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The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene : effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice

Krais, Annette M LU ; Speksnijder, Ewoud N; Melis, Joost P M; Indra, Radek; Moserova, Michaela; Godschalk, Roger W.; van Schooten, Frederik J.; Seidel, Albrecht; Kopka, Klaus and Schmeiser, Heinz H., et al. (2016) In Archiv fur Toxikologie 90(4). p.51-839
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... (More)

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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@article{838e8192-73d3-41d9-9c5e-dd3556a4b66c,
  abstract     = {<p>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.</p>},
  author       = {Krais, Annette M and Speksnijder, Ewoud N and Melis, Joost P M and Indra, Radek and Moserova, Michaela and Godschalk, Roger W. and van Schooten, Frederik J. and Seidel, Albrecht and Kopka, Klaus and Schmeiser, Heinz H. and Stiborova, Marie and Phillips, David H. and Luijten, Mirjam and Arlt, Volker M},
  issn         = {0003-9446},
  keyword      = {Activation, Metabolic,Animals,Benzo(a)pyrene,Carcinogens, Environmental,Cytochrome P-450 CYP1A1,DNA Adducts,DNA Damage,Inactivation, Metabolic,Kidney,Male,Mice, Inbred C57BL,Mice, Mutant Strains,Microsomes, Liver,NAD(P)H Dehydrogenase (Quinone),Tumor Suppressor Protein p53,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {4},
  pages        = {51--839},
  publisher    = {Springer},
  series       = {Archiv fur Toxikologie},
  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},
  url          = {http://dx.doi.org/10.1007/s00204-015-1531-8},
  volume       = {90},
  year         = {2016},
}