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

Annette M Krais,David H Phillips,Joost P M Melis,Albrecht Seidel,Ewoud N Speksnijder,Frederik-J Van Schooten,Mirjam Luijten,Roger W Godschalk,Radek Indra,Volker M Arlt,Klaus Kopka,Marie Stiborova,Heinz H Schmeiser,Michaela Moserova

doi:10.1007/s00204-015-1531-8

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1531-8) contains supplementary material, which is available to authorized users.

Highlights

The TP53 tumour suppressor gene, which encodes the protein p53, is often described as the guardian of the genome and is the most commonly mutated gene in human tumours (Olivier et al 2010)
We found that BaP-induced CYP1A1 expression was regulated through a p53 response element (p53RE) in the regulatory region of CYP1A1, thereby providing a novel pathway for the induction of CYP1A1 by polycyclic aromatic hydrocarbons (PAHs) such as BaP (Wohak et al 2014)
cytochrome P450 (CYP)-mediated metabolic activation to bind to DNA, these findings suggest that the differences in DNA adduct formation observed in liver and kidney with the parent compound

Summary

Introduction

The TP53 tumour suppressor gene, which encodes the protein p53, is often described as the guardian of the genome and is the most commonly mutated gene in human tumours (Olivier et al 2010). It controls cellular processes to maintain genomic integrity, including repair to remove DNA damage (Taneja et al 2011). Arch Toxicol (2016) 90:839–851 of the normal p53 response by TP53 mutation leads to increased risks of tumour development. TP53 is mutated in over 50 % of sporadic tumours, and various environmental carcinogens have been found to be associated with characteristic mutational signatures in TP53 (Olivier et al 2010). Besides its role in DNA damage response, p53 has been found to regulate metabolic pathways, thereby linking p53 to cancer, and to other diseases such as diabetes and obesity (Maddocks and Vousden 2011)

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