title: Identification of a new stilbene-derived inducer of paraoxonase 1 and ligand of the Aryl hydrocarbon Receptor.
abstract: Paraoxonase 1 (PON1) is a high-density lipoprotein-associated enzyme, synthesized in the liver and secreted into the blood. PON1 displays antioxidant properties and is involved in organophosphorous compounds and oxidized lipids degradation. Because of these beneficial effects, pharmacological regulation of PON1 appears to be highly relevant in toxicology and cardiology. Recent studies undertaken on the regulation of the PON1 promoter in our laboratory have identified resveratrol, through its activation of the Aryl hydrocarbon Receptor (AhR), as a putative inducer of PON1. We have tested a new modulator of AhR, (Z)-2,3-bis (4-nitrophenyl)-acrylonitrile, and established that it is a more potent inducer of PON1 at the mRNA, protein and enzymatic activity as compared to resveratrol. It also acts by activating the AhR. However, in contrast with traditional AhR agonists, it does not induce cyp1A1 transcription. (Z)-2,3-bis (4-nitrophenyl)-acrylonitrile is therefore a specific AhR modulator targeting PON1.
authors.affiliation: INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 Rue des Saints Pères, 75006 Paris, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Guyot
authors.forename: Xavier
authors.initials: X
authors.lastname: Coumoul
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Chassé
authors.forename: Farid
authors.initials: F
authors.lastname: Khallouki
authors.forename: Jean François
authors.initials: JF
authors.lastname: Savouret
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D043303:Aryldialkylphosphatase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C570603:2,3-bis(4-nitrophenyl)acrylonitrile; D004791:Enzyme Inhibitors; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D043303:Aryldialkylphosphatase; D000181:Acrylonitrile; D000077185:Resveratrol