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Open Access Journal
International Journal of Medical Research and Pharmaceutical Sciences
Volume 4 (Issue 6): June 2017 ISSN: 2394-9414
DOI- 10.5281/zenodo.809201 Impact Factor- 3.109
©International Journal of Medical Research and Pharmaceutical Sciences http://www.ijmprsjournal.com/
1
THERAPEUTIC EFFECTS OF ANTHOCYANINS FROM VACCINIUM
GENUS L
Karcheva-Bahchevanska D.*1, Lukova P.2, Nikolova M.3, Mladenov R.2& Iliev I.3
*1Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Pharmacy, Medical
University of Plovdiv, Bulgaria
2Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University
of Plovdiv, Bulgaria
3Department of Biochemistry and Microbiology, Faculty of Biology, University of Plovdiv "Paisii
Hilendarski", Bulgaria
.
Abstract
.
Keywords: Vaccinium spp.,
anthocyanins,
therapeutic effects.
The purpose of this review is to examine the botanical characteristics of four species
of Vaccinium genus: Vaccinium vitis-idaea L. (Lingonberry), Vaccinium myrtillus L.
(Bilberry), Vaccinium uliginosum L. (Bog bilberry) and Vaccinium arctostaphylos L.
(Caucasian whortleberry) as well as to consider the chemical composition and
therapeutic effects of anthocyanins isolated from these species.
The following therapeutic properties have been found in the extracts rich in
anthocyanins and obtained by fruits or leaves of Vaccinium spp.: vasoprotective, anti-
inflammatory, anti-diabetic, antimicrobial, anticancer, genoprotective and
antioxidant.
Introduction
GenusVaccinium L. includes around 450 species found mostly in the northern hemisphere of our planet. These are
predominantly shrubs or vines and belong to the Ericaceae family (heather). The fruits and leaves of these
Vaccinium species produce a wide range of compounds: flavonoids such as anthocyanins, flavonols, flavanols
(catechins), phenolic acids (benzoic and cinnamic acid derivatives), chromones, coumarins, lignans, iridoids, sterols,
and triterpenoids1-3. The principal components are flavonoids (anthocyanins)3. Over 116 anthocyanins and flavonoid
compounds have been isolated and identified within the Vaccinium genus3. Extracts of anthocyanins from
Vaccinium fruits and leaves demonstrate various pharmacological effects such as antidiabetic4, anti-inflammatory5,6,
vasoprotective7, antimicrobial8, antitumor9,10, genoprotective11, and antioxidative12-24.
Botanical characteristics and distribution of genus Vaccinium L. in Bulgaria
The Ericaceae family (heather) includes 140 genera and 3500 species. Seven genera and twelve species have been
found in Bulgaria. The distribution is cosmopolitan, especially in temperate and cool areas. They are not found in
steppes and deserts. The habitus of the species consists of evergreen or deciduous shrubs and semi-shrubs,
sometimes small trees25.
There are four species found in natural habitats throughout Bulgaria: Vaccinium vitis-idaea (Lingonberry),
Vaccinium myrtillus (Bilberry), Vaccinium uliginosum (Bog Bilberry) and Vaccinium arctostaphylos (Caucasian
whortleberry). The latter is protected under the Biological Diversity Act26. These are deciduous or evergreen shrubs,
reaching a height of up to 25 cm (V. vitis-idaea), 40 cm (V. myrtillus), 70 cm (V. uliginosum), and 3 m (V.
arctostaphylos). The leaves are arranged consecutively and have short stems or almost sessile ones; the edge of the
leaf lamina is entire or serrated. The blossoms are 4- or 5-sectional, collected in axil bunches. The corolla is bulb-
tobell-shaped, thestamen are 8-10 in number, the ovary is positioned low with 4-5 carpels. The fruit is a juicy blue,
blue-black or red berry with small seeds26 (Figure 1).
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Volume 4 (Issue 6): June 2017 ISSN: 2394-9414
DOI- 10.5281/zenodo.809201 Impact Factor- 3.109
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2
Vaccinium vitis-idaea L. Vaccinium myrtillus L.
Vaccinium uliginosum L. Vaccinium arctostaphylos L.
Figure 1. Images of Vaccinium species, distributed in Bulgaria (www.plantarium.ru)
The parts useful for pharmacological purposes are the leaves and fruits. The fruits are produced between July and
September.
In Bulgaria, Caucasian whortleberry is only found in the Strandzha Mountains at an altitude of 150-300 m in humid
shaded areas. The other Vaccinium species are wide-spread in stony or grassy locations, in coniferous and more
rarely broad-leaf forests in almost every Bulgarian mountains. These are also found at altitudes of 700-2000 m for
Lingonberry, 900- 2200 m for Bilberry, and 1700-2500 m for the Bog Bilberry26.
Main components of the polyphenol composition responsible for the pharmacological
activity
According to the European Pharmacopoeia 827 fresh V. myrtillus fruits are classified according to anthocyanin
content, defined as cyanidin-3-O-glucoside chloride (minimum 0.3%), and dried V. myrtillus fruits - according to
tannin content, defined as pyrogallol (minimum 1%).
The main isolated components of Vaccinium myrtillus fruit, responsible for the biological activity are flavonol-O-
glycosides such as quercetin-3-rhamnoside (quercitrin), quercetin-3-glucoside (isoquercitrin), quercetin-3-
Open Access Journal
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Volume 4 (Issue 6): June 2017 ISSN: 2394-9414
DOI- 10.5281/zenodo.809201 Impact Factor- 3.109
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3
galactoside (hyperoside), and kaempferol-3-glucoside (astragalin), myricetin glycosides, as well as over 15
anthocyanins (total quantity of approximately 0.5%), which have been identified as 3-arabinosides, 3-glucosides,
and 3-galactosides of five anthocyanidins: cyanidin, delphinidin, malvidin, peonidin, and petunidin (Figure 2). The
quantity of glycosides of cyanidin and delphinidin (Figure 3) makes up to 64% of the total anthocyanins content7,28.
The flavonoids quercetin and quercetin-3-rutinoside (rutin), along with 11 other anthocyanins have been isolated
from the fruit of Vaccinium uliginosum; with the most abundant being petunidin-3-glucoside and malvidin-3-
glucoside29. In the fruit of Vaccinium vitis-idaea, evidence has been found only of the presence of quercetin
glycosides and glycosides of cyanidin (3-arabinosides, 3-glucosides, and 3-galactosides)28. Nine anthocyanins have
been found in Vaccinium arctostaphylos, with the most characteristic being cyanidin-3-O-xyloside, delphinidin-3-O-
xyloside, malvidin-3-O-xyloside, and petunidin-3-O-xyloside30,31.
The content of organic acids in Vaccinium myrtillusis 3-7% (predominantly citric and malic acid). The fruit also
contain up to 10% tannins7.
The phenolic acids р-coumaric, caffeic, ferulic, chlorogenic, and ellagic have been isolated in genus Vaccinium1,2.
According to data by Kader et al. (1996) chlorogenic acid is predominant in Bog Bilberry, and according to Chen et
al. (2001) benzoic acid is present in the largest quantity in Lingonberry32,33.
The health benefits of the fruits of these species include maintaining good eyesight, prevention of socially
significant disease such as cardiovascular disease and cancer, diabetes, rheumatoid arthritis, Parkinson's and
Alzheimer's disease2. It is considered that the main components responsible for this protective action are the
phenolic compounds they contain, such as anthocyanins, flavones, flavonols, and phenolic acids2.
Phenolic compounds are synthesized by plants in order to protect against adverse environmental conditions, such as
drought, UV light, insects, viruses, bacteria, or physical damage2,34. Phenolic compounds contain one or more
aromatic rings in their molecules with one or more hydroxyl groups as substitutes. Phenolic compounds are mostly
found in the form of glycosides with predominant sugar residues of glucose, xylose, arabinose, rhamnose, often
bound to organic acids, lipids, and amines.
Anthocyanins are a large group of water soluble pigments, which give the fruits their red, violet, and blue color.
Anthocyanins are glycoside-bound polyphenols, and though rarely, are found in free form as aglycones, called
anthocyanidins. Cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin are the six anthocyanidins
most frequently found in the fruits29. These are indicated in Figure 2.
Figure 2. Chemical structure of anthocyanidins.
Anthocyanins are usually found as mono-, di- or triglycosides, where sugar residues are bound at С3, and more
rarely at С5or С7. The most common sugar residues are glucose, galactose, rhamnose, arabinose, rutinose, and
Anthocyanidin R1R2
Cyanidin -OH -H
Delphinidin -OH -OH
Malvidin -OCH3-OCH3
Pelargonidin -H -H
Peonidin -OCH3-H
Petunidin -OH -OCH3
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sophorose, which are usually acilated with acids such as р-coumaric, caffeic, ferulic, and more rarely bnezoic or
acetic acid35.
(1) (2)
Figure 3. Chemical structure of cyanidin-3-O-glucoside (1) and delphinidin-3-O-glucoside (2).
Around 35 glycosides (anthocyanins) have been isolated and identified within the Vaccinium genus3. Most of these,
contained in the four species V. myrtillus, V. uliginosum, V. vitis-idaea, V. arctostaphylos are specified in Table 1.
Table 1. Isolated and identified anthocyanidins and anthocyanins from Vaccinium species, distributed in Bulgaria.
Anthocyanidins and
anthocyanins
Species of Vaccinium genus
V.
myrtillus
(fruits)
V.
uliginosum
(fruits)
V.
vitis-idaea
(fruits)
V.
arctostaphylos
(fruits)
Cyanidin
+
[36, 37]
- - -
Delphinidin
(leaves and fruits)
+
[37]
- - -
Cyanidin-3-О-glucoside
+
[36, 38]
+
[31]
+
[39]
-
Cyanidin-5-О-glucoside
+
[40]
- - -
Cyanidin-3,5-О-
diclucoside
+
[40]
- - -
Cyanidin-3-О-
arabinoside
+
[36, 37]
+
[31]
+
[39, 41]
-
Cyanidin-3-О-
galactoside
+
[5, 38]
+
[31]
+
[39]
-
Cyanidin-3-О-xyloside
+
[37]
- -
+
[31]
Delphinidin-3-О-
arabinoside
+
[36, 38]
+
[31]
+
[42, 43, 44]
-
Delphinidin-3-О-
galactoside
+
[36, 38]
+
[31]
+
[42, 43, 44]
-
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Therapeutic effects
Antidiabetic activity
The polyphenols contained in genus Vaccinium exhibit antidiabetic properties, inhibiting glucohydrolase enzimes α-
amylase (EC 3.2.1.1), α-glucosidase (EC 3.2.1.20), and β-glucosidase (EC 3.2.1.21)46,47. Wangеt al. (2012) found
that the fruit shells demonstrate about 4 times greater inhibitory activity compared to the fruit core48. This is
probably due to the fact that the external layers of such shells are rich in anthocyanins48. There are two presumed
possible inhibition mechanisms of anthocyanin enzymes. One is competitive inhibition, resulting from the structural
similarity between the enzyme substrate and the glycoside groups of the anthocyanins. The second - polar groups
present on the surfaces of the enzymes interact with the hydroxyl groups of the anthocyanins. As a result, the
molecular configuration of the enzyme changes at a 3D level, its hydrophilic and hydrophobic behavior alter enzyme
activity4.
The antidiabetic potential of the anthocyanins includes a reduction of blood glucose, glycosuria, and glycated
hemoglobin. They prevent the production of free radicals, protect pancreatic β-cells, increase insulin secretion,
improve insulin resistance, and reduce the absorption of sugars in the small intestines4.
Delphinidin-3-О-
glucoside
+
[36, 38]
+
[31, 45]
+
[39]
+
[31]
Delphinidin-3-О-xyloside - - -
+
[31]
Malvidin-3-О-
arabinoside
+
[44]
+
[31, 45]
- -
Malvidin-3-О-
galactoside
+
[36, 38]
+
[45]
+
[42, 43, 44]
+
[31]
Malvidin-3-О-glucoside
+
[36, 38]
+
[31, 45]
+
[42, 43, 44]
+
[31]
Malvidin-3-О-xyloside - - -
+
[30]
Peonidin-3-О-
arabinoside
+
[36, 38]
+
[31]
+
[42, 43, 44]
-
Peonidin-3-О-glucoside
+
[36, 38]
+
[31]
+
[42, 43, 44]
-
Peonidin-3-О-galactoside
+
[36, 38]
+
[31]
+
[42, 43, 44]
-
Petunidine-3-О-
galactoside
+
[36, 38]
+
[45]
+
[42, 43, 44]
+
[31]
Petunidine-3-О-
glucoside
+
[36, 38]
+
[31, 45]
+
[42, 43]
+
[31]
Petunidine-3-О-xyloside - - - +
[30]
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Low doses of cyanidin-3-O-galactoside show synergistic action in combination with acarbose with regard to the
inhibitory activity on intestinal α-glucosidase49. The inhibitory potential of cyanidin-3-O-glucoside is greater than
that of cyanidin and cyanidin-3-O-galactoside50.
Anti-inflammatory activity
The pretreatment of ТНР-1 macrophages with cyanidin-3-О-β-glucoside, typical for genus Vaccinium, over 12 hours
can improve the expression and the transcription activity of the nucleus receptor γ, activated by peroxisome
proliferator (PPARγ) and a liver X receptor α(LXRα). In addition, pretreatment of these cells causes dose-
dependent inhibition of lipopolysaccharide (LPS) induced nitrous oxide synthase and cyclooxygenase-2 (СОХ-2)
(EC 1.14.99.1), along with a reduction of the nitrous oxide (NO) and prostaglandin Е2 (PGE2)6.
Karlsen et al. (2010) report reduced concentration of inflammatory biomarkers in the plasma within a controlled trial
performed with 31 patients, consuming bilberry juice for 4 weeks. Significant reduction is noted in plasma levels of
highly sensitive C-reactive protein (hsCRP) and proinflammatory cytokine interleukin 6 (IL-6)5.
Vasoprotective activity
An extract of Bilberry fruit, containing 25% anthocyanidins, has vasoprotective and anti-inflammatory activity in
test animals. In rabbits, chloroform induced skin capillary permeability is reduced after intraperitoneal
administration of the extract at a dose of 25-100 mg/kg of body weight or intragastric administration of anthocyanins
at a dose of 200-400 mg/kg of body weight. The anti-inflammatory effect of the extract persists longer when
compared to that of mepyramine. Anthocyanins at a dose of 25-100 mg/kg of body weight and intragastric
administration showed effectiveness both in the capillary permeability test and the vascular resistance in animals
subjected to a diet deficient in vitamin P7.
Antimicrobial activity
The antimicrobial activity of V. vitis-idaea has been evaluated with regard to the two pathogenic microorganisms in
the oral cavity - Streptococcus mutans and Fusobacterium nucleatum. Minimum inhibitory concentrations of 125
and 250 µg/ml were established against the growth of F. nucleatum and S. mutans. In order to achieve these
concentrations, the necessary flavonoids may be acquired from one tea spoon of fresh lingonberries (3g), containing
approximately 400 µg flavonoid glycosides, 4000 µg anthocyanins, and 750 µg flavan-3-ols. Fractions, enriched
with anthocyanins, flavan-3-ols, and procyanidins inhibit the growth of F. nucleatum at a concentration of 63-125
µg/ml and the growth of plankton S. mutans cells at varying MIC 125-250 µg/ml8.
Antitumor activity
The fruits of genus Vaccinium have demonstrated their ability to inhibit enzymes such as matrix metalloproteinases
(MMPs), which play an important role in the metastasis of cancer cells. Enriched anthocyanin fractions of
Vaccinium fruit extracts regulate the activity of matrix metalloproteinases in human prostate cancer10.
Katsube et al. (2003) compare ethanol extracts of 10 different berry species tested for the induction of apoptosis in
human tumor cells HL60 and НСТ116. The extract from V. myrtillus has shown the greatest efficacy. For the
aglycones delphinidin and malvidin, inhibitory activity has been found on HL60 cells, while for delphinidin and its
glycosides, the activity is expressed only for the НСТ116 cells9.
Genoprotective and anxiolytic activity
Barros et al. (2006) experimentally determine the possible effects of lyophilized fruit extracts from the genus
Vaccinium on the cognitive functions of rats after a 30-day feeding period. Certain tests are used, including a
labyrinth task, also monitoring the possibilities for DNA damage to the hippocampus and the cortex. The study
indicates that the extract improves significantly long-term memory and an anxiolytic effect is reported for the
labyrinth task. What is more, the extract reduces oxidative damage to brain tissue DNA11.
Antioxidant activity
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Fresh Vaccinium fruit are a rich source of anthocyanins - 1210 mg/100 g for Vaccinium myrtillus19,but their bio
availability is low, from 1.7% to 3.3%17. Despite this, unmodified anthocyanins and their metabolites may be found
in the blood, bile, liver, kidneys, heart, brain, urine, testes, prostate, and the lung of rats and/or mice15,17,20,21,23. Fruit
extracts have been shown to have an intracellular antioxidative activity51.
The antioxadant potential is determined in vitro through several basic methods based on scavenging free radicals
using 2,2-diphenyl-1-picrylhydrazyl (DPPH) or 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS),
ferric reducing ability of plasma (FRAP), oxygen radical absorbance capacity (ORAC), and lipid peroxidation
inhibition assay16,18. Following solid-phase extraction in order to obtain anthocyanin-rich extracts from five species
of berries, the extract from Vaccinium fruits demonstrated the highest capacity for preventing the formation of
hydroxyl radicals (HORAC) - 1293 μmol GAE/g13.
Many polyphenols demonstrate antioxidative properties by actively participating in oxidation reduction processes
within cells. These can neutralize free radicals by donating an electron or a hydrogen atom (Н+). The highly
conjugated system in their molecule and the presence of certain hydroxyl groups, such as the 3-hydroxy group in
flavonols, are considered to be crucial for their antioxidative activity. Polyphenols suppress the formation of free
radicals by reducing the rate of oxidation by inhibiting the formation or deactivating ROS (reactive oxygen species).
It has been found that polyphenols usually do not act alone but as co-antioxidants or participate in the regeneration
of cofactors and prosthetic groups of enzymes24. Another possible mechanism of antioxidant action of polyphenols
is by inhibition of xanthine oxidase (EC 1.1.3.22) and induction of secretion of endogenous antioxidant enzymes
such as glutathione peroxidase (EC 1.11.1.9), catalase (EC 1.11.1.6), and superoxide dismutase (EC 1.15.1.1)14.
Wang et al. (1997) report higher values of antioxidative activity of cyanidin-3-O-glycoside and cyanidin-3-O-
rhamnoglucoside compared to Trolox52.
Numerous observations indicate that anthocyanins are active for cardioprotection and neuroprotection as well as
antitumor, normolipidemic and normoglycemic agents12,22. The common mechanism at the core of these different
effects may be related to the antioxidative properties of phenolic compounds, including anthocyanins.
Conclusion
Scientific research has contributed significantly to the fact that anthocyanins have become not only food products
but also therapeutic agents. The selected literature data on anthocyanins raise the hope for their wide-spread use in
prevention and therapy of many diseases.
Acknowledgements
The authors express their gratitude to the Medical University of Plovdiv for the financial support in this study made
in connection with the project SDP - 05/2015.
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