Bioavailability and Antioxidant Activity of Black Chokeberry (Mechanisms of Action: A Review

Bioavailability and Antioxidant Activity of Black
Chokeberry (Aronia melanocarpa) Polyphenols:

in vitro and in vivo Evidences and Possible
Mechanisms of Action: A Review
Petko N. Denev, Christo G. Kratchanov, Milan Ciz, Antonin Lojek, and Maria G. Kratchanova
Abstract: Black chokeberry (Aronia melanocarpa) is a distinctive berry with a high content of polyphenol compounds
and possesses one of the highest in vitro antioxidant activities among fruits. The bioavailability of aronia polyphenols
seems to be low, but there is ample evidence for chokeberry health benefits including antidiabetic, cardioprotective,
hepatoprotective, antimutagenic, and anticarcinogenic effects. This review presents the available information for the
bioavailability and antioxidant activity of chokeberry polyphenols and explains the possible mechanisms of action in vivo
in the prevention and treatment of oxidative stress-related diseases. The review shows the available data for chokeberry
antioxidant activity in vitro, in isolated cells and cell lines, and in vivo, in both human subjects and animals. It is evident that
in vivo antioxidant action of chokeberry extends far beyond radical scavenging and includes suppression of reactive oxygen
and nitrogen species formation, inhibition of prooxidant enzymes, restoration of antioxidant enzymes, and probably
cellular signaling to regulate the level of antioxidant compounds and enzymes. The original contribution of this work
is that it compiles the available information up to date and outlines the gaps and future directions in the assessment of
chokeberry antioxidant action in vivo.
Introduction by other enzymes like xanthine oxidase and xanthine dehydroge-

Life on earth is inconceivable without oxygen (O2 ), but in nase which reduce O2 to O2 ·− and by the auto-oxidation of many
higher concentration this vital element is toxic to aerobes. Most biomolecules like glyceraldehydes, FMNH2 , FADH2 , adrenalin,
of the damaging effects of O2 are due to oxygen radicals, which in- noradrenalin, and dopamine (Kirsch 2003). The most important
clude superoxide (O2 ·− ), hydroperoxyl (HOO· ), hydroxyl (HO· ), source of O2 ·− in vivo is the mitochondrial electron transport
peroxyl (ROO· ), and alkoxyl (RO· ) radicals (Gilbert 1981). These, chain and hemoglobin in human erythrocytes, which also could
together with the nonradicals hydrogen peroxide (H2 O2 ), ozone be a source of superoxide radicals (Rifkind 2004). Hydroxyl radi-
(O3 ), and singlet oxygen (1 O2 ) constitute the so-called reactive cals are the most potent oxidants among ROS. Physiologically they
oxygen species (ROS). ROS together with the reactive nitro- are being produced mainly through Fenton-like reactions catalyzed
gen species (RNS) nitric oxide (NO), peroxynitrite (ONOO− ), by transition metal ions, UV-induced homolytic cleavage of H2 O2
peroxynitrate, and so on, are constantly produced in our bodies (von Sonntag 1987), γ -ray-assisted homolytic fission of water, and
through numerous physiological reactions and processes. Exper- hypochlorous acid reacting with O2 · – (Folkes and others 1995).
imental evidence has directly or indirectly suggested that there Peroxyl and alkoxyl radicals are good oxidizing agents, which can
are 6 major reactive species causing oxidative damage in the hu- easily abstract hydrogen atom from different biomolecules. In vivo
man body. These species are superoxide anion, H2 O2 , peroxyl they are formed through the reaction of carbon-centered radicals
radicals, hydroxyl radical, singlet oxygen, and peroxynitrite. Su- with O2 or by the decomposition of organic peroxides (Forni and
peroxide is formed in vivo by NADPH oxidase in phagocytic cells Willson 1986). H2 O2 is continuously produced in many tissues
in vivo and mitochondria are the biggest contributors to its gen-
eration both by monoamine oxidases and by dismutation of O2 · –
(Halliwell and Gutteridge 2007). Singlet oxygen is often gener-
MS 20120387 Submitted 2/13/2012, Accepted 5/23/2012. Authors Denev ated by photosensitization reactions and its detrimental effect is
and Kratchanova are with Laboratory of Biologically Active Substances, 139 Ruski expressed mainly in skin and eye damage. Peroxynitrite is gener-
Blvd, Plovdiv-4000, Bulgaria, Author Kratchanov is with Vitanea Ltd., 20 d-r
G.M.Dimitrov str., Plovdiv-4000, Bulgaria, and Authors Ciz and Lojek are with Inst.
ated by the reaction of NO with superoxide radical and the biggest
of Biophysics of the Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska contributors for NO generation are the nitric oxide synthase en-
135, 612 65 Brno, Czech Republic. Direct inquiries to author Kratchanova (E-mail: zymes. To counteract the assault of all ROS and RNS, living
[email protected]). cells have elaborated a complex biological defense system com-
posed of enzymatic and nonenzymatic antioxidants that convert

c 2012 Institute of Food Technologists
doi: 10.1111/j.1541-4337.2012.00198.x Vol. 11, 2012 r Comprehensive Reviews in Food Science and Food Safety 471
Antioxidant activity of chokeberry . . .
ROS/RNS to harmless species. The term antioxidant is defined aronia berries are widely distributed mainly in the east-south and
as any substance that in low concentrations, compared to those central parts of Europe and cultivated as an industrial crop (Hardin
of an oxidizable substrate, significantly delays or prevents oxidation 1973; Seidemann 1993; Strigl and others 1995). Aronia berries
of the substrate (Halliwell and Gutteridge 2007). By mechanism of are distinctive with a high content of polyphenols and possess
action antioxidants are divided into preventive and chain-breaking one of the highest antioxidant activities among plant species. In
antioxidants. Preventive antioxidants act as the first line of defense the last few years there has been increasing research interest in
by suppressing the formation of ROS and RNS. The scavenging chokeberry, generating a significant number of scientific publica-
antioxidants remove active species rapidly before they can attack tions. Recently, several articles reviewed the chemical composition
biologically essential molecules. For example, superoxide radical and medicinal potential of the berries (Kulling and Rawel 2008),
is converted to oxygen and H2 O2 by superoxide dismutase (SOD) their potential health benefits (Valcheva-Kuzmanova and Belcheva
and H2 O2 can then be converted to water and oxygen by catalase. 2006) and their clinical effectiveness (Chrubasik and others 2010).
In contrast, no enzymatic action is known to scavenge ROO. , So far there is no review available assessing the bioavailability of
HO. , 1 O2 , and ONOO− (Huang and others 2005). Therefore, chokeberry polyphenols and the connection between their in vivo
the burden of defense relies on a variety of nonenzymatic antiox- antioxidant activity and potential health benefits. The aim of this
idants such as vitamins C and E and many phytochemicals such effort was to review the available information on the bioavail-
as polyphenols that have the ability to scavenge oxidants and free ability and antioxidant activity of chokeberry and to explain the
radicals. These scavenging antioxidants act as the second line of antioxidant mechanisms implicated in the prevention and treat-
defense in vivo. Various enzymes function in a third line of defense ment of oxidative stress-related diseases by aronia. Reviewed are
by repairing damage, clearing wastes, and reconstitution lost func- the available data for chokeberry antioxidant activity in vitro, in
tion. In addition, the adaptation mechanism functions as a fourth isolated cells and cell lines, and in vivo, in both human subjects and
line of defense in which appropriate antioxidants are generated animals. The original contribution of this work is that it compiles
at the right time and transferred to the best position in the right the available information up to date and outlines the gaps and fu-
concentration. Furthermore, there is increasing evidence show- ture direction in the assessment of chokeberry antioxidant action
ing that some antioxidants act as a cellular signaling messenger to in vivo.
regulate the level of antioxidant compounds and enzymes (Niki
2010). Usually there is a balance between the antioxidants and Antioxidant Activity of Aronia and Its Major
the prooxidants in vivo, but several factors like stress, radiation, Polyphenols in vitro
nutrition, polluted atmosphere, smoking, and so on, disrupt the Kulling and Rawel (2008) reviewed the polyphenol con-
oxidative balance leading to so-called oxidative stress, which im- stituents of aronia fruit very well. In Table 1 we present updated
poses the necessity to contribute exogenous antioxidants with the information including the polyphenol composition of choke-
diet. Oxidative stress is a physiological state, which is believed to berry juice. It is known that processing of berries into juice
be a prerequisite for the development of many diseases including can significantly affect polyphenol composition; and quite of-
cardiovascular disease (CVD), stroke, and neurodegenerative dis- ten bioavailability studies and clinical trials are performed with
orders such as Alzheimer’s disease and Parkinson’s disease (Davies juices, since they are more convenient to store and ingest in
2000; Fenkel and Holbrook 2000; Sayre and others 2008). The comparison to berries. Chokeberries are a rich source of an-
injury caused by oxidative stress can affect all organ systems. For thocyanins (ACN), proanthocyanidins (PACNs), and hydroxycin-
example, LDL oxidation is the initial step in atherosclerosis, lead- namic acids. Flavonols (quercetin glycosides) and flavan-3-ols (epi-
ing to CVD and oxidized DNA is the basis in mutagenesis and is catechin) are also present as minor components in the berries. The
involved in carcinogenesis (Berliner and others 1995). chemical structures or the major chokeberry polyphenols are pre-
A growing amount of evidence indicates that the consumption sented in Figure 1. The total amount of anthocyanins in fresh
of plant foods is correlated with a lower risk from development of berries varies in the range 357 to 1790 mg/100 g fresh weight
arteriosclerosis and oxidative stress-related diseases (Ellingsen and (FW). Compared to other berries the aronia anthocyanin profile
others 2008). In contrast, diets poor in plant-based foods and rich is very simple consisting almost exclusively of cyanidin glycosides,
in animal products and ingredients are related to an increased risk namely cyanidin-3-arabinoside, cyanidin-3-galactoside, cyanidin-
for CVD and certain types of cancer (Rissanen and others 2003). 3-glucoside, and cyanidin-3-xyloside. Cyanidin-3-galactoside and
Most of the antioxidants taken with the diet are of plant origin cyanidin-3-arabinoside are the predominant representatives with
and the richest sources are herbs, cereals, fruits and vegetables in a cumulative content >90% in the berries (Oszmianski and
which polyphenol substances, carotenoids, vitamin C, and vitamin Wojdylo 2005). There is also 1 paper reporting minor amounts
E are the biggest contributors to their antioxidant activity. In the of pelargonidin-3-arabinoside and traces of pelargonidin-3-
last decades, polyphenolic compounds have gained much attention galactoside (Wu and others 2004). Chokeberry proanthocyanidins
and have been subject to thorough research because of their an- consist exclusively of (-)-epicatechin units bonded by a C4 to C8
tioxidant properties and beneficial effect beyond vitamin action. linkage. Their content in fresh berries varies in the range 664 to
Polyphenols are the most abundant antioxidants taken with the 2120 mg/100 g and the following composition of proanthocyani-
diet (Ross and Kasum 2002), with over 8000 known compounds, dins has been reported: monomers (0.78%), dimmers (1.88%),
which makes them one of the largest chemical groups in the plant trimers (1.55%), 4 to 6-mers (6.07%), 7 to 10-mers (7.96%), and
kingdom. Natural polyphenols are structurally diverse and vary >10-mers (81.72%) (Wu and others 2004). Hellstrom and oth-
from single molecules such as phenolic acids to highly polymer- ers (2009) reported that different varieties of chokeberry con-
ized structures like tannins (Harborne and Simmonds 1964). tain between 80 and 95% extractable PACNs and >10-mers
Aronia (Aronia melanocarpa), with the common name choke- amounted to 97–99.5%of the extractable PACNs. The hydrox-
berry, originates from the eastern parts of North America. Around ycinnamic acids are represented by significant amounts of chloro-
1900 it was transferred to Europe and in the 1960s the plant was genic (61 to 193 mg/100 g FW) and neochlorogenic acids (85 to
established as a cultivar in the former Soviet Union. Nowadays 123 mg/100 g FW). Quercetin and several quercetin glycosides
472 Comprehensive Reviews in Food Science and Food Safety r Vol. 11, 2012
Table 1–Polyphenol constituents in aronia berries and juices.
Sample Berries (mg/100 g) Reference Juices (mg/L) Reference

Total polyphenols 719 Jakobek and others 2007b 7093 Valcheva-Kuzmanova and others
2007b
778–1285 Rop and others 2010 8100 Hellstrom and others 2010
1064 Jakobek and others 2007a 9154 Jakobek and others 2007c
2556 Zheng and Wang 2003
6902 Benvenuti and others 2004
3440 (DW) Kolesnikov and Gins 2001
3760 (DW) Hudec and others 2006
4210 (DW) Kahkonen and others 1999
7849 (DW) Oszmianski and Wojdylo 2005
Total proanthocyanidins 664 Wu and others 2004 2800 Hellstrom and others 2010
1740–2170 Hellstroom and others 2009 2934 Skoczynska and others 2007
Total anthocyanins 357 Jakobek and others 2007b 1068 Valcheva-Kuzmanova and others
2007b
428 Zheng and Wang 2003 1250–2500 Fuchs and others 1996
434 Jakobek and others 2007a 3042 Jakobek and others 2007c
461 Benvenuti and others 2004
470–1790 Fuchs and others 1996
1480 Wu and others 2006
Antocyanins
Cyanidin-3-arabinoside 99 Jakobek and others 2007a 51 Skoczynska and others 2010
94–155 Rop and others 2010 647 Jakobek and others 2007c
142 Zheng and Wang 2003 1000 Hellstrom and others 2010
146 Slimestead and others 2005
Cyanidin-3-galactoside 101–120 Rop and others 2010 125 Skoczynska and others 2010
126 Zheng and Wang 2003 1817 Jakobek and others 2007c
279 Jakobek and others 2007a 2100
315 Slimestead and others 2005
Cyanidin-3-glucoside 1.7 Zheng and Wang 2003 7.1 Skoczynska and others 2010
10 Slimestead and others 2005 74 Jakobek and others 2007c
Jakobek and others 2007a
38 Oszmianski and Wojdylo 2005
42 (DW)
Cyanidin-3-xyloside 10 Slimestead and others 2005 5.9 Skoczynska and others 2010
15 Jakobek and others 2007a
47 Zheng and Wang 2003
Pelargonidin-3-arabinoside 2.3 Wu and others 2004
Flavonols
Quercetin derivatives >17 Slimestead and others 2005
Quercetin 7.1 Jakobek and others 2007a 118 Valcheva-Kuzmanova and others
Häkkinen and others 1999 2007b
8.9 Jakobek and others 2007b
9.2
Quercetin-3-galactoside 30.2 Zheng and Wang 2003 28.3 Skoczynska and others 2010
37(DW) Oszmianski and Wojdylo 2005
Quercetin-3-glucoside 27.3 Zheng and Wang 2003 22.5 Skoczynska and others 2010
Quercetin-3-rutinoside 15 (DW) Oszmianski and Wojdylo 2005 16.8 Skoczynska and others 2010
Quercetin 3-vicianoside 11.5 Skoczynska and others 2010
Quercetin 3-robinobioside 11.7 Skoczynska and others 2010
Kaemferol 0.53 Jakobek and others 2007a
0.69 Jakobek and others 2007b
Flavan-3-ols
Epicatechin 47–84 Rop and others 2010 14.8 Skoczynska and others 2010
15.4 (DW) Oszmianski and Wojdylo 2005
Hydroxycinnamic acids
Chlorogenic acid 61 Slimestead and others 2005 455 Skoczynska and others 2010
113 -196 Rop and others 2010 800 Hellstrom and others 2010
Neochlorogenic acid 84 -117 Rop and others 2010 492 Skoczynska and others 2010
123 Slimestead and others 2005 1200 Hellstrom and others 2010
291(DW) Oszmianski and Wojdylo 2005

c 2012 Institute of Food Technologists Vol. 11, 2012 r Comprehensive Reviews in Food Science and Food Safety 473
Anthocyanins Flavan-3-ols Flavonols

OH OH OH
OH OH OH
HO O HO O HO O
OR OH OH
OH OH OH O
R = arabinose – cyanidin-3-arabinoside (-)-Epicatechin Quercetin

R = galactoside – cyanidin-3-galactoside
R = glucoside – cyanidin-3-glucoside
R = xylose – cyanidin-3-xyloside
Proanthocyanins
Hydroxycinnamic acids OH
HO COOH OH
O
O
HO OH
HO O OH
OH
OH
OH OH O
HO OH
OH
OH
Chlorogenic acid OH
(5-Caffeoylquinic acid)
OH O
HO COOH HO OH
OH
O OH
OH O
HO O HO
OH
OH OH
OH OH
Neochlorogenic acid Procyanidin (4β→8 bonds)

(3-Caffeoylquinic acid)
Figure 1–Chemical structutes of chokeberry main polyphenols.
(quercetin-3-galactoside, quercetin-3-glucoside, and quercetin-3- Table 2 summarizes the available data for antioxidant activity of
rutinoside) were also detected in aronia berries but in relatively aronia berries, extracts, and juices measured by different in vitro
low concentrations of about 71 mg/100 g FW. Rop and others assays. It is obvious that aronia antioxidant action can be assessed
(2010) reported that epicatechin is also present in the berries in with numerous assays including ORAC, TRAP, DPPH, ABTS,
concentrations of 47 to 84 mg/100 g FW. The content of to- and HORAC which rely on the generation of different radicals,
tal phenolis of aronia berries has been determined to be in the acting by different mechanisms. Depending upon the reactions
range 690 to 2556 /100 g FW and 3440 to 7849 mg/100 g DW involved, these assays can roughly be classified as 2 types: assays
(Table 1). It is evident that chokeberries vary significantly in their based on hydrogen atom transfer (HAT) reactions and assays based
contents of total and individual polyphenol components, which on electron transfer (ET). The majority of HAT-based assays ap-
could be attributed to the analytical techniques used and various ply a competitive reaction scheme in which antioxidant and sub-
environmental and genetic factors such as cultivar, harvest time, strate compete for thermally generated peroxyl radicals through
habitat, fertilization, climate, maturation, and so on. the decomposition of azo compounds. These assays include
% inhibition
inhibition of lipid peroxidation, ORAC, and TRAP. ET-based
scavenging,
Superoxide
21–37g
anion
assays measure the capacity of an antioxidant in the reduction of
an oxidant, which changes color when reduced. ET-based assays
include ABTS and DPPH methods (Huang and others 2005).
The HORAC method measures the metal-chelating activity of
% inhibition
scavenging, antioxidants under the conditions of Fenton-like reactions and
Hydroxyl
22–34 g
radical
hence indicates the protecting ability against formation of hy-

droxyl radical. The methods used embrace different aspects of the
antioxidant action and give a broader view on the antioxidant po-
tential of aronia. This is important since it is recommended to use
more than 1 antioxidant assay for a detailed understanding of the
HORAC,
GAE/g
GAE/g
1265 l
µmol
principles of antioxidant properties of substances (Ciz and others

2010). Since antioxidants scavenge ROS/RNS by hydrogen atom
transfer, HAT methods more than others are considered as physi-
peroxidation,
ologically relevant. ORAC and TRAP methods assess the radical

% inhibition
Inhibition
12–20 g
of lipid
scavenging activity of the sample against peroxyl radicals, which

physiologically are the most important ones. Aronia polyphenols
are potent inhibitors of lipid peroxidation, which is very impor-
tant since lipids are very susceptible to peroxidation in vivo. DPPH
and ABTS assays are very rapid and easy to perform but have
% inhibition
scavenging,
some serious limitations. For example, DPPH. radical is a resis-

27–41 g
No
tant nitrogen radical in contrast to highly reactive physiologically

relevant radicals. Often antioxidants, which react fast with peroxyl
radicals react very slowly with DPPH. There is also published
evidence that DPPH. reacts reversibly with some polyphenols
439(DW) e
103.2 k
Result
resulting in altered radical-scavenging values (Huang and others

79 f
2005).
Several studies found very good correlation between the total
phenol content and antioxidant activity of aronia samples measured
ABTS
μmol TE/100 g
by ORAC, TRAP, and TEAC (Wu and others 2004; Jakobek and
others 2007a; Denev and others 2010). In all cases the correla-
μmol TE/g
Units
mgTE/mL
tion was better than that of anthocyanins and antioxidant activity,

Table 2–Antioxidant activity of aronia and aronia products determined by different in vitro assays.
showing that all polyphenols in chokeberry determine antioxidant

properties rather than only the dominating anthocyanins.
Table 3 summarizes in vitro antioxidant activity of the most
279 (DW)e
important phenolic constituents of chokeberry. Antioxidant ac-

8.9–16 g
Result
181 f
72.4i
1.8 h
36 m
60 k
63 j
tivity of phenolic compounds is determined by several struc-

tural characteristics: the number and arrangement of the hydroxyl
groups and the presence of 3-OH group and ortho-dihydroxy
DPPH,
substitution in the B ring of flavonoids, as well as others. A 2,

μmol TE/100 g
3 double bond in conjugation with the 4-oxo function in the

μmolTE/mL
IC50 (mg/L)
μmol TE/g
mmolTE/L
Units
mgTE/mL
EC50 (mg)
C ring is also a prerequisite for good antioxidant activity (Bors

AAE/kg
and others 1990; Salah and others 1995; Rice-Evans and others
1996). Among the polyphenols present in aronia quercetin pos-
sesses many of the structural characteristics necessary for potent
antioxidant activity, and it is the most potent antioxidant among
4051 l
TRAP
µmol
TE/g
the aronia monomer phenolics followed by cyanidin glycosides

and chlorogenic acid. Zheng and Wang (2003) estimated that
anthocyanins, flavonols, and hydroxycinnamic acids contribute
ORACL b ,
about 59.4% (95 μmol) of the total antioxidant activity of choke-

µmol
TE/g
2.4c
berry without assuming the possible synergism/antagonism be-

tween the individual antioxidants. This means that 40% of the
antioxidant activity of chokeberries could be attributed to PACNs
k Bermudez-Soto & Tomas-Berberan 2004.
ORACH a ,
j Valcheva Kuzmanova and others 2007d.

160.2 d
5165 l
µmol
making them the biggest contributors to aronia antioxidant

TE/g
158 c
activity.
References: c Wu and others 2004.
e Oszmianski and Wojdylo 2005.
m Gabrielska and others 1999.

ORACH = Hydrophilic ORAC.
h Benvenuti and others 2004.

i Jakobek and others 2007c.
f Jakobek and others 2007b.
ORACL = Lipophilic ORAC.
Bioavailability of Polyphenols
d Zheng and Wang 2003.
l Denev and others 2010.

g Rop and others 2010.
Juice concentrate
The capacity of antioxidants in vivo is determined by many

factors, which should be taken into consideration in its assess-
ment. One such factor is bioavailability. The antioxidants should
Sample
Extract
Berries
be absorbed, transported, distributed, and retained properly in the

Juice
biological fluids, cells, and tissues. Since a bioavailability study

b
a

Table 3–Antioxidant activity of aronia main polyphenols determined by different assays.
Inhibition of lipid
MeLo emulsion, % peroxidation, %
inhibitionb inhibition b
DPPH, % scavenged radicalsb
Compound ORAC, µmolTE/mga 17 µM 50 µM 250 µM 10 µM 25 µM
Cyanidin-3-galactoside 11.5 25 47 85 86 89
Cyanidin-3-arabinoside 12.3 26 50 76 98 99
Cyanidin-3-glucoside 14.8 32 52 83 92 92
Cyanidin-3-xyloside 11.9
Quercetin 34 77 95 96 97
Quercetin-galactoside 13.4
Quercetin-glucoside 15.8
Chlorogenic acid 7.4 38 35 65 7 80
References: a Zheng and Wang 2003;
b Kahkonen and Heinonen 2003.
allows determination of real exposure of the human organism terols; (2) protein oxidation—protein carbonyl hydroperoxides;
to the tested compounds, such results are an important and es- disulfide -SS-; -SOH, -SOOH, -SOOOH; aldehyde-modified
sential topic. The capacity and efficacy of antioxidants in vivo protein; hydroperoxide-modified protein; crosslinked protein;
may be assessed most accurately by the effect of antioxidant com- dityrosine, albumin dimer, creatol, myeloperoxide; (3) DNA
pounds on the level of oxidation in biological fluids and tissues, oxidation—Commet assay, thyamine glycol; 5-hydroxyuracil; 8-
such as plasma, erythrocytes, urine, and cerebrospinal fluids, from hydroxyguanine; 8-nitro-, chloro-, bromo-guanine. The ratio
humans and experimental animals. Saliva and tears may also be of cis,trans/trans,trans-HODE (Nam and others 2007; Yoshida
used. Research on polyphenol bioavailability allows us to corre- and others 2007), linoleoyl tyrosine 2-deoxyguanosyl ester (a
late polyphenol intakes with one or several accurate measures of conjugate product from unsaturated fatty acid, protein, and
bioavailability (such as concentrations of key bioactive metabo- DNA; Khatib and others 2007) and acrolein (Tomitori and oth-
lites in plasma and tissues) and with potential health effects in ers 2005) has also been proposed. Antioxidants (ratio of oxi-
epidemiologic studies (Manach and others 2004). Bioavailability dized/reduced forms of glutathione and coenzyme) could be used
appears to differ greatly among the various phenolic compounds as well. As can be seen from this review, just a few of these
and the most abundant ones in our diet are not necessarily those biomarkers have been used in the investigation of aronia health
that have the best bioavailability profile. Metabolism of dietary benefits.
antioxidants is another factor, strongly affecting their bioavailabil-
ity. Usually, after absorption, polyphenols are subjected to 3 main Bioavailability of Aronia Polyphenols
types of conjugation: methylation, sulfation, and glucuronidation. Anthocyanins
Interestingly, unlike other flavonoids that are absorbed and ex- Anthocyanins are broadly distributed and many plants, in-
creted, most anthocyanins do not appear to undergo extensive cluding berries, contain several structurally diverse anthocyanins.
metabolism of the parent anthocyanidin to glucuronide, sulfate, They appear to be poorly absorbed in the small intestine, so
or methyl derivatives (Miyazawa and others 1999; McGhie and significant amounts probably pass into the large intestine where
others 2003; Ichiyanagi and others 2005). Moreover, the structure bacterial degradation occurs. There are reports that cyanidin-
of the resulting metabolites could be totally different from the based anthocyanins undergo cleavage of the sugar moiety fol-
parent compounds, and they may, or may not exert antioxidant lowed by ring fission of the released cyanidin, which produces
properties. Plasma concentrations are good markers for bioavail- 3,4-dihydroxybenzoic acid (protocatechuic acid; Aura and others
ability, but may vary according to the nature of the polyphenol and 2005; Vitaglione and others 2007; Galvano and others 2008). De-
the food source. Usually they are on the order of nanomolar to tecting and quantifying the trace levels of complex anthocyanin
low micromolar concentrations (Hollman and others 1997; Graefe profiles in plasma and urine after absorption, excretion, and po-
and others 2001). Generally, among the polyphenols present in tential phase I and phase II metabolism appears to be very difficult.
aronia catechin and quercetin are more efficiently absorbed than Fortunately, because of its simple anthocyanin profile aronia is pre-
anthocyanins, which appear in plasma at very low concentrations ferred for bioavailability studies of cyanidin and its glycosides. That
(Miyazawa and others 1999; Cao and others 2001; Matsumoto and is why aronia anthocyanins have been investigated most thoroughly
others 2001). An objective way to measure the antioxidant action in comparison to its other phenolic constituents. Kay and others
of an antioxidant in vivo is the use of oxidative stress/oxidative de- (2004) investigated the metabolic conversion of aronia-derived
fense biomarkers. Recently, Niki (2010) reviewed them outlining cyanidin glycosides in human subjects. Volunteers consumed ap-
the most significant ones. Oxidation products of lipids (Maoodi proximately 20 g chokeberry extract containing 1.3 g cyani-
and others 2008; Niki 2008; Yin and others 2009; Nakanishi and din 3-glycosides. Cyanidin-3-galactoside accounted for 66.0% of
others 2009), oxidative modification and expression of proteins the detected anthocyanins in the urine and serum samples. The
and sugars (Hawkins and others 2009; Rabbani and Thornalley metabolites were identified as glucuronide conjugates, as well
2009), and strand breaks of DNA and oxidation products of DNA as methylated and oxidized derivatives of cyanidin-3-galactoside
bases (Dizdaroglu and others 2002) have been used as oxidative and cyanidin glucuronide. The consumption of 4 cyanidin gly-
stress biomarkers. Some of the most used biomarkers summarized cosides (cyanidin 3-galactoside, cyanidin 3-arabinoside, cyanidin
by Niki (2010) are: (1) lipid oxidation—ethane and penthane 3-xyloside, and cyanidin 3-glucoside) resulted in the appearance of
in exhaled gas; thiobarbituric acid-reactive substances (TBARS); at least 10 individual anthocyanin metabolites in human urine and
conjugated dienes; hydroperoxide aldehydes; ketones; isoprostane; serum. Urine samples (22 to 24 h) showed cyanidin 3-galactoside
neuroprostane; isofuran; neurofuran; lyso PC, oxidized LDL, oxys- and metabolized derivatives of cyanidin 3-galactoside to persist in
the urine at levels of 0.011 to 0.013 nmol/L. Additionally, the con- as cyanidin glycosides as well as being metabolized to methylated
centrations of identifiable anthocyanins and anthocyanin metabo- and/or glucuronidated derivatives. Anthocyanins appeared in the
lites in the serum were observed at a level of 350.8 nmol/L within blood within 30 min after the consumption of chokeberry juice,
2 h postconsumption, with a cumulative total serum concentration which authors related to absorption in the upper part of the di-
reaching 591.7 nmol/L. The data obtained indicated the presence gestive tract, suggesting at least in part absorption of anthocyanin
of both cyanidin-3-galactosides and cyanidin glucuronides in the from the stomach. Similarly to the other studies the glucuronida-
urine. Mono- and dimethylated cyanidin-3-galactoside derivatives tion was the major metabolic route of chokeberry anthocyanins,
and glucuronide derivatives were also detected. Interestingly 1 an- while methylation played a minor role in the metabolism of those.
thocyanin metabolite occurred in the urine but not in the serum, The elimination half-life of plasma total anthocyanins was calcu-
which may indicate that this metabolic product is either formed lated as 2.4 h.
exclusively in the kidney, accumulates in the kidney, or the con- It is evident that the available bioavailability data of aronia antho-
centration of this metabolite in the serum may have been below cyanins give controversial information. There are big differences
the detection limit of the analytical technique used. This com- in the number of the recovered metabolites in blood and urine and
pound was highly metabolized cyanidin 3-galactoside. The parent the amounts of the recovered parent anthocyanins in the human
aglycone cyanidin was not identified, neither in urine nor in the and animal studies. These differences could be attributed to the
serum samples. Total urinary analysis revealed that cyanidin galac- variation in the administered doses of anthocyanins, the specifics of
toside and its metabolites accounted for 84.0% of the identified animal and human metabolism and the analytical technique used.
anthocyanins. Of these, 55.3% was the parent compound cyanidin- Metabolism of ingested flavonoids is not necessarily the same in
3-galactoside. In the serum, cyanidin galactosides accounted for animal models as it is in human subjects and frequently the dosages
89.4% (529.3 nmol/L) of the anthocyanins, with 66.0% being the used in such studies are untranslatable to a regular human dietary
parent compound. It must be noted that the study design included regimen. In summary, it could be concluded that chokeberry an-
the ingestion of an extremely high dose of anthocyanins (1.3 g) thocyanins are recovered in blood and urine in nanomolar concen-
and the metabolic route under these circumstances may differ from trations. Glucuronidation and methylation seem to be the major
the route following the ingestion of a diet-relevant dose of antho- pathways in aronia anthocyanin metabolism, whereas sulfation was
cyanins. In a more recent study Wu and others (2005) investigated not observed. It is likely that conjugation affects the biological ac-
the urinary excretion of anthocyanins in chokeberry-fed pigs. A tivity of anthocyanins and these metabolic products are likely, in
total of 18 different ACN-based compounds, including 4 major part, responsible for the reported health benefits associated with
original ACNs and 14 metabolites were identified in the urine in the consumption of anthocyanins.
contrast to the 11 ACN-based compounds in the urine described
in the human study of Kay and others (2004). Of the total ACN- Proantocyanidins
based compounds in the urine, cyanidin-3-galactoside accounted Proanthocyanidins differ from most other plant polyphenols be-
for 60.7% of the total, which is similar to findings of Kay and oth- cause of their polymeric nature and high molecular weight. This
ers (2004). In another pharmacokinetic study a more diet-relevant particular feature should limit their absorption through the gut
dose of chokeberry anthocyanins (721 mg cyanidin-3-glycosides) barrier; oligomers larger than trimers are unlikely to be absorbed
was given to human subjects orally (Kay and others 2005). The re- in the small intestine in their native forms. There are numer-
sults indicated that cyanidin-3-glycosides are rapidly absorbed and ous feeding studies with animals and human subjects indicating
metabolized extensively following a moderate-to-high oral dose that polymeric procyanidins are not absorbed (Espin and others
in humans. In contrast to the other studies with aronia ACNs, the 2007). Most pass unaltered to the large intestine where they are
parent anthocyanins represented only 32.0% of the total antho- catabolized by the colonic microflora yielding a diversity of phe-
cyanins detected with 68.0% identified as conjugated metabolites. nolic acids (Deprez and others 2000; Gonthier and others 2003a;
Additionally only 32.5% (347.85 μg) of the anthocyanins excreted Appeldoorn 2009a) including 3-(3-hydroxyphenyl)propionic acid
in the urine (total 24 h) were the parent compounds with 67.5% and 4-O-methyl-gallic acid, which are absorbed into the circula-
(723.69 μg) occurring as conjugated metabolites. The metabolites tory system and excreted in urine. In vitro experiments using single
were identified as glucuronidated and methylated derivatives of layers of Caco-2 cells as a model of absorption in the small intes-
the parent cyanidin-3-glycosides. Glucuronidation was the major tine showed that only the dimers and trimers of flavanols are able
metabolic pathway observed for anthocyanin metabolism, repre- to cross the intestinal epithelium (Deprez and others 2001). Pro-
senting 59.8% and 57.8% of the total anthocyanins detected in cyanidin B2 is very poorly absorbed in rats, whereas procyanidin
the blood and urine, respectively, and methylation was the second B3 is not absorbed (Baba and others 2002; Donovan and others
most commonly observed metabolic transformation. In an elegant 2002). There is also a report of minor quantities of procyanidin
study Wiczkowski and others (2010) investigated the bioavail- dimers B1 and B2 being detected in human plasma (Sano and
ability of anthocyanins from chokeberry juice providing 0.8 mg others 2003). Individual procyanidins in an extremely high dose
of anthocyanins/kg of body weight using healthy volunteers. In (1 g/kg body weight) were fed to rats after which dimers, trimers,
contrast to other studies, this was the first time when fresh choke- tetramers, and pentamers were detected in plasma (Shoji and oth-
berry juice with a dietary-relevant dose of anthocyanins was used ers 2006). It remains to be determined whether procyanidins can
in a bioavailability study. Eight cyanidin derivatives were found in be similarly detected in urea-extracted plasma after the ingestion
blood and urine after juice consumption. The maximum plasma of more nutritionally relevant doses.
anthocyanin concentration of 2.9 nmol/L was reached at 1.3 h. So far, no bioavailability study has been conducted with aronia-
The anthocyanins’ urine excretion rate was the highest within the isolated proanthocyanidins and there is only 1 piece of indirect
first 2 h. In total 0.02% of the ingested anthocyanins was excreted evidence for the bioavailability of aronia proanthocyanidins. It is a
by the renal route during 24 h, mainly as metabolites of cyanidin. study with purple aronia (Aronia arbutifolia) performed by Jakesevic
After consumption, analysis of both plasma and urine of all volun- and others (2011) which revealed that in the caecal contents of
teers showed that chokeberry anthocyanins were absorbed intact chokeberry-fed groups, 4-hydroxyphenylacetic acid (4-HPA) and

3-hydroxyphenylacetic acid (3-HPA) were identified as metabo- ers 2005; Stalmach and others 2009) and also for the substantial
lites. The detected phenolic acids were probably metabolites of recoveries of flavan-3-ols in ileal fluid by human subjects with an
microbial degradation of aronia proanthocyanidins. Interestingly ileostomy (Stalmach and others 2010).
3,4-dihydroxyphenylacetic acid (diHPA), which is the main prod- In regards to the bioavailability of aronia polyphenols can be
uct of proanthocyanidin microbial degradation, was not detected concluded that, although very abundant in aronia, proanthocyani-
in the chokeberry-fed mice. Instead, the authors detected 3-HPA dins are poorly absorbed and their action is thus restricted to the
and 4-HPA, which are suggested to be metabolites of diHPA lower intestine. The same appears to be true for anthocyanins.
dehydroxylation at meta and para positions (Appeldoorn and oth- The intake of monomeric flavonols and flavanols with chokeber-
ers 2009a). Despite their poor absorption proanthocyanidins may ries is very low and it is not very likely that they have a sig-
exert local activity in the gastrointestinal tract or activity medi- nificant influence on plasma polyphenol concentrations. Chloro-
ated by phenolic acids produced through microbial degradation. genic and neochlorogenic acids are found in significant concentra-
Their local action may nevertheless be important because the in- tions in chokeberries, but esterification decreases their intestinal
testine is particularly exposed to oxidizing agents and may be absorption.
affected by inflammation and numerous diseases such as cancer
(Halliwell and others 2000). Polyphenol concentrations in the Antioxidant activity of chokeberry polyphenols in isolated
colon can reach several hundred micromoles per liter (Scalbert cells and cultured cells
and Williamson 2000) and, together with a few carotenoids, they Cultured cells have often been used as a substrate to evaluate
constitute the only dietary antioxidants present in the colon, be- the protective effects of antioxidants against various oxidants. The
cause vitamins C and E are absorbed in the upper segments of the advantage of using cultured cells is that various oxidants and cell
intestine. types, including model systems for some specific disease, can be
used for the evaluation of antioxidant effect (Niki 2010). How-
Hydroxycinnamic acids ever, together with the advantages, the use of such in vitro systems
Despite the scarcity of studies performed on the bioavailability is pursued by some drawbacks as well. For example, the concentra-
of hydroxycinnamic acids, when ingested in the free form, these tion of the antioxidant added into the culture medium should be
compounds are rapidly absorbed from the small intestine and are chosen very carefully (Niki 2010). Many of the antioxidant studies
conjugated and, in particular, glucuronidated in the same way with cell cultures are performed with aronia extracts containing
that flavonoids are (Cremin and others 2001). However, the only polyphenols at nonphysiologically achievable levels. At physiologi-
representatives in aronia, chlorogenic and neochlorogenic acids, cal concentrations, these polyphenols may not exhibit the reported
are naturally esterified and this impairs their absorption. Human effect. Therefore, these cell line systems must be used mainly to
tissues and biological fluids do not possess esterases capable of investigate the underlying mechanisms of oxidative stress and an-
hydrolyzing chlorogenic acid to release caffeic acid (Plumb and tioxidant action of the extracts. Following ingestion much of the
others 1999; Olthof and others 2001; Rechner and others 2001), dietary flavonoids and polyphenols appear in the circulatory sys-
which is a more potent antioxidant. This has also been observed tem, not as the parent compounds but as glucuronide, methyl,
in rats (Azuma and others 2000; Andreasen and others 2001). and sulfate metabolites with totally different structures from the
Only the colonic microflora would be capable of carrying out parent compounds. In the case of aronia it is favorable that its an-
this hydrolysis and some of the bacterial strains involved have thocyanins appear to a high extent unaltered in serum and urine
been identified (Couteau and others 2001), but the efficiency which makes the performed studies with isolated cells and cell
of absorption of phenolic acids is markedly reduced when they lines more physiologically plausible and related to the potential
are present in the esterified form rather than in the free form health benefits.
(Gonthier and others 2003b).
Antioxidant activity of aronia polyphenols in platelets
Flavonols and flavan-3-ols Ryszawa and others (2006) investigated the effects of choke-
Flavonols and flavan-3-ols are present in very small amounts in berry extracts on superoxide production and aggregation in
chokeberries and probably because of that they have not been sub- platelets from subjects with significant cardiovascular risk factors
jected to bioavailability studies. Since they possess the highest an- (hypertension, hypercholesterolemia, smoking, and diabetes melli-
tioxidant activity, it is worth to discuss their fate in vivo and to judge tus). Superoxide production was significantly increased in patients
indirectly, the bioavailability of aronia flavonols and flavan-3-ols. with cardiovascular risk profile when compared to controls. Aro-
Investigations with other products, such as onions that contain sub- nia polyphenol-rich extracts caused a significant concentration-
stantial amounts of flavonols, indicate that quercetin-O-glucosides dependent decrease in superoxide production only in patients with
are hydrolyzed and a number of metabolites including quercetin- cardiovascular risk factors, while no effect was observed in the
3’-O-sulphate, quercetin-3’-O-glucuronide, and isorhamnetin-3- control group. Aronia extracts abolished the difference in superox-
O-glucuronide appear in plasma in submicromolar concentrations. ide production between risk factor patients and controls and ex-
The profile of urinary metabolites is markedly different to that in erted significant concentration-dependent antiaggregatory effects
plasma, indicating that phase II metabolism is operative (Mullen in both studied groups, indicating that these effects may be inde-
and others 2006). pendent of its ability to modulate superoxide production. The anti-
Studies with rats have led to suggestions that flavan-3-ol aggregatory effects of chokeberry extracts were similar irrespective
monomers may be removed from the bloodstream in the liver of an aggregation-inducing agent (collagen or thrombin). More-
and returned to the small intestine in the bile (Kida and others over, they appear to be independent of platelet NO release as NOS
2000; Kohri and others 2001). To what extent enterohepatic trans- inhibition by L-NAME did not lead to their abrogation. In another
port of flavan-3-ol metabolites occurs in human subjects remains study (Olas and others 2008a) chokeberry extract (total polyphe-
to be established. The bioavailability studies with flavan-3-ols are nols 309.6 mg/g) in concentrations of 5 to 50 μg/mL showed
characteristic for the high urinary excretion (Manach and oth- protective effects against peroxynitrite-induced oxidative/nitrative
damage to human platelet proteins and lipids and significantly H2 O2 production and CL response compared to controls. The
inhibited platelet protein carbonylation and thiol oxidation as es- oxidative metabolism of neutrophils was decreased by aronia juice
timated with 5,5’-dithio-bis-(2-nitro-benzoic acid). The tested treatment in both groups. In a model of gastric digestion aro-
extract caused a distinct reduction of platelet lipid peroxidation nia juice significantly decreased the oxidative metabolism of neu-
induced by peroxynitrite. The exposure of blood platelets to per- trophils in healthy and obese subjects. The juice inhibited H2 O2
oxynitrite at a concentration of 0.1 mM resulted in a distinct production within the range of 10 to 50% v/v and the CL response.
depletion of free thiol groups in platelet proteins. The presence This activity can be explained either by the scavenger effect of the
of the tested extract from aronia protected platelet protein thiols juice on ROS or by the functional changes that cells undergo in
from oxidation induced by ONOO− and this effect was dose- the presence of the juice. Phorbol 12-myristate 13-acetate (PMA)
dependent. The aronia extract suppressed peroxynitrite toxicity, is an oncogenic substance that induces a translocation-activation
expressed as TBARS. In another set of experiments, the authors process by protein kinase C (PKC). The inhibition of the respi-
observed an increased level of biomarkers of oxidative/nitrative ratory burst by phagocytes could depend on interference of the
stress such as 3-nitrotyrosine in platelet proteins from breast cancer juice with the PMA-dependent activation of PKC. The authors
patients. This study provided evidence of antioxidant properties of observed proapoptotic effects of nonstimulated neutrophils after
the extract and its ability to scavenge peroxynitrite, which forms 24 h of incubation with aronia juice and suggested that choke-
in the vascular system and may cause oxidative/nitrative stress and berry polyphenols interfere with NADPH oxidase and/or ROS
damage some biomolecules in platelets such as proteins and lipids and promote apoptosis.
(Olas and others 2004). In an in vitro model system Kedzierska
and others (2010) showed that the commercial chokeberry extract Antioxidant activity in endothelial cells
(Aronox), due to antioxidant action, distinctly reduced the oxida- Vascular inflammation is a primary event in the pathogene-
tive/nitrative stress in platelets isolated from patients with invasive sis of atherosclerosis, which can elicit acute coronary syndromes.
breast cancer. The authors observed that all markers of oxidative An early stage in the inflammatory process is endothelial activa-
stress were significantly higher in the blood platelets obtained from tion, which is directly responsible for the recruitment of circu-
the patients in comparison with the control group. Aronia extract lating leucocytes. This process is self-maintaining and is medi-
was also found to improve antiplatelet action of human umbil- ated through the cell adhesion molecules (CAMs) expressed on
ical vein endothelial cells towards ADP-activated platelets, and the surface of endothelial cells, including ICAM-1 and VCAM-1
this effect was dose-dependent (Luzak and others 2010). The an- (Galkina and Ley 2007). Altered expression of CAMs has been im-
tiplatelet effect of aronia extract was shown to be higher than that plicated in a variety of chronic inflammatory conditions, including
of resveratrol indicating the extract may play an important role as a atherosclerosis. Pharmacological agents that display an inhibitory
component of the human diet in the prevention of cardiovascular effect on endothelial cell activation should have antiinflammatory
or inflammatory diseases where blood platelets are involved (Olas activity (Libby 2006). In a study performed by Zapolska-Downar
and others 2008b). The experiments have shown that aronia ex- and others (2012), human aortic endothelial cells (HAECs) were
tracts (5 to 50 μg/mL) reduce platelet adhesion, aggregation, and pretreated with various concentrations (primarily 50 μg/mL) of
generation of O2 −. in blood platelets. Another study investigated aronia extract prior to treatment with TNFα (10 ng/mL). The
the influence of aronia extract on clot formation (using human tested extract inhibited the proinflammatory response of endothe-
plasma and purified fibrinogen) and brin lysis using the model lial cells by inhibiting the expression of ICAM-1 and VCAM-1,
of hyperhomocysteinemia (Malinowska and others 2012). Aronia as determined by using flow cytometry and real-time RT-PCR,
extract reduced the adverse effects of homocysteine on hemostatic respectively, attenuated the phosphorylation of NF-kB p65, and
properties of fibrinogen or plasma, suggesting its possible protec- decreased intracellular ROS production in TNFα-treated HAECs.
tive properties in hyperhomocysteinemia-induced CVD. More- Moreover, the inhibitory effect of the tested extract on the TNFα-
over, aronia extract increased the plasma antioxidant activity, in induced VCAM-1 expression was similar to that of ibuprofen and
the model of hyperhomocysteinemia, which may modulate the PDTC, and on TNFα-stimulated ICAM expression was much
hemostatic properties of human plasma. Another set of in vitro ex- greater than that observed for the 2 antiinflammatory drugs. The
periments showed that aronia extract prolonged clotting time and preincubation of the HAECs with aronia extract resulted in a re-
decreased the maximal velocity of fibrin polymerization in human duction in TNFα-stimulated increased adhesiveness for peripheral
plasma. Moreover, thrombin incubation with the extract resulted blood mononuclear leucocytes (PBMLs), which may be an im-
in the inhibition of amidolytic activity of this enzyme (Bijak and portant mechanism by which aronia extract exerts its antiinflam-
others 2011). matory and antiatherogenic effects. It was also found that TNFα
induced higher levels of NF-kB phosphorylation that could be
Effect of aronia polyphenols on neutrophils decreased in HAECs when pretreated with the aronia extract,
It is known that activated neutrophils generate extremely high suggesting that the antiinflammatory properties of this extract in
amounts of ROS, but these are normally targeted at pathogens in- vitro are mediated, at least in part, by the inhibition of NF-kB
side intracellular phagosomes. This beneficial antimicrobial func- activation. The NF-kB redox-sensitive transcription factor plays
tion, if not controlled, contributes to the tissue-damaging ef- a key role in TNFα-induced ICAM-1 and VCAM-1 expression
fects of inflammatory reactions. Zielinska-Przyjemska and others (de Winther and others 2005) and its role in the pathogenesis of
(2007) investigated the in vitro effect of aronia juice on oxidative atherosclerosis has been indicated since its active form is present
metabolism and apoptosis of neutrophils from obese and nonobese in atherosclerotic lesions (Brand and others 1996). It is known
individuals. Neutrophils were isolated and oxidant production was that ROS are implicated in the activation of NF-kB and interfere
characterized by luminol-dependent chemiluminescence (CL) and with signaling pathways, which leads to phosphorylation and sub-
flow cytometric dichlorofluorescein oxidation assay. Caspase-3 ac- sequent degradation of phosphorylating kinases IkB. Based on the
tivity, a marker of apoptosis execution, in human neutrophils was results, the authors assumed that the inhibitory effect of choke-
used. Neutrophils from obese individuals had a significantly higher berry extract on ICAM-1 and VCAM-1 expression and NF-kB

activation were due to antioxidant properties. In another set of same concentration. The authors proposed that aronia polyphenols
experiments it was found that aronia extract produced dose- and may induce an increase in antioxidant capacity through enhance-
endothelium-dependent vasorelaxation of coronary arterial rings ment of plasma SOD or other enzymes. In colon cancer models,
and the effect was higher compared to bilberry and elderberry Malik and others (2003) revealed that 24-h exposure of human
extracts (Bell and Gochenaur 2006). It is known that ROS impair HT-29 colon cancer cells to 50 μg monomeric anthocyanin/mL
endothelial NO functions through direct damage to the endothe- of aronia extract resulted in 60% growth inhibition. The treated
lium as well as by chemical quenching of NO. Factors that can cells showed a blockage at G1/G0 and G2/M phases of the cell
enhance or protect the endothelial NO system, or scavenge and cycle. The cell cycle arrest coincided with an increased expression
inactivate ROS, have the potential to prevent CVD. The authors of the p21WAF1 and p27KIP1 genes and decreased expression of
suggested that the vasoprotective effect of aronia extract could be cyclin A and B genes. Prolonged exposure to the extract resulted
attributed to the high antioxidant activity of the extract, which in no further change in the cell numbers, indicating a cytostatic
would tend to reduce the effective concentration of superoxide inhibition of cell growth. The authors reported that chokeberry
or ROS reaching the arterial endothelium. More importantly, this extract inhibited cyclooxygenase-2 (COX-2) gene expression in
ability to prevent loss of endothelium-dependent, NO-mediated HT-29 cells in a concentration-dependent manner, but did not
relaxation was achieved at an extremely low concentration that translate into decreased protein levels or protein activity. Nor-
could be achieved in human plasma after oral consumption of mal colon cells, NCM460, did not show a significant change in
aronia products. In another set of experiments Aronox extract expression of either COX-1 or COX-2 genes. Cyclooxygenase
significantly decreased 7β-hydroxycholesterol-induced apoptosis enzymes catalyze the oxygenation of arachidonic acid, leading to
and ROS generation and ameliorated the collapse of the mito- formation of prostaglandins. Numerous epidemiological studies
chondrial transmembrane potential with subsequent inhibition of have shown that inhibition of COX genes is linked to colon can-
cytochrome C release in endothelial cells. Furthermore, down- cer prevention, and upregulation in the expression of COX-2 has
regulation of Bcl-2 and up-regulation of caspase-3 activation were been observed in colorectal adenomas and carcinomas. Drugs, es-
reversed by Aronox (Zapolska-Downar and others 2008). pecially nonsteroidal antiinflammatory drugs, which inhibit the
COX-2 enzyme, can delay or prevent colon cancer (Prescott and
Antioxidant activity in cancer cell lines Fitzpatrick 2000). In a similar study by the same authors (Zhao
ROS and RNS, and damage caused by these species, are impli- and others 2004) chokeberry anthocyanin-rich extract was investi-
cated in the pathogenesis of a variety of diseases, including cancers gated for its potential chemopreventive activity against colon can-
(Valko and others 2006; Fang and others 2009; Trachootham and cer. The growth of colon-cancer-derived HT-29 and nontumori-
others 2009). There is much evidence that during cancer the en- genic colonic NCM460 cells exposed to the extract (10 to 75 μg
dogenous antioxidant protective system of the body is depleted. of monomeric anthocyanin/mL) was monitored. HT-29 cell
Changes in glutathione content have been reported in several ma- growth was inhibited by 50% after 48 h of exposure to 25 μg/mL
lignancies. In cancer patients the content of reduced glutathione in extract. Most importantly, the growth of NCM460 cells was not
erythrocytes is also decreased, which may promote oxidative stress inhibited at lower concentrations of the extract, illustrating greater
in patients with invasive breast cancer and patients with benign growth inhibition of colon cancer, as compared to nontumori-
breast cancer (Kumar and others 1995; Della Rovere and others genic colon cells. The reasons for the different susceptibilities of
2000; Ścibior and others 2008). During cancer therapy (radio- colon cancer versus nontumorigenic cell lines are unknown but
therapy or chemotherapy) ROS may also be generated in patients. may involve differences in gene expression between NCM cells
Results (Kim and others 2009) showed that doxorubicin can in- and tumor cell lines (Nimmrich and others 2000).
duce platelet cytotoxicity through ROS generation, decreased glu- In another model study Bermudez-Soto and others (2007a)
tathione levels and protein thiol depletion. The toxic side effects of demonstrated that repeated exposure to chokeberry juice has a
chemotherapy may be associated also with damage to different cel- potent in vitro antiproliferative effect toward the human colorectal
lular components induced by ROS. Blood platelets isolated from cancer cell line Caco-2 and that this antiproliferative effect may
patients with breast cancer may produce not only O2 −. , but also be mediated through arrest of the cells at the G/M checkpoint.
peroxynitrite (Kedzierska and others 2010), and moreover the level Through analysis of gene expression they detected changes in the
of O2 −. after phase I of the chemotherapy was significantly higher mRNA levels of several tumor markers typical for colon cancer
than the level of O2 −. in blood platelets obtained before or after and of proteins involved in proliferation and cell cycle that may
the surgery, indicating the role of chemotherapy in the generation be associated to the treatment. Among these was the tumor sup-
of ROS in blood platelets (Kedzierska and others 2012). Olas and pressor carcinoembryonic antigen-related cell adhesion molecule
others (2010) showed that the level of total glutathione, cysteine, 1 (CEACAM1) whose expression is known to be reduced in the
and cysteinylglycine in plasma from patients with invasive breast majority of early adenomas and carcinomas. The authors suggested
cancer and patients with benign breast diseases was 50% lower that CEACAM1, which has a significant regulatory role on cell
than the level of these thiols in the control plasma obtained from proliferation of particular interest at early stages of cancer devel-
healthy volunteers. Moreover, the levels of low-molecular-weight opment may be a potential target for chemoprevention by aronia
thiols in reduced forms (GSH, CSH, and CGSH) and in oxidized polyphenols. In an early study (Gasiorowski and others 1997) it
forms (GSSG, CSSC, and CGSSGC) in plasma from the patients was shown that chokeberry markedly inhibited the mutagenic ac-
were changed compared to the healthy group. On the contrary, the tivity of benzo[a]pyrene and 2-amino fluorene in the Ames test
level of homocysteine in plasma from patients with invasive breast and a significant decrease of sister chromatid exchanges frequency
cancer was 15% higher than in plasma of controls. In the presence induced by benzo(a)pyrene was observed in human blood-derived
of aronia extract (50 μg/mL) changes in the amount of thiols in lymphocytes cultured in vitro. In a study performed by Sueiro and
plasma from patients with invasive breast cancer and patients with others (2006) anthocyanins markedly inhibited the generation and
benign breast diseases were significantly reduced in vitro and the release of superoxide radicals by human granulocytes, and some
effect was stronger compared to that of pure resveratrol with the of the subfractions extracted from wild and cultivated chokeberry
showed >90% inhibitory activity to L1210 leukemia cells at a system. Digestion was carried out with a mixture of pepsin–HCl
concentration of 25 μg/mL and 50 μg/mL. Results of Lala and for 2 h, followed by incubation with pancreatin and bile salts
others (2006) showed a protective effect of chokeberry extract in at 37 ◦ C. Gastric digestion had no substantial effect on any of
colon carcinogenesis in vitro and indicated multiple mechanisms of the major phenolic compounds in chokeberry. However, aronia
action. The extract from A. melanocarpa has also shown anticancer polyphenols were significantly altered during the pancreatic diges-
effects, mediated by the increase of tumor suppressor genes as tion and this effect was more marked for anthocyanins (approxi-
well as by reduction of oxidative stress and resulting DNA damage mately 43% were lost during the 2-h treatment with pancreatin).
important for the proliferation of cancer cells. Flavonols and flavan-3-ols decreased by 26% and 19%, respectively.
Neochlorogenic acid decreased by 28%, whereas chlorogenic acid
Antioxidant activity of aronia polyphenols in pancreatic was increased by 24%. The losses were attributed mostly to the
β-cells chemical conditions during pancreatic digestion instead of inter-
Rugina and others (2011) evaluated the protective action actions with the digestive enzymes. The main advantage of this
of nanomolar concentrations of chokeberry extract against the study was the concentration of polyphenols used. Such concen-
oxidative stress induced by high doses of glucose (50 and trations (0.5 to 50 μg/mL) especially in the lower threshold, seem
100 mM) in pancreatic β-cells. The results indicated the scav- to be achievable in plasma during supplementation with aronia
enging effect of chokeberry anthocyanins on the intracellular extracts. However, there are important discrepancies between in
ROS species, and anthocyanins restored dose-dependently the vitro and in vivo results, such as those reported for the dimeric
strong decrease of glutathione (induced by high glucose), as com- flavan-3-ols in model systems (Zhu and others 2002), which dif-
pared to untreated cells. Enhanced oxidative stress due to high fered significantly by their fate in a in vivo human study (Rios and
glucose contributes to pathological changes in diabetes-related others 2002). Ingestion of aronia juice by rats increased stomach
liver complications. The glutathione (GSH) antioxidant system pH from 3.44 (control group) to 3.69–3.85 and ileal pH from
is critical for counteracting oxidative stress-induced intracellular 6.16 to 6.23–6.46. The juice decreased the concentration of cecal
injury. In a very recent study, Zhu and others (2012) evaluated ammonia, especially at medium and high doses, increased mi-
the mechanism of the anthocyanin-mediated regulation of GSH crobial α-glucosidase, decreased β-glucosidase, and had no effect
synthesis and reduction in intracellular ROS levels. The authors on β-glucuronidase activities in the cecal digesta (Wróblewska
observed that treatment of human HepG2 cells with the antho- and others 2008). Additionally, increased content of butyrate in
cyanin cyanidin-3-glucoside significantly reduced ROS levels in- short-chain fatty acids in cecal digesta was observed. In a very
duced by high glucose. Cyanidin-3-glucoside incubation increased recent study, Jakesevic and others (2011) fed mice for 10 d with
glutamate–cysteine ligase expression, which occurred independent purple chokeberry powder which has the same anthocyanin pro-
of the Nrf1/2 transcription factors, and mediated the reduction in file (cyanidin-3-galactoside – 66%) as found in black chokeberry.
ROS levels. The anthocyanin increased phosphorylation of cAMP Four anthocyanins were detected in the chokeberry powder and
response element binding protein (CREB) through protein kinase 3 of these anthocyanins were found in the cecum and colon of
A (PKA) activation. The decrease in ROS levels by cyanidin- mice. Interestingly, the concentration of cyanidin-3-arabinoside
3-glucoside led to a significant inhibition of phospho-mitogen- was only slightly lower compared to the galactoside in the in-
activated protein kinase kinase-4 (MKK4)–Jun N-terminal kinase testines, although its concentration was more than 30% higher
(JNK) signaling and thus a decrease in proapoptotic Fas expres- in the chokeberry powder compared to cyanidin-3-arabinoside.
sion. Consequently, the anthocyanin markedly ameliorated cell This indicates that cyanidin-3-galactoside is to higher extent ab-
apoptosis and improved viability in HepG2 cells. sorbed and/or degraded by gut microflora than the arabinoside.
Cyanidin-3-xyloside was found in the cecum and colon of mice
In vivo Evidence for Chokeberry Antioxidant Activity almost in the same amount as in the powder, which indicates that
Antioxidant activity in the gastro-intestinal tract (GIT) it was quite resistant to the degradation in the gut. The minor
It should be noted that the role of antioxidants in the GIT may component in the powder cyanidin-3-glucoside was not detected
be very important. The diet contains various prooxidants, includ- in the intestines.
ing metals such as iron, copper and heme, lipid hydroperoxides, In the studies performed by Tanaka and Yuda (1996) and
aldehydes, and nitrite, and elevated levels of lipid peroxides have Valcheva-Kuzmanova and others (2005) aronia juice was shown
been observed in the postprandial state. The activation of phago- to reduce significantly and dose-dependently the number and area
cytes in the gut may also increase the ROS/RNS, and gastric juice of indomethacin-induced gastric ulcers in rats. The administra-
may promote lipid peroxidation (Kanner and others 2001). These tion of indomethacin resulted in extensive lipid peroxidation, as
prooxidants may induce oxidative stress in the gastrointestinal tract evidenced by the accumulation of malondialdehyde (MDA) in the
to induce stomach ulcer and develop stomach, colon, and rectal gastric mucosa, which is in agreement with other studies indicating
cancers. The antioxidants contained in foods may suppress such that ROS are involved in the development of mucosal damage by
oxidative stress and related diseases in the gastrointestinal tract nonsteroidal antiinflammatory drugs such as indomethacin (Naito
before they are absorbed (Halliwell and others 2000). Many of and others 1998). The gastroprotective effect of aronia juice was
the colonic metabolites still have free –OH groups and maintain accompanied by a significant decrease in lipid peroxidation eval-
the antioxidant activity, so they can also contribute to enhance uated as gastric and plasma MDA concentrations. Besides that
plasma antioxidant capacity. Thus, in addition to the original phe- aronia juice caused an increase in mucus production, which is
nolic compounds, their metabolites also have to be considered another protective mechanism against indomethacin-induced gas-
to understand the biological and antioxidant functions of foods tric ulceration. The reduction of MDA in rat blood plasma by
(Fernandez-Panchon and others 2008). chokeberry supplementation was demonstrated also by Frejnagel
Bermudez Soto and others (2007b) investigated the effects of an and Zduńczyk (2008) suggesting that the extract had a preven-
in vitro gastric and pancreatic digestion on the stability and com- tive effect. The gastroprotective effect against ethanol-induced
position of the major polyphenols in chokeberry juice in a model acute gastric hemorrhagic lesions in rats was demonstrated by

Matsumoto and others (2004), suggesting that the anthocyanin (NDEA) on phase I and phase II enzymes and DNA damage
fraction was responsible for this effect. Anthocyanin-rich extract in rat liver. The forced feeding with chokeberry juice alone de-
from aronia was fed for 14 wk to male rats treated with a colon creased the activities of enzymatic markers of cytochrome P450,
carcinogen, azoxymethane (Lala and others 2006). The number CYP1A1, and 1A2. NDEA treatment also decreased the activity
and multiplicity of colonic aberrant crypt foci, colonic cell pro- of CYP2E1 but enhanced the activity of CYP2B. Pretreatment
liferation, urinary levels of oxidative DNA damage, and expres- with chokeberry juice further reduced the activity of these en-
sion of cyclo-oxygenase genes were measured as biomarkers of zymes. Modulation of P450 enzyme activities was accompanied
colon cancer. The lower levels of these specific biomarkers in by the changes in the relevant proteins levels indicating that juice
treated rats, with respect to controls, suggest a protective role of augmented DNA damage. Further study by the same authors ex-
the extract in colon carcinogenesis and indicate multiple mech- amined the hepatic and mammary gland carcinogen-metabolizing
anisms of action. As already mentioned, some of the bacterial enzyme expression altered by the polycyclic aromatic hydrocarbon
strains of the colonic microflora are capable to hydrolyze the 7,12-dimethylbenz[a]anthracene (DMBA) in female rats (Szaefer
abundant chlorogenic acid in chokeberries releasing caffeic acid, and others 2011). Pretreatment with chokeberry juice reduced
which is a more potent antioxidant. Moreover, 4-HPA and 3- the activity of CYP1A1 and increased that of CYP2B involved in
HPA were identified in the cecal contents of aronia-fed mice. The metabolic activation/detoxication of DMBA in rat liver, as well as
antioxidant activity and biological properties of these phenolic expression and activity of phase II enzymes but it had no effect
metabolites have been poorly assessed, but it has been shown that on these parameters in the mammary gland and DMBA-induced
phenylacetic acids possess anticarcinogenic activities (Samid and DNA damage in rat blood cells. This indicates that metabolic al-
others 1997; Thibout and others 1999) and diHPA or 4-HPA terations induced by chokeberry feeding are tissue-specific and
were more effective than their precursors (rutin and quercetin) depend on the class of carcinogen. Several studies have revealed
inhibiting in vitro platelet aggregation (Kim and others 1998). It is that the polyphenols present in chokeberries modulate the phase
expected that 3,4-dihydroxyphenylacetic acid is a potent antioxi- I and phase II enzymes and are involved also in NDEA activation
dant since it has 2 ortho hydroxyl groups present in its structure and detoxication (Krajka-Kuzniak and others 2004; Szaefer and
resulting in elevated antioxidant activity. It has been shown that others 2008). Recently Shih and others (2007) demonstated that
diHPA exhibit considerable antiproliferative activity in LNCaP anthocyanins exert their antioxidative effect through activation of
prostate cancer and in HCT116 colon cancer cells (Gao and others phase II enzymes. The results obtained in rat liver Clone 9 cells
2006). And diHPA exerted antiinflammatory properties by reduc- showed that treatment of anthocyanins leads to positive effects on
ing the secretion of proinflammatory cytokines, TNF-α, IL-1b, elevating the antioxidant capacity, including activated expression
and IL-6, all involved in the early stages of atherosclerosis from of glutathione-related enzymes (glutathione reductase, glutathione
lipopolysaccharide-stimulated human peripheral blood mononu- peroxidase, and glutathione S-transferase) and recruited GSH con-
clear cells. tent. In addition, the activity of NAD(P)H:quinone oxidoreduc-
tase (NQO1) was also promoted under the treatment of antho-
Hepatoprotective effect of aronia polyphenols in relation cyanin. This functions as the defense system against programmed
to antioxidant activity cell death induced by H2 O2 . All these data suggest that antho-
Aronia juice intake was shown to inhibit the endogenous cyanins are potent chemopreventive phytochemicals and could
generation of carcinogenic N-nitrosamines in rats treated with stimulate the antioxidant system to resist oxidant-induced injury.
aminopyrine plus sodium nitrate. In consequence, histopatholog- Hyperglycemia is considered one of the main factors in the
ical changes observed in the liver of rats fed with nitrosamine development of hepatic clinical manifestations in patients with
precursors were prevented by co-treatment with aronia juice. diabetes-related metabolic syndrome. Persistent and chronic hy-
The juice exerted a positive effect on blood and liver vari- perglycemia elicits an increase in oxidative stress, which in turn
ables, which was demonstrated by decreased concentrations of reduces the capacity of the antioxidant defense system and ac-
glutamic–oxaloacetic transaminase, glutamic–pyruvic transami- celerates the progress of diabetic complications through diverse
nase, and uric acid in serum, and lipid content in hepatocytes pathways (Brownlee 2001). Oxidative stress, due to the genera-
(Atanasova-Goranowa and others 1997). The hepatoprotective ef- tion of excessive ROS, interrupts intracellular homeostasis in the
fect of aronia juice was confirmed also against carbon tetrachloride redox status and sometimes induces cell damage and apoptosis or
(CCl4 )-induced acute liver damage in rats (Valcheva-Kuzmanova necrosis, thus potentially contributing to the devastating injury
and others 2004). The administration of CCl4 increased plasma and dysfunction of liver tissue (Rains and Jain 2011). Therefore,
aspartate transaminase (AST) and alanine transaminase (ALT) ac- oxidative stress and peroxidative liver damage seem to be a critical
tivities, induced lipid peroxidation (as measured by MDA content target in the prevention of diabetic liver disorders. In mammals
in rat liver and plasma) and caused a depletion of liver reduced the glutathione (GSH)-dependent antioxidant system plays a fun-
glutathione (GSH). Aronia juice dose dependently reduced the damental role in cellular defense against reactive oxidant species.
necrotic changes in rat liver and inhibited the increase of plasma The cytoprotective functions of GSH are due to its ability to
AST and ALT activities induced by CCl4 , and prevented MDA directly react with reactive electrophiles (Thompson and others
formation and depletion of GSH content in rat liver. The au- 2009). Failure to adequately replenish the depleted cellular GSH
thors proposed that the possible mechanisms of this effect might stores suddenly compromises cellular redox balance and cell via-
be similar to those proposed for the flavonoid silymarin (Lettéron bility. In the already mentioned study by Zhu and others (2012)
and others 1990) which inhibited CCl4 -induced lipid peroxidation it was demonstrated in vivo that the treatment of diabetic db/db
and hepatotoxicity in mice by a dual mechanism: by decreasing the mice with cyanidin-3-glucoside increased the GSH synthesis in
metabolic activation of CCl4 by cytochrome P450 into free radi- the liver through PKA–CREB-dependent induction of Gclc ex-
cals as well as by scavenging free radicals. A more recent study by pression. The effect was dose-dependent and largely increased
Krajka-Kuźniak and others (2009) examined the effect of choke- the GSH/GSSG ratio, which is considered an indicator of ox-
berry juice alone or in combination with N-nitrosodiethylamine idative defense/stress. The oxidative stress determined by lipid
peroxidation, neutrophil infiltration, and hepatic steatosis was stress in patients treated with chokeberry polyphenols. Another
attenuated in cyanidin-3-glucoside-treated db/db mice as well. consequence of the reduction in the oxidative stress levels caused
All these results demonstrated that the anthocyanin cyanidin-3- by chokeberry flavonoids is a reduction in Ox-LDL in the blood.
glucoside has the effect of activating GSH synthesis through a novel An immunohistochemical study performed by Kawa and oth-
antioxidant defense mechanism against excessive ROS production, ers (2008a) revealed that quercetin-3-O-glucuronide, one of the
contributing to the prevention of hyperglycemia-induced hepatic main quercetin metabolites in the circulatory system, accumu-
oxidative damage. The production of ROS may also stimulate lates in macrophage-derived foam cells of human atherosclerotic
proinflammatory cytokines, which leads to hepatocellular dam- lesions, but not in the normal aorta. In addition, mRNA expres-
age and cellular inflammation and, ultimately, the development of sion of the class A scavenger receptor and CD36, which play key
diabetic liver disorders. Consistently, cyanidin-3-glucoside is ca- roles in the formation of foam cells, was suppressed by treatment
pable of inhibiting hyperglycemia-induced steatosis that occurs as with quercetin-3-O-glucuronide. Similarly, immunohistochemi-
a result of oxidative stress, supporting the fact that hepatic injury cal studies have also shown that epicatechin-3-O-gallate is also
caused by hyperglycemia is antagonized by cyanidin-3-glucoside. specifically localized in macrophage-derived foam cells and simi-
Therefore, upregulation of the Gclc system by anthocyanin may larly suppresses gene expression of CD36 (Kawa and others 2008b).
be an important protective mechanism against excessive oxidative These findings provide novel insights into the bioavailability of di-
stress and the activation of stress-signaling pathways in the body. etary flavonoids and their potential mechanism in the prevention
However, it remains to be determined whether the effects re- of CVD. Determination of the actual bioavailability of polyphenol
ported are specific to cyanidin-3-glucoside or can be extended to metabolites in tissues may be even more important than is knowl-
the other anthocyanins presented in chokeberry. edge of their plasma concentrations. Data are still very scarce,
even from animal studies but polyphenols have been detected in a
Hypotensive and lipid-lowering effect wide range of tissues in mice and rats, including the brain (Datla
The mechanism of the antioxidant effect of flavonoids related and others 2001; Abd El Mohsen and others 2002), endothelial
to cardioprotection is complex and goes far beyond radical scav- cells (Youdim and others 2000), heart, kidney, spleen, pancreas,
enging, including both activity enhancement and protection of prostate, uterus, ovary, mammary gland, testes, bladder, bone, and
enzymes such as paroxynase, peroxide dismutase, glutathione re- skin (Chang and others 2000; Coldham and Sauer 2000; Kim and
ductase, as well as inhibition of inducible NO synthase, NADPH others 2000). It is still difficult to say whether some polyphenols
oxidase, and lipooxygenase (Law and others 1999). accumulate in specific target organs; probably the endothelium is
Blood pressure lowering properties of aronia juice and extract likely to be one of the primary sites of flavonoid action. Schramm
were observed in several studies. Treatment of spontaneously hy- and others (1999) showed that a rapid, energy-dependent transport
pertensive rats with the commercial aronia extract Aronox showed system is active in aortic endothelial cells for the uptake of morin
significantly lower systolic blood pressure compared with the con- and it is possible that this system also transports other hydroxylated
trol group (Park and Park 2011; Hellstrom and others 2010). phenolic compounds.
The effect seemed to be short-term and was generally highest The involvement of LDL cholesterol and triglycerides in the
after 3 h from the intake. Juice and polyphenols indicated weak development and progression of atherosclerosis is one of the best-
angiotensin-converting enzyme (ACE)-inhibitory activity mea- demonstrated cases in modern physiology. A positive correlation
sured in vitro. Authors of a later study hypothesized that chokeberry between LDL cholesterol or triglycerides and the risk of cardio-
polyphenols enhance endothelial NO production with an ACE- vascular events has been observed in many large-scale population
independent mechanism, for example, by activation of endothe- studies. The advantages of reducing these lipid level have been
lial nitric oxidase enzyme. Vasorelaxing properties of polyphe- shown with many intervention trials, since hyperlipidemia, char-
nols appear to be endothelium-dependent and recent study by acterized by increased low-density lipoprotein (LDL) cholesterol
Appeldoorn and others (2009b) have strongly suggested that the and decreased high-density lipoprotein cholesterol, is one of the
prime mechanism involves enhanced activation and/or increased major risk factors for atherosclerosis and CVD. Lipid lowering by
expression of endothelial NO synthase. The hypotensive effect was chokeberry products has been reported in several studies. Jurgonski
revealed also by Naruszewicz and others (2007) in a double-blind, and others (2008) investigated the changes in the gut, blood, and
placebo-controlled, parallel trial with 44 patients who had sur- internal organs of a rat prooxidative model with prediabetes and
vived myocardial infarction and had received statin therapy for at hyperlipidemia after dietary supplementation with aronia extract.
least 6 mo. The same study indicated that chokeberry polyphenols In order to mimic the metabolic syndrome in rats, the authors used
reduced the severity of inflammation in patients after myocardial a combination of a high-fructose diet, described as hypertriglyc-
infarct and can be used clinically for the secondary prevention of eridemic and prooxidative, supplemented with saturated fat, as well
ischemic heart disease. Compared to a placebo, aronia flavonoids as an injection of a low dose of streptozotocin (STZ), known as a
significantly reduced serum 8-isoprostans and oxygenated forms of causative agent of oxidative stress and, partly, necrosis of the β islet
LDL (Ox-LDL). As a result of oxidative stress in the vascular wall cells. Dietary supplementation with chokeberry extract decreased
OxLDL are formed and they are then taken up by macrophages the activity of maltase and sucrase as well as increased the activity
using CD-36 and LOX-1 receptors, thus contributing to the for- of lactase in the mucosa of the small intestine. Its ingestion led
mation of foam cells which are the basis for the development of also to the improvement of antioxidant status, especially the con-
early atherosclerotic lesions (Han and Nicholson 1998). Further- centration of a lipid peroxidation indicator (TBARS) in organ tis-
more, lowering of the level of adhesion molecules VCAM, ICAM, sues (liver, kidney, and lung), which was normalized. Cholesterol-
and MCP-1 was also significant as compared to the placebo and lowering and distinct hypoglycemic actions were also observed.
was associated with an increase in adiponectin concentration. Ad- The observed hypoglycemic action of the extract is in accordance
ditionally, a significant drop in the hsIL-6 and hsCRP level oc- with the hypoglycemic effect of chokeberry fruit juice seen in
curred in the group treated with chokeberry extract, which is experiments on the STZ-induced diabetic rat model, where au-
probably related to a significant reduction in the level of oxidative thors discussed as possible mechanisms of action cell stimulation

of glucose uptake and glycogen synthesis, increase in insulin se- from elevated physical activity. This was revealed in an interven-
cretion, as well as protection of pancreatic β cells from STZ- and tion study in which of 150 mL of chokeberry juice, containing
glucose-induced oxidative stress (Valcheva-Kuzmanova and others 23 mg/100 mL of anthocyanins, was given daily to rowers per-
2007a). Aronia juice significantly hindered an increase in plasma forming physical exercise for 1 mo. Before and after the supple-
lipids (total cholesterol, LDL cholesterol, and triglycerides) in rats mentation period, the subjects performed an incremental rowing
fed a cholesterol-containing diet (Valcheva-Kuzmanova and others exercise test. Blood samples were taken from the antecubital vein
2007b,c). In a human intervention study with men diagnosed before each exercise test, 1 min after the test, and following a 24-h
with mild hypercholesterolemia, regular chokeberry juice drink- recovery period. After the supplementation period, TBARS con-
ing resulted in reductions of total cholesterol, LDL cholesterol, centrations in the samples, collected 1 min after the exercise test
and triglycerides (Skoczynska 2007). Moderate, but significant de- and following a 24-h recovery period, were significantly lower in
creases in serum glucose, homocysteine, and fibrinogen concen- the subjects receiving chokeberry juice than in the control group.
trations were also observed. These beneficial metabolic changes In the supplemented group, glutathione peroxidase activity was
were associated with a significant hypotensive effect, as the re- lower in the samples collected 1 min after the exercise and SOD
sult of chokeberry juice drinking. Although the chokeberry juice activity was lower in the samples taken following a 24-h recovery,
administration did not change the total HDL cholesterol level, it as compared to the subjects receiving a placebo. These findings
increased the HDL subfraction of cholesterol, which is involved indicate that an increased intake of aronia polyphenols limits the
in reverse cholesterol transport, in postprandial lipid metabolism exercise-induced oxidative damage to red blood cells, most prob-
mediated by lipoprotein lipase, and takes part in coagulation as ably by enhancing the endogenous antioxidant defense system.
a cofactor of proteins C and S. The beneficial increase in HDL As demonstrated by Ohgami and others (2005), chokeberry
3 cholesterol in the serum of men treated with chokeberry juice extract exhibited a strong antiinflammatory effect on endotoxin-
could be connected with a reduction of cholesterol content in the induced uveitis in rats. The authors observed that the number
arterial wall as well as increased antithrombotic activity. Metabolic of inflammatory cells, the protein concentrations, and the lev-
changes observed in men with lipid disturbances were associated els of NO, PGE2, and TNF-α in the aqueous humor in the
with reduction in systolic and diastolic blood pressure as well. groups treated with extract were significantly decreased in a dose-
The lipid-lowering effect of aronia extract was found also in an- dependent manner. The antiinflammatory effect of 100 mg extract
other very recent human intervention study performed by Sikora was as strong as that of 10 mg prednisolone. The tested extract also
and others (2012). Although the exact mechanism is unclear, sev- suppressed LPS-induced iNOS and COX-2 protein expressions in
eral potential mechanisms may account for the lipid-lowering ef- RAW 264.7 cells in vitro and dose-dependently. The results suggest
fects of chokeberries. Such mechanisms may be the inhibition of that aronia extract reveals an antiinflammatory effect that is due
cholesterol absorption as demonstrated by tea catechins, improved to the direct blocking of the expression of the iNOS and COX-2
catabolism of lipoproteins as demonstrated for cyanidin, and in- enzymes and leads to the suppression of the production of NO,
crease in bile flow, biliary bile cholesterol, and biliary bile acids as PGE2, and TNF-α. It was found by Pawlowicz and others (2001)
demonstrated for grapefruit juice and naringin. Other mechanisms that anthocyanins from chokeberry increased fructose levels in the
accounting for the cholesterol-lowering effects of flavonoids are seminal fluid of men with oligospermia and increased levels of
inhibition of the enzyme 3-hydroxy-3methylglutaryl-CoA reduc- antibodies anti-O-LDL, which is characteristic with an increased
tase, leading to a reduction in cholesterol synthesis, and inhibition production of free radicals and enhanced oxidative stress.
of the enzyme acyl-CoA: cholesterol acyltransferase, leading to
a decrease in cholesterol esterification and a subsequent decrease Final remarks and future outlook
in its absorption and inclusion into lipoproteins. These enzyme- From this review it is evident that Aronia melanocarpa is an ex-
inhibiting activities have been demonstrated for naringin, hes- tremely rich source of polyphenols rendering it one of the high-
peretin, quercetin, and hesperidin. Lipid-lowering properties of est for in vitro antioxidant activities among fruits. Ironically, the
aronia could be referred to as preventive towards hyperlipidemia- polyphenols which are present in the highest amounts in choke-
induced oxidative stress diseases. berries (anthocyanins and proanthocyanidins) are the least well
absorbed. The intake of monomeric flavonols and flavanols with
Anticoagulant properties chokeberries is very low and it is not very likely that they have
Sikora and others (2012) observed significant inhibition of significant influence on plasma concentrations of polyphenols.
platelet aggregation after 1 mo of aronia extract administration by Chlorogenic and neochlorogenic acids are found in significant
men. Supplementation with aronia extract did not influence the concentrations in chokeberries, but esterification decreases their
general number of platelets in the blood of the examined patients intestinal absorption. Nevertheless, there is appreciable experi-
but led to lengthening of the time required to reach the aggrega- mental evidence of the effectiveness of Aronia products in a broad
tion maximum. In the case of coagulation induced by endogenic range of pathological conditions mediated by uncontrolled oxida-
thrombin, a significant decrease in the overall potential for coagu- tive processes. The first site of the antioxidant action of choke-
lation was induced after 1 or 2 mo of supplementation. Moreover, berry polyphenols is the gastrointestinal tract where they (mainly
after 1 mo a beneficial reduction in the overall potential for clot proanthocyanidins and their metabolites released by the gut mi-
formation and fibrinolysis was observed. It is evident that the an- croflora) could act as radical scavengers. The mechanisms of the
ticoagulant activity of aronia extracts could not be attributed to its in vivo antioxidant activity of aronia polyphenols after absorption
radical-scavenging effect but may be due to the inhibition of some spreads out far beyond radical scavenging and includes suppress-
enzymes, which is part of the third line of antioxidant defense. ing the formation of ROS and RNS, inhibition of prooxidant,
and restoration of antioxidant enzymes, and probably also cellu-
Other evidence for aronia antioxidant activity in vivo lar signaling to regulate the level of antioxidant compounds and
Pilaczynska-Szczesniak and others (2005) found that supple- enzymes. However, more research is needed to fully understand
mentation of aronia juice suppressed the oxidative stress resulting the exact mechanisms of chokeberry antioxidant activity in vivo.
Some potential investigations to reach this goal can be summarized Brownlee M. 2001. Biochemistry and molecular cell biology of diabetic
as follows: investigation of plasma antioxidant activity after supple- complications. Nature 414:813–20.
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Bioavailability and Antioxidant Activity of Black Chokeberry (Mechanisms of Action: A Review

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Bioavailability and Antioxidant Activity of Black Chokeberry (Mechanisms of Action: A Review

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Bioavailability and Antioxidant Activity of Black

Chokeberry (Aronia melanocarpa) Polyphenols:

Introduction by other enzymes like xanthine oxidase and xanthine dehydroge-

Table 1–Polyphenol constituents in aronia berries and juices.

Sample Berries (mg/100 g) Reference Juices (mg/L) Reference

Anthocyanins Flavan-3-ols Flavonols

R = arabinose – cyanidin-3-arabinoside (-)-Epicatechin Quercetin

Neochlorogenic acid Procyanidin (4β→8 bonds)

Figure 1–Chemical structutes of chokeberry main polyphenols.

hence indicates the protecting ability against formation of hy-

principles of antioxidant properties of substances (Ciz and others

ologically relevant. ORAC and TRAP methods assess the radical

scavenging activity of the sample against peroxyl radicals, which

some serious limitations. For example, DPPH. radical is a resis-

tant nitrogen radical in contrast to highly reactive physiologically

resulting in altered radical-scavenging values (Huang and others

tion was better than that of anthocyanins and antioxidant activity,

showing that all polyphenols in chokeberry determine antioxidant

important phenolic constituents of chokeberry. Antioxidant ac-

tivity of phenolic compounds is determined by several struc-

substitution in the B ring of flavonoids, as well as others. A 2,

3 double bond in conjugation with the 4-oxo function in the

C ring is also a prerequisite for good antioxidant activity (Bors

the aronia monomer phenolics followed by cyanidin glycosides

about 59.4% (95 μmol) of the total antioxidant activity of choke-

berry without assuming the possible synergism/antagonism be-

j Valcheva Kuzmanova and others 2007d.

making them the biggest contributors to aronia antioxidant

m Gabrielska and others 1999.

h Benvenuti and others 2004.

l Denev and others 2010.

The capacity of antioxidants in vivo is determined by many

be absorbed, transported, distributed, and retained properly in the

biological fluids, cells, and tissues. Since a bioavailability study

Table 3–Antioxidant activity of aronia main polyphenols determined by different assays.

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