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Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism

Laura E Wohak1,2, Annette M Krais1, Jill E Kucab1

  • 1Analytical 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.

Archives of Toxicology
|November 16, 2014
PubMed

Insights

The tumor suppressor gene TP53 influences how the body processes environmental polycyclic aromatic hydrocarbons (PAHs). Wild-type TP53 enhances the metabolism of PAHs, reducing DNA adduct formation and increasing CYP1A1 expression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Environmental Health

Background:

  • The TP53 gene is a critical tumor suppressor, frequently mutated in human cancers.
  • Cytochrome P450 (CYP) enzymes mediate the metabolic activation of polycyclic aromatic hydrocarbons (PAHs), environmental carcinogens.
  • The interplay between TP53 status and PAH metabolism remains incompletely understood.

Purpose of the Study:

  • To investigate the role of TP53 in the metabolic activation of PAHs by CYP enzymes.
  • To determine how different TP53 statuses affect DNA adduct formation and CYP1A1 expression in response to PAHs.

Main Methods:

  • Utilized isogenic colorectal HCT116 cells with varying TP53 genotypes (TP53(+/+), TP53(+/-), TP53(-/-), TP53(R248W/+), TP53(R248W/-)).
  • Exposed cells to benzo[a]pyrene (BaP), dibenz[a,h]anthracene, and dibenzo[a,l]pyrene.
  • Quantified DNA adducts using (32)P-postlabelling and measured CYP1A1 protein expression via Western blotting.

Main Results:

  • Significantly higher DNA adduct levels and PAH metabolites were observed in TP53(+/+) cells compared to other TP53 variants.
  • Bypassing metabolic activation with reactive PAH-diol-epoxides yielded similar adduct levels across all cell lines, indicating TP53's role in metabolism.
  • TP53(+/+) cells exhibited a greater induction of CYP1A1 protein expression, regulated by p53 binding to the CYP1A1 promoter.

Conclusions:

  • TP53 plays a significant role in regulating CYP1A1 induction and the metabolic activation of environmental PAHs.
  • This study reveals a novel pathway for CYP1A1 induction mediated by p53, highlighting its function in xenobiotic metabolism.
  • Understanding TP53's role in PAH metabolism offers insights into cancer prevention and environmental health strategies.
Keywords:
Benzo[a]pyreneCarcinogen metabolismCytochrome P450DNA adductsTumour suppressor p53

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