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

A.M. Krais, E.N. Speksnijder, J.P. Melis, R. Indra, M. Moserova, Roger W. Godschalk, Frederik-J. van Schooten, A. Seidel, K. Kopka, H.H. Schmeiser, M. Stiborova, D.H. Phillips, M. Luijten, V.M. Arlt

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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 32P-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.
Original languageEnglish
Pages (from-to)839-851
Number of pages13
JournalArchives of Toxicology
Volume90
Issue number4
Early online date1 Jan 2015
DOIs
Publication statusPublished - Apr 2016

Keywords

  • Benzo[a]pyrene
  • Tumour suppressor p53
  • Mouse models
  • Cytochrome P450
  • Carcinogen metabolism
  • DNA adducts
  • NUCLEOTIDE EXCISION-REPAIR
  • ARYL-HYDROCARBON RECEPTOR
  • AHR KNOCKOUT MICE
  • IN-VIVO
  • ADDUCT FORMATION
  • GENE-EXPRESSION
  • CONTAMINANT 3-NITROBENZANTHRONE
  • NAD(P)H-QUINONE OXIDOREDUCTASE
  • CYTOCHROME-P450 ENZYMES
  • TP53 MUTATIONS

Cite this

Krais, A.M. ; Speksnijder, E.N. ; Melis, J.P. ; Indra, R. ; Moserova, M. ; Godschalk, Roger W. ; van Schooten, Frederik-J. ; Seidel, A. ; Kopka, K. ; Schmeiser, H.H. ; Stiborova, M. ; Phillips, D.H. ; Luijten, M. ; Arlt, V.M. / The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice. In: Archives of Toxicology. 2016 ; Vol. 90, No. 4. pp. 839-851.
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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 32P-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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author = "A.M. Krais and E.N. Speksnijder and J.P. Melis and R. Indra and M. Moserova and Godschalk, {Roger W.} and {van Schooten}, Frederik-J. and A. Seidel and K. Kopka and H.H. Schmeiser and M. Stiborova and D.H. Phillips and M. Luijten and V.M. Arlt",
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language = "English",
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pages = "839--851",
journal = "Archives of Toxicology",
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Krais, AM, Speksnijder, EN, Melis, JP, Indra, R, Moserova, M, Godschalk, RW, van Schooten, F-J, Seidel, A, Kopka, K, Schmeiser, HH, Stiborova, M, Phillips, DH, Luijten, M & Arlt, VM 2016, 'The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice', Archives of Toxicology, vol. 90, no. 4, pp. 839-851. https://doi.org/10.1007/s00204-015-1531-8

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, A.M.; Speksnijder, E.N.; Melis, J.P.; Indra, R.; Moserova, M.; Godschalk, Roger W.; van Schooten, Frederik-J.; Seidel, A.; Kopka, K.; Schmeiser, H.H.; Stiborova, M.; Phillips, D.H.; Luijten, M.; Arlt, V.M.

In: Archives of Toxicology, Vol. 90, No. 4, 04.2016, p. 839-851.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice

AU - Krais, A.M.

AU - Speksnijder, E.N.

AU - Melis, J.P.

AU - Indra, R.

AU - Moserova, M.

AU - Godschalk, Roger W.

AU - van Schooten, Frederik-J.

AU - Seidel, A.

AU - Kopka, K.

AU - Schmeiser, H.H.

AU - Stiborova, M.

AU - Phillips, D.H.

AU - Luijten, M.

AU - Arlt, V.M.

PY - 2016/4

Y1 - 2016/4

N2 - 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 32P-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.

AB - 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 32P-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.

KW - Benzo[a]pyrene

KW - Tumour suppressor p53

KW - Mouse models

KW - Cytochrome P450

KW - Carcinogen metabolism

KW - DNA adducts

KW - NUCLEOTIDE EXCISION-REPAIR

KW - ARYL-HYDROCARBON RECEPTOR

KW - AHR KNOCKOUT MICE

KW - IN-VIVO

KW - ADDUCT FORMATION

KW - GENE-EXPRESSION

KW - CONTAMINANT 3-NITROBENZANTHRONE

KW - NAD(P)H-QUINONE OXIDOREDUCTASE

KW - CYTOCHROME-P450 ENZYMES

KW - TP53 MUTATIONS

U2 - 10.1007/s00204-015-1531-8

DO - 10.1007/s00204-015-1531-8

M3 - Article

VL - 90

SP - 839

EP - 851

JO - Archives of Toxicology

JF - Archives of Toxicology

SN - 0340-5761

IS - 4

ER -