CYP1A1 induction in the colon by serum: involvement of the PPARα pathway and evidence for a new specific human PPREα site

We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro. Our purpose was (i) to identify the molecular mechanism involved and (ii) to characterize the inducer compound(s) in serum involved at least in part. Serum was fractionated on hydrophobic co...

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Bibliographic Details
Published in:PloS one 2011-01, Vol.6 (1), p.e14629
Main Authors: Villard, Pierre-Henri, Barlesi, Fabrice, Armand, Martine, Dao, Thi-Mai-Anh, Pascussi, Jean-Marc, Fouchier, Francis, Champion, Serge, Dufour, Claire, Giniès, Christian, Khalil, Ayman, Amiot, Marie-Josephe, Barra, Yves, Seree, Eric
Format: Article
Language:English
Subjects:
Aldehydes - pharmacology
Binding Sites
Biochemistry, Molecular Biology
Biomarkers
Chromatography
Colon
Colon - metabolism
Colorectal cancer
Cystic fibrosis
Cytochrome
Cytochrome P-450 CYP1A1 - biosynthesis
Cytochrome P-450 CYP1A1 - genetics
Cytochrome P450
Deoxyribonucleic acid
DNA
Experiments
Fatty acids
Food
Gastroenterology and Hepatology
Gastroenterology and Hepatology/Colon and Rectum
Gastroenterology and Hepatology/Gastrointestinal Cancers
Gene expression
Hexanal
Humans
Hydrophobicity
Life Sciences
Ligands
Linoleic acid
Lipid peroxidation
Lipids
Liver cancer
Lung cancer
Mass spectrometry
Monooxygenase
Mutagenesis
Mutation
Peroxidation
Peroxisome proliferator-activated receptors
PPAR alpha - genetics
PPAR alpha - metabolism
Promoter Regions, Genetic
Regulatory sequences
Response Elements
Scientific imaging
Serum - chemistry
Signal Transduction
Solid phase methods
Transcriptional Activation - drug effects
Transcriptional Activation - genetics
Women
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Summary:We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro. Our purpose was (i) to identify the molecular mechanism involved and (ii) to characterize the inducer compound(s) in serum involved at least in part. Serum was fractionated on hydrophobic columns. PPARα involvement was demonstrated by gene reporter assays, DNA mutagenesis and EMSA. Gene expression was evaluated by qRT-PCR. Serum samples were analyzed using HS-SPME-GC-MS. The inductive effect of serum did not depend on the AhR pathway and was enhanced by cotransfection of PPARα cDNA. Mutations in the PPAR response elements of the CYP1A1 gene promoter suppressed this effect. One of the PPRE sites appeared highly specific for human PPARα, an unreported PPRE property. A link was found between CYP1A1 inducibility and serum hydrophobic compounds. Characterization of sera showed that hexanal, a metabolite produced by peroxidation of linoleic acid, was involved in CYP1A1 induction by serum, possibly along with other serum entities. We demonstrate that serum induces CYP1A1 via the PPARα pathway and that hexanal is one of the serum inducers. The two PPRE sites within the CYP1A1 promoter are functional and one of them is specific for PPARα.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0014629