CYP1A1 Induction in the Colon by Serum: Involvement of the PPAR[alpha] Pathway and Evidence for a New Specific Human PPRE[alpha] Site

• 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: Biological products; Cytochrome P-450; Gene expression; Genes; Metabolites; Unsaturated fatty acids
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014629

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. PPAR[alpha] 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 PPAR[alpha] 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 PPAR[alpha], 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 PPAR[alpha] 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 PPAR[alpha].