Effects of trans-Resveratrol on Copper-Dependent Hydroxyl-Radical Formation and DNA Damage: Evidence for Hydroxyl-Radical Scavenging and a Novel, Glutathione-Sparing Mechanism of Action

Abstract

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties. The phenolic antioxidant has been identified as a potential cancer chemopreventative agent and its presence in red wine has been suggested to be linked to the low incidence of heart disease in some regions of France. Recently, however, resveratrol was reported to promote DNA fragmentation in the presence of copper ions (K. Fukuhara and N. Miyata, 1998, Bioorg. Med. Chem. Lett. 8, 3187–3192), prompting us to investigate this phenomenon in mechanistic detail. By acting as a reducing agent, resveratrol was found to promote hydroxyl-radical (•OH) formation by DNA-bound Cu(II) ions. However, in the presence of either ascorbic acid or glutathione (i.e., under more physiological conditions), the phenolic lost this property and behaved as an antioxidant. In the ascorbate system, resveratrol had no effect on the rate of •OH formation, but protected DNA from damage by acting as a radical-scavenging antioxidant. In contrast, in the glutathione system, resveratrol inhibited •OH formation via a novel mechanism involving the inhibition of glutathione disulfide formation. We have concluded, therefore, that the DNA-damaging properties of resveratrol, identified recently by Fukuhara and Miyata, will be of no significance under physiological conditions. To the contrary, we have demonstrated that the phenolic behaves as a powerful antioxidant, both via classical, hydroxyl-radical scavenging and via a novel, glutathione-sparing mechanism.