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Page 4 of 36 Dave et al. J Cancer Metastasis Treat 2020;6:46 I http://dx.doi.org/10.20517/2394-4722.2020.106

as grape (Vitis vinifera) is a rich source of resveratrol. Specifically, resveratrol is found in seeds, skin, woody
parts, and petioles. Therefore, red wine generally has a higher content of resveratrol than white wine,
since, during the production of the wine, parts of grapes in which resveratrol is present are macerated for
[21]
a longer period of time . During grape fermentation, the formation of alcohol facilitates the solubility of
resveratrol which further leads to its extraction.

Polygonum cuspidatum is an extremely rich source of resveratrol and used as a therapeutic regimen for
[22]
cardiovascular diseases in Chinese and Japanese traditional medicine practice . Similarly, the rhizome
of Veratrum formosanum, containing abundant resveratrol, has been applied to treat hypertension in East
Asia .
[23]
Pharmacokinetic properties of resveratrol
Resveratrol is primarily metabolized by phase II enzymes in the liver. Through enterohepatic transport in
bile, some of the compound returns to the small intestine . Moreover, resveratrol can stimulate its own
[24]
[25]
metabolism by increasing the action of phase II hepatic detoxifying enzymes . Although trans-piceid,
the naturally occurring glucoside, exhibits biological activities, glucuronide metabolites of resveratrol in
humans seem to be less active.

The high rate of resveratrol metabolism produces conjugated sulfates and glucuronides which maintain
[26]
some biological activity . Although metabolites can differ in their nature and quantity between
subjects due to inter-individual variability, there are major five types of metabolites in the human
urine: two isomeric forms of resveratrol monoglucuronide, resveratrol monosulfate, monoglucuronide
dihydroresveratrol and monosulfate dihydroresveratrol [27,28] . In human urine samples, cis metabolites have
been found, mainly as cis-resveratrol-4′-sulfate, cis-resveratrol-4′-O-glucuronide and cis-resveratrol-3-O-
glucuronide [29,30] . Even though the cis-isomer displayed comparable activities to the trans-isomer in some
experimental settings [31,32] , the trans-isomer is generally considered dominant and exerts greater activity.
Other dietary components may influence metabolism. For example, quercetin has the potential to inhibit
resveratrol glucuronidation and sulfation in the duodenal and liver, thus increasing bioavailability .
[33]

Biological activities of resveratrol
Spearheaded by conceptualization of the “French Paradox”, the potential health benefits of phenolic
compounds present in wine and grapes have been extensively studied. As a brief background, in the
northern region of France, the dietary intake of saturated fat is relatively high. However, relative to other
parts of the world where a similar amount of high saturated fat is consumed, the mortality due to coronary
heart disease is reduced. This phenomenon, termed the “French Paradox”, was attributed to the relatively
high wine consumption of the French . This possible benefit of wine was not ascribed to alcohol content,
[34]
since alternative alcoholic beverages such as beer were not perceived to be effective in this regard. In turn,
this led to speculation regarding the effectiveness of chemical constituents in wine other than alcohol. It is
[35]
known that grapes, and consequently wine, contain scores of phytochemicals , but a conundrum exists
since these components are also found in other sectors of the diet. Alas, when the cancer chemopreventive
[36]
potential of resveratrol was first described , it was recognized this is a compound uniquely associated
with the grape (and wine), and, in fact, grapes and wine are the dominant dietary source of this biologically
active compound. Thus, resveratrol was perceived by some as a key to the “French Paradox” and many
[37]
studies followed to explore broader biologic potential .
Because of its physical and chemical properties, resveratrol can either interact with receptors present on
the cell surface or move passively through cell membranes. Therefore, at the cellular level, action may
be initiated by either triggering signaling pathways when binding to the cell membrane receptors, or by
[38]
facilitating intracellular mechanisms . Accordingly, as discussed in previous reviews [39,40] , resveratrol