Induction of the paraoxonase-1 gene expression by resveratrol

Objective - The human paraoxonase-1 (PON-1) is a high-density lipoprotein-associated enzyme, mainly secreted by the liver, that displays protective properties toward cardiovascular disease and organophosphate intoxication. Resveratrol is a polyphenolic phytoalexin found in grapes and wine and is thought to display cardioprotective effects. It is able to interact with transcriptional modulators such as the estrogen receptor alpha (ERalpha). We investigated the effect of resveratrol on the PON-1 gene expression. Methods and Results - PON-1 activity assays, Northern blot, and transfection experiments showed that resveratrol increased the PON-1 gene expression in human hepatocyte primary cultures and in the HuH7 hepatoma cell line involving a transcriptional mechanism. The resveratrol effect was not ERalpha-dependent and was surprisingly mediated by the aryl hydrocarbon receptor (AhR) and an unconventional AhR responsive element in the PON-1 gene promoter. This agonist effect of resveratrol was specific for this DNA motif and was not observed on classical AhR responsive elements. Conclusions - These observations suggest that the PON-1 gene induction may be involved in the cardioprotective properties of resveratrol. They also highlight a ligand-dependent differential modulation of AhR-sensitive genes.