moserova, RW. Godschalk, FJ. van Schooten, A. Seidel, K. Kopka, HH. Schmeiser, M. Stiborova, DH. Phillips, M. Luijten, VM. Arlt,

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$a 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.

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$a Speksnijder, Ewoud N $u 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.

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$a Melis, Joost P M $u 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.

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$a Indra, Radek $u Department of Biochemistry, Faculty of Science, Charles University, 12840, Prague 2, Czech Republic.

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$a Moserova, Michaela $u Department of Biochemistry, Faculty of Science, Charles University, 12840, Prague 2, Czech Republic.

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$a Godschalk, Roger W $u Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD, Maastricht, The Netherlands.

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$a van Schooten, Frederik-J $u Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD, Maastricht, The Netherlands.

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$a Seidel, Albrecht $u Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer-Foundation, 22927, Grosshansdorf, Germany.

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