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The Importance of Arugula (Eruca sativa) and Pharmacological Eects
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Chapter 17
Overview of Extraction,
Isolation, and Bioavailability
Enhancement of Resveratrol:
Phytochemistry and Bioavailability
of Resveratrol
Seren Gundogdu
Faculty of Pharmacy, Hacettepe University, Turkey
341
Ayse Kuruuzum-Uz
Faculty of Pharmacy, Hacettepe University, Turkey
ABSTRACT
Natural products derived from plants have long been and will continue to be substantial sources of
therapeutic agents in disease prevention and treatment. Resveratrol, which is a bioactive compound in
a polyphenol structure, is found in significant amounts in several plant/food sources such as grapes,
peanuts, strawberries, blueberries, pistachios, red mulberries, cranberries, and tomatoes. These functional foods rich in resveratrol be used widely owing to resveratrol does not show significant toxicity at
low doses. Today, there is an increasing interest in polyphenols due to their antioxidant properties. The
antioxidant effect of resveratrol underlies many of its medicinal effects, such as its neuroprotective and
positive effect on neurodegeneration. In addition, it is outstanding with anti-inflammatory, antitumor,
antiviral, antidiabetic, cardioprotective, and life-prolonging effects. Studies on resveratrol have previously focused on its pharmacological activities but recently have focused on its low bioavailability which
poses a major problem to show the predicted effect.
INTRODUCTION
Resveratrol (trans-3,5,4’-trihydroxy-stilbene) is one of the outstanding phytochemicals in plant-based
DOI: 10.4018/978-1-6684-5129-8.ch017
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Overview of Extraction, Isolation, and Bioavailability Enhancement of Resveratrol
drug discovery and was first isolated from the roots of Veratrum grandiflorum by Takaoka in 1940, and
Polygonum cuspidatum roots were later used for this purpose (Takaoka, 1940). Resveratrol contains two
aromatic rings and three hydroxyl groups connected by an ethylene bridge.
The biosynthesis of resveratrol takes place through a combination of phenylpropanoid and polyketide
pathways (Giovinazzo et al., 2012). Resveratrol is widely in the families of Cyperaceae, Dipterocarpaceae, Fabaceae, Fagaceae, Liliaceae, Moraceae, Myrtaceae, Pinaceae, and Vitaceae, including species
such as Vitis vinifera, Arachis hypogaea, Morus rubra, Pistacia vera, Vaccinium myrtillus, Fragaria L.,
and Polygonum cuspidatum (also known as Japanese knotweed/Itadori tea) (Tian & Liu, 2020). Vine
and P. cuspidatum compared to other plant species; Its gained importance due to their high resveratrol
capacity and widespread consumption of fresh or processed products (wine, vinegar, dried grape, e.g.)
(Keskin et al., 2009).
Glycoside forms of both cis- and trans- isomers of resveratrol exist in nature. The glycoside known
as the major form of resveratrol is a resveratrol-3-O-β-D glycoside, also called “piseid or polydatin”.
In addition, there are different stilbene compounds in the dimer, trimer, and tetramer structure of resveratrol in nature. For example, the major oligomer ε-viniferin in grapes is the dehydrodimer of resveratrol. Various resveratrol oligomers have been identified in grapevine, including dimers, trimers, and
tetramers derived from ε-viniferin (Niesen et al., 2013; Romero-Pérez et al., 1999; Udenigwe et al.,
2008). Resveratrol-derived dimers synthesized by oxidative coupling are in the structure of resorcinol.
In addition to their antioxidant effects, they show neuroprotective, anti-HIV, and cytotoxic effects on
various cell lines (Menezes & Diederich, 2019; Wang et al., 2014).
Various extraction, separation/purification protocols, and chromatographic methods have been improved to optimize the extraction and isolation of resveratrol by researchers. Supercritical liquid extraction, High-speed counter-current chromatography, Ultrasonically Assisted Microwave Extraction (UAE),
and High-performance liquid chromatography (HPLC)-Diode-Array Detection (PDA)-Electrospray
Ionization (ESI) have come to the fore among separation-purification and identification methods. In
these methods, optimum conditions are developed for parameters such as solvent type, temperature, and
extraction time (Beyer & Biziuk, 2008).
Resveratrol is an important phytomolecule with its antioxidative, anti-inflammatory, antitumor, antiviral, antidiabetic, cardioprotective, protective against eye diseases, phytoestrogen, and life-extending
properties (Colica et al., 2018; Gündoğdu et al., 2021). The French paradox has demonstrated that it has
a preventive impact, especially in the case of coronary heart disease (Liu et al., 2007).
Pharmacokinetic studies have become highly necessary to maintain its biological activity, keep it
stable, and make it more resistant to oxidative degradation as resveratrol’s structure is unstable when
exposed to light. In light of these therapeutic effects and bioavailability of resveratrol, which can be used
as a food/nutraceutical or medicine, well-formulated resveratrol-bearing tablets, capsules, nanoparticles,
and controlled-release formulations based on encapsulating techniques such as solid lipid nanoparticles
formulations should be used (Nunes et al., 2020).
This chapter gives knowledge about resveratrol, advanced studies on its extraction, isolation, identification and bioavailability.
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Overview of Extraction, Isolation, and Bioavailability Enhancement of Resveratrol
BACKGROUND AND MAIN FOCUS OF THE CHAPTER
Although the highest resveratrol content was is in P. cuspidatum, many other food sources such as grape
(Vitis vinifera, Vitis thunbergii), peanut (Arachis hypogaea), strawberry (Fragaria L.), cranberry (Vac-
cinium macrocarpon), blueberry (Vaccinium myrtillus), peanut (Pistacia vera), red mulberry (Morus
rubra), tomato (Solanum lycopersicum), Phoenix dactylifera and dark chocolate are among the rich
sources of resveratrol. Therefore, the P. cuspidatum plant, which takes a significant place in the synthesis
of resveratrol, has led to the rise of products with commercial importance (Huang et al., 2005; Gündoğdu
et al., 2021; Tian & Liu, 2020).
Chemical Structure of Resveratrol
Resveratrol exists in nature as trans- and cis-isomers, commonly in the trans-form. However, its glycosylated form (trans-resveratrol-3-O-β-D glycoside, polydatin, piceid) is more stable and durable in
oxidative degradation (Figure 30.1) (Şöhretoğlu et. al., 2018; Venugopal & Liu, 2012).
Figure 1. Molecular structures of trans-resveratrol and piceid (Baur&Sinclair, 2006).
Trans-resveratrol is well-known to be abundant, particularly in the skins of colored grape types
(0.30-14.10 mg/g fresh; 9.30-78.50 mg/g dry weight) (Keskin et al., 2009). Although the high biological
activities of P. cuspidatum are attributed to trans-resveratrol, as in grapes, the level of trans-resveratrol
in P. cuspidatum is many times lower than the level of polydatin. For this reason, if hydrolyzed polydatin
to resveratrol, the manufacture of resveratrol will be highly increased. At this point; extraction, isolationpurification, and identification techniques come to the forefront (Wang et al., 2013).
Extraction and Isolation of Resveratrol
Among the many techniques for extraction of resveratrol, the most frequently used are Solvent Extraction
(by shaking or Soxhlet apparatus), Microwave-Assisted Solvent Extraction, Ultrasonication Extraction,
Microwave-Accelerated Extraction, Supercritical Fluid Extraction, and Membrane Extraction techniques.
In these techniques, optimum conditions are developed for parameters such as solvent type, temperature,
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Overview of Extraction, Isolation, and Bioavailability Enhancement of Resveratrol
Table 1. Some extraction and isolation-purification methods for resveratrol
Plant Sources Extract
95% Ethanol
Methanol
(MeOH)
Polygonum
cuspidatum
Polygonaceae
(Japanese knotweed)
Vitis vinifera
Vitaceae
Vitis thunbergii
Vitaceae
Morus rubra
Moraceae
Arachis hypogaea
Fabaceae
Pistacia vera
Anacardiaceae
Water (H2O)
95% MeOH
EtOH: H2O
(80:20 v/v)
EtOH: H2O
(80:20 v/v)
EtOH: H2O
(80:20 v/v)
(EtOH)
MeOH
H2O
MeOH
MeOH
EtOH
Extraction, Isolation-Purification
Methods and Conditions
Solvent Extraction, Liquid–Liquid Extraction (65 °C, 12h),
Hydrolysis (pH=1, 75 °C, 8h) and HPLC (Nucleosil 100 C18 reverse-
phase column)
Ultrasonication Extraction (45°C, 20 min) and Molecularly Imprinted
Polymer-HPLC (Inertsil ODS-2 C18)
Soxhlet Extraction (4 h), Supercritical Fluid Extraction (40 MPa, 100
°C, 45 min) and HPLC (C18 reverse-phase column)
Supercritical CO2 Extraction
(30 MPa, 50 °C, 20 kg/h vCO2)
Solvent Extraction and
Enzymic Hydrolysis (pH=5, 50 °C, 24h)
High-Speed Counter-Current Chromatography
(Spherigel ODS C18 column, 20 °C, 700 rpm)
High-Speed Counter-Current Chromatography
(Shim-pack VP ODS column, 40 °C, 1500 rpm)
HPLC (Hypersil Gold C18, Nucleosil C18, ODS Hypersil, Lichrospher
100-RP, Superspher RP-18)
Silica gel Column Chromatography [n-hexane−EtOAc (10:1,
5:1) and CH2Cl2−MeOH (15:1, 10:1, 5:1, 0:1)], Sephadex LH-20
[MeOH−H2O, (3:1)], PTLC [(CH2Cl2−MeOH, 5:1)]
Solvent, and Solid Phase Extraction (60 °C, 30 min), HPLC
(Discovery C18 column)
Magnetic Solid Phase Extraction, LC-MS/MS (Hypersil Gold C18
column), HPLC-DAD (Nucleosil 120 C18, Al2O3−ODS C18 column)
and GC-MS (DB-5MS capillary column)
HPLC-DAD (Hypersil-ODS column) and GC-MS (DB-5MS
capillary column)
References
Wang et al.,
(2013)
Zhuang et al.,
(2008)
Beňová et al.,
(2010)
Yu et al., (2005)
Zhi-fang et al.,
(2009)
Chu et al., (2005)
Yang et al., 2001
Soleas et al., 1997;
Tzanova & Peeva,
2018
Huang et al., 2005
Shrikanta et al.,
2015
Ibern Gómez et
al., 2000; Lang
et. al., 2019;
Tokuşoğlu et al.,
2005
Tokuşoğlu et al.,
2005
and extraction time (Beyer & Biziuk, 2008). Various protocols and combined chromatographic methods
have been developed by researchers to optimize the extraction and purification of resveratrol from P.
cuspidatum (Table 1).
For extraction, conventional methods (including distillation, liquid-liquid extraction, or Soxhlet extraction) by heating under reflux with methanol/ethanol are used. And then filtration, concentration, several
clean-up steps, separation and purification (various column chromatographies) pursue. These methods,
which are many inherent disadvantages, are usually time-consuming and require the disposal of plenty
of toxic and unecological solvents (Beyer & Biziuk, 2008). For example, in a study comparing soxhlet
and supercritical fluid extraction methods for the isolation of resveratrol from P. cuspidatum roots; al-
though the time of the supercritical fluid extraction method is five times shorter than the extraction time
of soxhlet, it has been reported that this technique is not very convenient for polar compounds such as
resveratrol (Beňová et al., 2010). In addition to new extraction methods such as microwave-accelerated
extraction and supercritical fluid extraction, enzymatic hydrolysis is also preferred in obtaining high
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Overview of Extraction, Isolation, and Bioavailability Enhancement of Resveratrol
recovery resveratrol from sources rich in polydatin (Zhi-fang et al., 2009; Wang et al., 2013). Also, the
results of different studies displayed that the optimized High-Speed Counter-Current Chromatography
method which eco-friendly extraction technology, can be used successfully for large-scale separation
of resveratrol (Chu et al., 2005; Yang et al., 2001). Afterward this extraction, and isolation-purification
1H-13
study, resveratrol has been identified with various methods such as
C NMR, ESI-MS/MS (Chu et
al., 2005; Yang et al., 2001; Wang et al., 2013).
Pharmacokinetics and Bioavailability Enhancement of Resveratrol
Researchers investigated the pharmacokinetic parameters of resveratrol such as absorption, distribution,
metabolism, and elimination in terms of many variables (dose, dosage form, administration, e.g.). In vitro
and in vivo pharmacokinetic studies on resveratrol have revealed that, in addition to the administered
dose-effect resveratrol absorption, the dosage form, route of administration, and diet have a substantial
impact on resveratrol absorption (Huang et al., 2019).
Resveratrol is rapidly absorbed by the gastrointestinal tract immediately after intragastric administration and reaches its maximum plasma concentration (C
(Soleas et al., 2001). In an ex vivo percutaneous absorption assay, the plasma resveratrol level was 12.53
mg after 24 hours of administration of a cream containing a sustained release emulsion containing 20
mg of resveratrol. In addition, studies are reporting that the glycosylated form of resveratrol, which is
steady and more resistant to oxidative degradation, is better absorbed from the human gastrointestinal
system (Polonini et al., 2014; Venugopal & Liu, 2012). The distribution of resveratrol, which has shown
in vivo investigations to be localized in the liver, brain, gut, and adipose tissues, has not been fully
characterized (Andres-Lacueva et al., 2012). Afterward, resveratrol is exposed to a first-pass effect in
enterocytes and hepatocytes following oral administration and is known to undergo subsequent glucuronidation (Lastra & Villegas, 2005). As with many bioactive ingredients, Phase II metabolic enzymes
play a role in resveratrol biotransformation, and the effect of intestinal microbiota on metabolism is
critical. So much the more, the UDP-glucuronosyltransferase (UGT) family appears to be prominent in
the metabolism of resveratrol. The main glucuronides and sulfates of resveratrol are have been reported
to resveratrol-3-O-glucuronide, resveratrol-O-glucuronide and resveratrol-3-O-sulfate, resveratrol-Osulphate and resveratrol-3-O-disulfate, respectively (Wang & Sang, 2018). In the final step, resveratrol
and its metabolites are eliminated in the urine. At this point, researchers have developed resveratrol-loaded
microparticle and nanocapsule forms to delay the elimination, and it has been noted that it is eliminated
more slowly compared to the standard form (Huang et al., 2019). In vivo toxicity studies on rats, mice
and rabbits showed that resveratrol at a dose of 0.75-210 g/kg/day was well tolerated and did not show
any toxic effects (Crowell et al., 2004; Williams et al., 2009).
Due to the low bioavailability issues, studies on resveratrol have focused on enhancing bioavailability, and different dosage forms containing resveratrol have been tried considering pharmacokinetic and
toxicity studies. In one of the bioavailability enhancing studies, it was observed that the antidiabetic effect of resveratrol on the pancreatic β TC cell line was increased (insulin secretion increased up to 85%)
by loading resveratrol from new lipid-based, non-vesicular drug delivery systems into nanocochleates
(Yücel et al., 2018). In a bioavailability enhancement study in C57BL mice has been reported resveratrol (100 mg/kg; oral gavage) or resveratrol (100 mg/kg; oral gavage)+piperine (10 mg/kg; oral gavage)
was administered and serum resveratrol concentrations were measured in mice at periodic intervals.
With the addition of piperine, the AUC and the maximum serum resveratrol concentration (Cmax)
) within 30 minutes of high-dose administration
max
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Overview of Extraction, Isolation, and Bioavailability Enhancement of Resveratrol
increased to 229% and 1544%, respectively, thereby significantly improving the in vivo bioavailability
of resveratrol (Johnson et al., 2011). On the other hand, zein nanoparticles which are inexpensive, safe,
and effective choices for producing nanoparticles (NPs), have been prepared to improve the stability
and oral bioavailability of resveratrol and loaded into zein NPs using the resveratrol nanoprecipitation
method in recent times. As a result of this study, it was reported that zein NPs protect resveratrol from
metabolization and resveratrol-loaded zein nanoparticles maintain their stability at +4 °C for at least
one month (Nunes et al., 2020).
CONCLUSION
Resveratrol (3,5,4′-trihydroxystilbene) which is a well-known phytoalexin, has commonly been used in
medicine, health products, and cosmetic industries on account of its various pharmaceutical and healthpromoting properties such as anti-inflammatory, anticancer, cardioprotective, and life-extending effects.
Trans-resveratrol is easy oxidizable and photosensitive, also poor bioavailability of resveratrol attributable to insufficient solubility, quick metabolism, and elimination led to limited practical applications of
resveratrol in clinical. To benefit from the pharmacological effects of resveratrol, which can be taken
as food/nutraceutical or medicine, the count of studies should be increased in which rapid, advanced,
reproducible, and environmentally friendly advanced techniques are used instead of conventional methods
for extraction, separation-purification, and identification. Then resveratrol-loaded tablets, capsules, and
nanoparticle formulations with improved bioavailability should be developed.
ACKNOWLEDGMENT
This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
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