Resveratrol or trihydroxystilbene belongs to a class of polyphenolic compounds called stilbenes. Individual plants produce resveratrol and other stilbenoids in response to stress, injury, fungal infection, or ultraviolet (UV) radiation. Resveratrol is a fat-soluble compound that occurs in both trans and cis molecular configurations. Both cis- and trans-resveratrol also occur as glucosides, bound to a glucose molecule. One major resveratrol derivative is resveratrol glucoside, also called price.
Since the early 90s, when the presence of resveratrol in red wine was established, the science community has been searching the effects of resveratrol on health. It was said that resveratrol intake through moderate red wine consumption might help explain the fact that French people have a relatively low incidence of coronary heart disease (CHD) even though they are consuming foods high in saturated fat, a phenomenon dubbed the “French Paradox.” Reports on resveratrol to prevent cancer, delay the development of cardiovascular and neurodegenerative diseases, improve glycemic control in type 2 diabetes, and elongate lifespan in experimental models have continued to generate scientific interest.
Metabolism and Bioavailability
Initial studies of the trans-resveratrol in humans found traces of the unmetabolized resveratrol in the plasma upon oral exposure of trans-resveratrol doses of 5 to 25 mg. Indeed, trans-resveratrol appears to be well absorbed by humans when taken orally, but its bioavailability is relatively small due to its rapid metabolism and elimination. Once absorbed, resveratrol is rapidly metabolized by conjugation to glucuronic acid and sulfate, forming resveratrol glucuronides, sulfates, and sulfa glucuronides. Sulfate conjugates are the primary forms of resveratrol metabolites found in plasma and urine in human.
Studies found that the administration of single doses of 25 mg of trans-resveratrol to healthy individuals resulted in peak blood concentrations of total resveratrol around 60 minutes later, at about 1.8-2 liter, depending on whether resveratrol was administered in wine, vegetable juice, or grape juice. A study in 40 healthy subjects who received single ascending doses of oral trans-resveratrol showed that plasma concentrations of unmetabolized resveratrol peaked between 0.8 and 1.5 hours after resveratrol administration. These values were remarkedly below those used to elicit chemopreventive effects of resveratrol in vitro experiments. In contrast, following a single oral dose of 5 g of trans-resveratrol, the peak plasma concentrations of particular resveratrol conjugates were found to be about two to eight times higher than those of unmetabolized resveratrol. Compared to a single dose administration, the repeated intake of 5 g/day of trans-resveratrol for 29 days was found to result in significantly greater peak plasma concentrations of trans-resveratrol and two resveratrol glucuronide conjugates. Repeated doses of 1 g/day of trans-resveratrol could yield maximum plasma concentrations of about 22 μM for resveratrol sulfate (the most abundant sulfate conjugate in humans) and about 7-8 μM for typical monoglucuronide conjugates.
Some studies have examined the influence of food matrix on resveratrol absorption and bioavailability. One study had reported that bioavailability of trans-resveratrol from red wine did not differ when the wine was consumed with a meal versus on an empty stomach. In another, the absorption of supplemental resveratrol was found to be delayed, but not reduced, by the presence of food in the stomach. A third study concluded that it reduced by the amount of fat in the diet, but not by the co-administration of quercetin or alcohol.
Information about the bioavailability of resveratrol in humans is important because most of the experimental research conducted to date has been exposing cells to resveratrol concentrations up to 100 times greater than peak plasma concentrations observed in humans, and in animal models given very high (non-dietary) doses of resveratrol. While cells that line the walls of the digestive tract are exposed to unmetabolized resveratrol, other tissues are exposed to resveratrol metabolites. At present, little is known about the biological activity of resveratrol metabolites. If some muscles are capable of converting resveratrol metabolites back to resveratrol, stable resveratrol conjugates in tissues could make the body regenerate it after it pools.
The biological significance of resveratrol has been primarily investigated in test tubes and cultured cells, and to a lesser extent, in animal models. Of note, a recent publication by Tomé-Carneiro et al. thoroughly reviewed the most relevant preclinical studies published in the past decades. It is important always to remember that many of the biological activities discussed below were observed in cells with resveratrol at higher concentrations than those likely to be achieved in humans consuming resveratrol orally.
Direct Antioxidant Activity
In the test tube, resveratrol effectively scavenges (neutralizes) free radicals and other oxidants and inhibits low-density lipoprotein (LDL) oxidation. Resveratrol was found to induce antioxidant enzymes, including superoxide dismutase, thioredoxin, glutathione peroxidase-1, heme oxygenase-1, and catalase, and inhibit reactive oxygen species (ROS) production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX). However, there isn’t much evidence that resveratrol is an important antioxidant in vivo. While oral consumption of resveratrol, circulating and intracellular levels of resveratrol in humans are likely to be much lower than that of other important antioxidants, such as vitamin C, uric acid, vitamin E, and glutathione. Moreover, the antioxidant activity of resveratrol metabolites, which comprise most of the circulating resveratrol, may be lower than that of resveratrol.
Estrogenic and antiestrogenic activities
Endogenous estrogens are steroid hormones synthesized by humans and other mammals; these hormones bind to estrogen receptors within cells. The estrogen-receptor interacts within unique sequences in the DNA to modulate the expression of estrogen-responsive genes. The chemicals of resveratrol are very similar to the synthetic estrogen agonist, diethylstilbestrol, suggesting that resveratrol might also function as an estrogen agonist, might bind to estrogen receptors and elicit similar responses to endogenous estrogens. Although, in cell culture experiments, resveratrol was found to act either as an estrogen agonist or as an estrogen antagonist depending on such factors as cell type, estrogen receptor isoform, and the presence of endogenous estrogens. Most recently, resveratrol was shown to improve endothelial wound healing through an ERα-dependent pathway in an animal model of arterial injury.