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

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• 作者：Laura E. Wohak ; Annette M. Krais ; Jill E. Kucab ; Julia Stertmann…
• 关键词：Benzo[a]pyrene ; Tumour suppressor p53 ; Cytochrome P450 ; Carcinogen metabolism ; DNA adducts
• 刊名：Archives of Toxicology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：90
• 期：2
• 页码：291-304
• 全文大小：1,169 KB
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• 作者单位：Laura E. Wohak (1) (2)
  Annette M. Krais (1)
  Jill E. Kucab (1)
  Julia Stertmann (1)
  Steinar Øvrebø (3)
  Albrecht Seidel (4)
  David H. Phillips (1)
  Volker M. Arlt (1)
  
  1. 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
  2. Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK
  3. Department of Biological and Chemical Working Environment, National Institute of Occupational Health, Oslo, Norway
  4. Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer-Foundation, Grosshansdorf, Germany
  
• 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0738

文摘

The tumour suppressor gene TP53 is mutated in more than 50 % of human tumours, making it one of the most important cancer genes. We have investigated the role of TP53 in cytochrome P450 (CYP)-mediated metabolic activation of three polycyclic aromatic hydrocarbons (PAHs) in a panel of isogenic colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/−), TP53(−/−), TP53(R248W/+) or TP53(R248W/−) were treated with benzo[a]pyrene (BaP), dibenz[a,h]anthracene and dibenzo[a,l]pyrene, and the formation of DNA adducts was measured by 32P-postlabelling analysis. Each PAH formed significantly higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. There were also significantly lower levels of PAH metabolites in the culture media of these other cell lines. Bypass of the need for metabolic activation by treating cells with the corresponding reactive PAH-diol-epoxide metabolites resulted in similar adduct levels in all cell lines, which confirms that the influence of p53 is on the metabolism of the parent PAHs. Western blotting showed that CYP1A1 protein expression was induced to much greater extent in TP53(+/+) cells than in the other cell lines. CYP1A1 is inducible via the aryl hydrocarbon receptor (AHR), but we did not find that expression of AHR was dependent on p53; rather, we found that BaP-induced CYP1A1 expression was regulated through p53 binding to a p53 response element in the CYP1A1 promoter region, thereby enhancing its transcription. This study demonstrates a new pathway for CYP1A1 induction by environmental PAHs and reveals an emerging role for p53 in xenobiotic metabolism. Keywords Benzo[a]pyrene Tumour suppressor p53 Cytochrome P450 Carcinogen metabolism DNA adducts