title: CYP1A1 induction in the colon by serum: involvement of the PPARα pathway and evidence for a new specific human PPREα site.
abstract: BACKGROUND
  We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INRA, UMR1260, Nutriments Lipidiques et Prévention des Maladies Métaboliques, Marseille, France.
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Villard
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.forename: Martine
authors.initials: M
authors.lastname: Armand
authors.forename: Thi-Mai-Anh
authors.initials: TM
authors.lastname: Dao
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Francis
authors.initials: F
authors.lastname: Fouchier
authors.forename: Serge
authors.initials: S
authors.lastname: Champion
authors.forename: Claire
authors.initials: C
authors.lastname: Dufour
authors.forename: Christian
authors.initials: C
authors.lastname: Giniès
authors.forename: Ayman
authors.initials: A
authors.lastname: Khalil
authors.forename: Marie-Josephe
authors.initials: MJ
authors.lastname: Amiot
authors.forename: Yves
authors.initials: Y
authors.lastname: Barra
authors.forename: Eric
authors.initials: E
authors.lastname: Seree
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D001665:Binding Sites; D003106:Colon / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D044967:Serum / Q000737:chemistry; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
chemical_list: D000447:Aldehydes; D047493:PPAR alpha; C010463:n-hexanal; D019363:Cytochrome P-450 CYP1A1