Resulting from increased production of free radicals
oxidative stress plays a key role in the pathogenesis of
certain human diseases including atherosclerosis, ischemia
and reperfusion injury of many organs, diabetes
neurodegenerative disorders, arthritis, gastrointestinal
dysfunctions, AIDS, aging, tumor promotion and
carcinogenesis
1-3. Biological oxidative stress of free
radicals is controlled by endogenous antioxidants including
the scavenger enzymes superoxide dismutase (SOD)
glutathione peroxidase (GSH-Px) and catalase (CAT) and
by exogenous dietary antioxidants vitamin E, C
carotenoids and flavonoids
4, 5. Briefly, antioxidants
are potent scavengers of free radicals and serve as inhibitors
of neoplastic processes.
The grape, having many established nutritional and
medicinal properties for consumers, is a highly potent
antioxidant and recognized for its wide spectrum of
biological properties 6. Generally, the seeds and leaves
of grapevine are used in herbal medicine and its fruits are
consumed as a dietary supplement 7. In this review
several scientific studies about antioxidant effects of grape
and its bioactive constituents are described.
Grape Composition
The principle components of grape are water, sugar and
acids. It is a good source of water (81-87 %), carbohydrates
(12-18 %), proteins (0.5-0.6 %), and fat (0.3-0.4 %).
Additionally, the grape contains significant amounts of
potassium (0.1-0.2 %), vitamin C (0.01-0.02 %), and
vitamin A (0.001-0.0015 %) and also has a little amount
of calcium (0.01-0.02 %) and phosphorus (0.08-0.01 %)
8. Grapes are also a major source of other nutrients like
boron 9, a possible substance for bone health. Nutritional.
The total extractable phenolics in grape are present at
only 10 % or less in pulp, 60-70 % in the seeds and 28-35
% in the skin. The phenol content of seeds may range
from 5 % to 8 % by weight 11, 15 and grape seeds are
rich sources of proanthocyanidins (90 %) 15. The
chemical structures of some important biologically active
grape derived constituents are given in Figure 3.
Figure 3. Chemical structures of some important biologically active compounds from grapes.
analysis per serving with 100 g grape gives ~78 calories
of energy, ~0.5 g of protein, ~19 g of carbohydrate
~0.3 g of fat (3% calories from fat), ~0.18 mg of sodium
~155 mg of potassium, 0.4 g of fiber, 13 mg of calcium
9 mg of phosphorus, and 10 mg of vitamin C 8.
Grapes are rich in polyphenols 10 and polyphenolic
substances in grape and products are usually divided into
two groups: flavonoids and non-flavonoids. The flavonoids
have a common core, the flavan nucleus, consisting of
two benzene rings (A and B) linked by oxygen containing
pyrane ring (C) (Figure 1).
The most common flavonoids are (i) flavonols including
kaempferol, quercetin and myricetin; (ii) flavan-3-ols
including highly polymerized oligomers of monomeric
(+)-catechins, (-)-epicatechins, (-)-epicatechin
-3-O-gallate and dimeric, trimeric and tetrameric
procyanidins and (iii) anthocyanins 11, 13. The non-
flavonoids, phenols with only one aromatic ring, are
derivatives of hydroxycinnamic acid (caffeic acid
p-coumaric acid) and of hydroxybenzoic acid (gallic acid).
Another class of non-flavonoids are stilbene and stilbene
glycosides, with trans- resveratrol (trans-3,5
40-trihydroxystilbene) as its most well known
representative 14. Their essential structure skeleton
comprises two aromatic rings joined by a methylene
bridge (Figure 2).
Antioxidant Effects of Grape
Grape phenolics, including flavonoids and related
polyphenols from grape, grape fruit and grape seeds have
generated remarkable interest based on positive reports
of their antioxidant properties and ability to serve as free
radical scavengers. The specific mode of inhibition of
oxidation is not clear, but they may act by scavenging
lipid alkoxyl and peroxyl radicals by acting as
chain-breaking antioxidants, e.g, as hydrogen donors and
chelating metal ions, the appropriate structural features
provided 16.
The antioxidant activity of grape seed polyphenols is
superior to other well-known antioxidants, such as vitamin
C, vitamin E and ß-carotene. Some clinical studies have
confirmed that grape seed procyanidins and
proanthocyanidins are 20 times more potent than vitamin
C and 50 times more potent than vitamin E as antioxidant
17.
Free radicals generated during oxidative stress have many
cellular targets, but one of the primary targets is cellular
lipids. Lipid peroxidation of polyunsaturated fatty acid
(PUFA) results in formation of alkoxyl and peroxyl radicals
(primary products) that are highly reactive and relatively
short-lived. Secondary products of lipid peroxidation
include numerous aldehydes, including malondialdehyde
the 4-hydroxyalkenals, and acrolein 18. Cardiovascular
diseases are associated with modifications in fatty acid
metabolism and excessive lipid peroxidation of LDL.
These oxidation products are also implicated in the
formation of thromboxane, which leads first to enhance
platelet aggregation, then to artery blockage, and finally
to thrombosis 19. The accumulation of lipid oxidation
products from LDL can be attributed to the low levels of
plasma antioxidants. Grape seed polyphenols reduce the
risk of heart disease by inhibiting the oxidation of LDL.
A study by Bouhamidi et al 20 shown that PUFA
peroxidation was inhibited by low concentrations of grape
seed proanthocyanidins (2mg/1). Short-term ingestion of
purple grape juice decreased LDL susceptibility to
oxidation in coronary artery disease patients 21 and in
hypercholestemic human subjects supplemented with
grape seed proanthocyanidin extract 22, 23.
Procyanidin supplementation in rat and rabbit reduced
ischemia/reperfusion damage in the heart and this was
associated with an increase in plasma antioxidant activity
24. Another study demonstrated that oral administration
of grape skin extract significantly reduced systolic, mean
and diastolic arterial pressure in a hypertensive rat model
25.
Procyanidin B4, catechin, and gallic acid at low
concentrations (10 µmol/1, 25 µmol/1) were reported to
be good cellular preventive agents against DNA oxidative
damage. However, these compounds may induce cellular
DNA damage at higher concentrations (150 µmol/1) 26.
Similarly, grape seed demonstrated significant protective
ability against oxidative damage in rat leukocytes 27.
Grape seed extract (50 mg/kg) reduced the incidence of
free-radical-induced lipid peroxidation in the central
nervous system of aged rats and reduced hypoxic ischemic
injury in neonatal rat brain 28. In another study, the
extract (100 mg/kg, 30 days) was able to inhibit the
accumulation of age related oxidative DNA damage in
the spinal cord and in various brain regions 29. The
administration of grape seed extract (100 mg/kg, 30 days)
to aged rats increased memory performance and reduced
reactive oxygen species (ROS) production, which may
be related to enhancement of the antioxidant status in the
central nervous system 30. Proanthocyanidin intake
(75 mg/kg, 9 weeks) was effective at up-regulating the
antioxidant defense mechanism by attenuating lipid
peroxidation and protein oxidation in the adult rat brain
31.
The administration of grape seed extract, which contains
38.5% procyanidins, prevented the progression of cataract
formation by their antioxidative action in hereditary
cataractous rats 32.
In recent years there is an increasing evidence of the
cancer chemopreventive properties of antioxidants such
as catechins and procyanidins 33. Although antioxidants
may play a role in the primary prevention of cancer in
part by reducing the oxidative modification of DNA 34
the same action might be expected to be counter productive
against radiation therapy and chemotherapeutic agents
that act solely via the production of reactive oxygen
species and induction of apoptosis 35. Chemotherapeutic
agents including the anthracyclines, most alkylating agents
platinum-coordination complexes, epipodophyllotoxins
and camptothecins are known to generate a high level of
oxidative stress in biological systems 36. Preclinical
studies involving the use of in vitro systems and animal
models support the contention that the administration of
antioxidants during cancer chemotherapy affects
antineoplastic efficacy or the development of side effects.
Oxidative stress induced by low levels of hydrogen
peroxide has been shown to elevate the LD50 of several
types of antineoplastic agents and to block drug-induced
apoptosis in neoplastic cells, causing cells to undergo
necrosis instead of apoptosis 37,38. These effects of
hydrogen peroxide are prevented by the addition of certain
antioxidants. The reduced cytotoxicity of anticancer agents
in the presence of hydrogen peroxide, an effect that might
also occur during chemotherapy-induced oxidative stress
may result from the effects of the cellular products
generated by ROS. In addition, several studies 39, 40
have provided evidence that antioxidants can decrease
the adverse effects of radiation therapy. Similarly, in our
studies grape seed proanthocyanidins resulted in highly
effective protection against methotrexate and radiotherapy
induced injury by increasing antioxidant enzyme activities
in rat liver tissues 41, 42.
Recently, pretreatment of resveratrol (10 mg/kg/day p.o.)
mostly found in grape seed and skin, prevented oxidative
damages and resulted in a reduction of the hazardous
effects of ionizing radiation (800 cGy whole-body) on
rat liver and ileum tissues 43. Resveratrol reduces the
generation of H2O2 and normalizes the levels of oxidized
glutathione reductase and myeloperoxidase (MPO)
activities. By normalization of the ROS levels, resveratrol
limits the oxidative stress, which inhibits NO synthesis
by eNOS necessary for vasorelaxation. Furthermore
resveratrol inhibits vasoconstrictor endothelin-1
surproduction and cytosolic phospholipase A2 activity
stimulated by oxidative stress44. Resveratrol has shown
protective effects against ischemia reperfusion in the
skeletal muscles of rat due to its potent antioxidant
properties 45. Also pretreatment with resveratrol
(10 µmol/1) prevented ethanol -induced disruption of
embryonic growing in blastocytes and ESC-B5 embryonic
stem cells 46.Interestingly low doses of resveratrol can
sensitize to low doses of cytotoxic drugs and so provide
an innovative strategyto enhance the efficacy of anticancer
therapy in various human cancers 47. By these
properties, resveratrol appears to be a good candidate in
chemopreventive and chemotherapeutic strategies.
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