CYP1A1 induction in the colon by serum: involvement of the PPARα pathway and evidence for a new specific human PPREα site
2011
Villard , Pierre-Henri (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Barlesi , Fabrice (Université de la Méditerranée (Aix-Marseille 2), Marseille(France). Assistance Publique Hôpitaux de Marseille) | Armand , Martine (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Dao , Mai Anh (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Pascussi , Jean-Marc (Institut de Recherche pour le Développement, Montpellier(France).) | Fouchier , Francis (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Champion , Serge (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Dufour , Claire (INRA , Avignon (France). UMR 0408 Sécurité et Qualité des Produits d'Origine Végétale) | Ginies , Christian (INRA , Avignon (France). UMR 0408 Sécurité et Qualité des Produits d'Origine Végétale) | Ayman , Khalil (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Amiot-Carlin , Marie Josephe (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Barra , Yves (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques ) | Seree , Éric (INRA , Marseille (France). UMR 1260 Nutrition, Obésité et Risques Thrombotiques )
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. Conclusion 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
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