Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism.
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 (32)P-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.
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.|Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK.
Laura E
LE
Wohak
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.
Annette M
AM
Krais
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.
Jill E
JE
Kucab
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.
Julia
J
Stertmann
Department of Biological and Chemical Working Environment, National Institute of Occupational Health, Oslo, Norway.
Steinar
S
Øvrebø
Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer-Foundation, Grosshansdorf, Germany.
Albrecht
A
Seidel
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.
David H
DH
Phillips
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. volker.arlt@kcl.ac.uk.
Volker M
VM
Arlt
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology* / Q000506:poisoning / Q000633:toxicity*; D018736:DNA Adducts; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018675:Toxicity Tests; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D065693:Cytochrome P-450 Enzyme Inducers; D018736:DNA Adducts; D016660:NAD(P)H Dehydrogenase (Quinone); D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D016159:Tumor Suppressor Protein p53; C111235:AHR protein, human; C495901:TP53 protein, human; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; C447479:NQO1 protein, human
Benzo[a]pyrene; Carcinogen metabolism; Cytochrome P450; DNA adducts; Tumour suppressor p53