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Molecular and Cellular Biology, June 2004, p. 5209-5222, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5209-5222.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism

Cédric Gouédard, Robert Barouki,1,2* and Yannick Morel1,3

INSERM UMR-S 490, Université René Descartes, 75270 Paris Cedex 06,1 Centre d'études du Bouchet, 91710 Vert-le-Petit,3 Service de Biochimie, Hôpital Européen Georges Pompidou, 75015 Paris, France2

Received 5 November 2003/ Returned for modification 6 January 2004/ Accepted 30 March 2004

Human paraoxonase 1 (PON-1) is a serum high-density lipoprotein-associated enzyme mainly secreted by the liver. It has endogenous and exogenous substrates and displays protective properties with respect to cardiovascular disease and organophosphate intoxication. In the HuH7 human hepatoma cell line, PON-1 activity and mRNA levels were increased by dietary polyphenolic compounds such as quercetin but also by toxic ligands of the aryl hydrocarbon receptor (AhR) such as 3-methylcholanthrene (3-MC). However, the 2,3,7,8-tetrachlorobenzo(p)dioxin (TCDD) was a poor inducer. Transient and stable transfection assays indicated that these compounds increased the PON-1 gene promoter activity in an AhR-dependent manner, since their effect was inhibited by 7-keto-cholesterol and AhR-directed short interfering RNA. Deletions and mutations studies showed that a xenobiotic responsive element (XRE)-like sequence within the PON-1 promoter mediated the effect of 3-MC and quercetin. In contrast with consensus XREs from the cytochrome P450 1A1 gene, the PON-1 XRE-like element mediated preferentially the effect of quercetin compared to the results seen with TCDD. Furthermore, AhR binding to this element was preferentially activated by quercetin. These observations provide a molecular mechanism for the regulation of the cardioprotective enzyme PON-1 by polyphenols. They suggest also that AhR ligands may differentially regulate gene expression depending on the DNA target sequence.

* Corresponding author. Mailing address: INSERM UMR-S 490, Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France. Phone: 33 1 42 86 20 75. Fax: 33 1 42 86 20 72. E-mail: Robert.Barouki{at}univ-paris5.fr.

Molecular and Cellular Biology, June 2004, p. 5209-5222, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5209-5222.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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