Multifaceted approach to resveratrol bioactivity: Focus on antioxidant action, cell signaling and safety

Abstract

Resveratrol (RVT) is a naturally occurring trihydroxy stilbene that displays a wide spectrum of physiological activity. Its ability to behave therapeutically as a component of red wine has attracted wide attention. The phenol acts as a protective agent involving various body constituents. Most attention has been given to beneficial effects in insults involving cancer, aging, cardiovascular system, inflammation and the central nervous system. One of the principal modes of action appears to be as antioxidant. Other mechanistic pathways entail cell signaling, apoptosis and gene expression. There is an intriguing dichotomy in relation to pro-oxidant property. Also discussed are metabolism, receptor binding, rationale for safety and suggestions for future work. This is the first comprehensive review of RVT based on a broad, unifying mechanism.

Figure 1

Resveratrol structure. The compound is a stilbene derivative containing three phenolic groups. Hence, it can exert AO action which evidently plays an important role in the protective effects observed against oxidative insult involving various body constituents. Metabolic studies show major formation of water-soluble conjugates. Many investigations deal with cell signaling pathways in the bioactivity. Particular focus has been devoted to antiaging, anti-cancer actions, cardio protection and prevention of CNS damage.

Figure 2

Resveratrol radical. The illustrated phenoxy radical is generated during the widespread AO action of RVT. The radical formation is facile due to the high degree of resonance stabilization afforded by this species. Hence, energetically, this radical is favored over the ones that would be formed from the meta-hydroxy resorcinol group in the other ring. Radical propagation is terminated by C-C radical coupling leading to a more stable dimer.

Figure 3

Resveratrol quinone. This stilbene quinone would be expected from facile oxidation of RVT. However, we are unable to find any report of its formation. It may be that it is present only in very small amounts making for greater difficulty in isolation. Nevertheless, only minor quantities will suffice for the catalytic generation of large amounts of ROS. Quinone formation is one rationale for the observed pro-oxidant effects of RVT involving redox cycling with oxygen leading to ROS.

Figure 4

Enol tautomer of cyclohexane-1,2-dione. Although the keto form is generally favored over the enol tautomer, in the case of “4,” hydrogen bonding of enol with the carbonyl results in increased contribution of enol to the equilibrium state.

Figure 5

Mono-hydrogen bonded quinone. This structure is analogous to that in Figure 4. Hence, the enol moiety is stabilized.

Figure 6

Diketo-enol tautermer of “3” (Fig. 3). Structure “5” (Fig. 5) shows the stabilization of an enol group by H-bonding, similar to that in “4” (Fig. 4). Since this is now less likely for the other enol group. It may tautomerize mostly to the keto form as illustrated in “6” (Fig. 6). The ability to redox cycle would be substancially decreased due to absence of the quinone functionality. The conjugated α-dicarbonyl structure in “6” (Fig. 6) should be capable of electron uptake, but not be a good generator of ROS.

Figure 7

Di-hydrogen bonded quinone. Perhaps both enols participate in H-bonding with the carbonyl. Therefore, the quinone structure is maintained.

Figure 8

Quinone metabolite of PCB. This metabolite route to “8” is quite similar to that proposed for RVT, which provides support for the proposed oxidative metabolism. The monohydroxy metabolite of PCB is analogous to RVT.