Sei sulla pagina 1di 13

JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

Available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/jff

Bioavailability of anthocyanins and derivatives

Iva Fernandesa, Ana Fariaa,b,c, Conceição Calhaub,d, Victor de Freitasa, Nuno Mateusa,*
a
Chemistry Investigation Centre (CIQ), Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto,
Rua do Campo Alegre, 4169-007 Porto, Portugal
b
Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
c
Faculty of Nutrition and Food Sciences, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
d
CINTESIS – Center for Research in Health Technologies and Information Systems, University of Porto, Al. Prof Hernâni Monteiro,
4200-319 Porto, Portugal

A R T I C L E I N F O A B S T R A C T

Article history: Anthocyanins are naturally occurring compounds widespread in plant-derived foodstuffs
Available online 24 June 2013 and therefore abundant in human diet. There are evidences regarding the positive associ-
ation of their intake with healthy biological effects displayed in vivo. This review aims to
Keywords: highlight some aspects regarding anthocyanins bioavailability; these include a short intro-
Absorption ductory part of anthocyanin chemistry, stability, occurrence and intake. This first part is
Anthocyanins followed by a more detailed one concerning the main topic of the review that includes
Bioavailability the bioavailability and metabolism of anthocyanins. Special attention is given to the con-
Metabolism tribution of the gastric mucosa to anthocyanin absorption as the result of the high content
Microbiota of intact anthocyanins (20–25%) detected is plasma few minutes after intake. The contribu-
tion of intestinal tissue and the microbiota impact in anthocyanin absorption and bioactiv-
ity is also highlighted. Despite the biological activities that have been associated with these
compounds, anthocyanins appear to be rapidly absorbed and eliminated, reaching only low
maximal concentrations in plasma and urine. Some possible critical factors that may con-
tribute to this paradox were also explored including the ability of a compound to cross
membranes, the effect of pH, digestive enzymes, biliary acids and microbiota, the lack of
sensitivity of the analytical method, the possible ingestion of pigments (anthocyanin deriv-
atives, especially in the case of red wine) and the influence of the food matrix. Generally,
the bioavailability of anthocyanins is presumed but whether the effect is due to the native
compounds or other forms, which mechanism are involved or which factors have crucial
impact on bioavailability still remain underexplored.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction Over the years, the scientific community has been focus-
ing on these amazing molecules trying to understand antho-
Anthocyanins are one of the most widespread families of nat- cyanins and their properties. Many different chemical
ural pigments in the plant kingdom, thereby constituting a structures from numerous natural sources have been charac-
part of the world natural heritage. They confer a great diversity terized and their physical–chemical properties determined
of colours, touching practically all visible spectra, from or- (Deroles, 2009); their biosynthesis pathways have been eluci-
ange and red through purple and blue hues. dated, and new plants with ‘‘a la carte’’ colours created by

* Corresponding author. Tel.: +351 220402562.


E-mail address: nbmateus@fc.up.pt (N. Mateus).
1756-4646/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jff.2013.05.010
JOURNAL OF FUNCTIONAL FOODS 7 (2 0 14 ) 5 4–66 55

genetic engineering (Davies, 2009); their benefits for human between five species (flavylium cation, carbinol base, chal-
health are being discovered, and the applications of anthocy- cone, quinonoidal base and anionic quinonoidal base) is crit-
anins as colorants or putative bioactives have been exploited ical and deeply related to the colour displayed by
by food, pharmaceutical and cosmetic industries. anthocyanins (Fig. 2) (Brouillard & Delaporte, 1977; Brouillard
& Dubois, 1977; Brouillard & Lang, 1990).
2. Anthocyanins chemistry and stability
3. Occurrence and intake
Attending to their chemical nature, anthocyanins naturally oc-
cur as glycosides of flavylium (2-phenylbenzopyrylium) salts Polyphenols arise from the secondary metabolism of plants,
and are commonly based on six anthocyanidins: pelargonidin being virtually present in all foods and beverages from plant
(Pg3glc), cyanidin (Cy3glc), peonidin (Pn3glc), delphinidin origin such as vegetables, fruits, cocoa, tea and wine. How-
(Dp3glc), petunidin (Pt3glc) and malvidin (Mv3glc) (Fig. 1). ever, the daily intake of polyphenols is difficult to estimate
The sugar moieties vary but are usually glucose, rhamnose, and depend on several factors. Recently, the construction
galactose or arabinose (Francis, 1989). The sugar moiety may and application of a database with polyphenols content in
be a mono or disaccharide unit, and it may be acylated with foods has facilitated this task (Neveu et al., 2010).
a phenolic or aliphatic acid (Mazza & Miniati, 1993). These In 2000, Scalbert and Williamson reported 1 g/day as the
compounds differ in the methoxyl and hydroxyl substitution total dietary intake of polyphenols, which were values way
pattern of the aromatic B ring. Despite the most common anth- above the ones described for vitamin C or E which are the
ocyanidins being just six, there are 539 anthocyanins reported classical dietary antioxidants (Scalbert & Williamson, 2000).
to be isolated from plants (Andersen & Jordheim, 2005). The Later, Pérez-Jiménez and colleagues confirmed polyphenol
more widespread anthocyanins in fruits are glycosilated in daily intake of about 1 g/day by using a French cohort and a
the 3-OH position (3-O-monoglycosides) and, in less exten- phenolic content in foods database. Even so, this value can
sion, in both position 3-OH and 5-OH (3,5-O-diglycosides). be higher due to a lack or insufficient data on food contents
Anthocyanins have characteristic physicochemical proper- for more complex polyphenols (Perez-Jimenez et al., 2011).
ties that confer them its unique colour and stability. They are Anthocyanins are part of human diet as they can be found
highly reactive molecules and thus sensitive to degradation in red wine, some cereals and root vegetables (aubergines,
reactions. Oxygen, temperature, light, enzymes and pH are beans, cabbage, radishes, onions) but mainly due to its pres-
among the factors that may affect anthocyanins chemistry ence in red fruits such as cherries, strawberries, plums, black-
and, consequently, their stability and colour. Anthocyanins berries, raspberries, grapes, red currants and black currants.
may be degraded through several processes occurring during Anthocyanins are mainly found in skin but can also appear
their extraction, food processing and storage. The fact that in in the flesh, e.g., cherries and strawberries. Usually, the con-
aqueous solution they co-exist in pH-dependent equilibrium tent in anthocyanins increases during ripening and can reach
values up to 2–4 g/kg fresh weight in blackcurrants, blackel-
derberry or blackchokeberry (Clifford, 2000; Mazza & Velioglu,
R1 1992; Perez-Jimenez, Neveu, Vos, & Scalbert, 2010). Red wine is

OH

HO O
R2

OR 3
OH

Anthocyanins R1 R2
Pg3glc H H
Pn3glc OCH3 H
Cy3glc OH H
Mv3glc OCH3 OCH3
Pt3glc OCH3 OH
Dp3glc OH OH
Fig. 2 – Schematic representation of the molar fraction of
Fig. 1 – Representation of the general structure of anthocyanin equilibrium form according to the GI tract pH
anthocyanins (flavylium form). R3 is a sugar moiety. adapted from (Nave et al., 2010).
56 JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

also a good source of anthocyanins and contains approxi- The difficulty in overcoming those analytical problems
mately 200–350 mg of anthocyanins per L; in addition, as may contribute significantly to the low bioavailability of
the wine ages, these anthocyanins can be converted into anthocyanins, which does not justify all the biological activi-
more complex structures such as anthocyanin-pyruvic ties previously associated with the huge consumption of this
acid adducts and vinylpyranoanthocyanin-catechins (Fig. 3) flavonoid class.
(Clifford, 2000; Oliveira, de Freitas, Silva, & Mateus, 2007; Extensive knowledge of the bioavailability of anthocyanins
Perez-Jimenez et al., 2010; Pissarra et al., 2004; Silberberg is thus essential if their health effects are to be understood
et al., 2006; Sousa et al., 2007). (Fig. 4).
After ingestion, anthocyanins are readily detected in plas-
4. Bioavailability and metabolism of ma in their parent forms, possibly as a result of their absorp-
anthocyanins tion through the gastric wall (Cao, Muccitelli, Sanchez-
Moreno, & Prior, 2001; Cao & Prior, 1999; Milbury, Cao, Prior,
Anthocyanins, for consumers that eat berries and drink red & Blumberg, 2002; Mulleder, Murkovic, & Pfannhauser, 2002).
wine on a routine basis, are major dietary components. How- It has been only recently that studies were conducted to
ever, the key difference compared to the other flavonoid gly- determine tissue concentrations of anthocyanins. The stom-
cosides, is that anthocyanins undergo re-arrangements in ach exhibited only native anthocyanins, while in other organs
response to pH and temperature (Brouillard & Delaporte, (jejunum, liver, and kidney) native and methylated anthocya-
1977) (Fig. 2). Physiological temperatures are highly suitable nins as well as conjugated anthocyanidins (monoglucuro-
both thermodynamically and kinetically for observing the nides) were detected (Talavéra et al., 2005).
chalcone tautomer (Brouillard & Delaporte, 1977). The limited In another work, pigs were fed with diets supplemented
available experimental evidence indicates that in the acidic with blueberries for 4 weeks. Although no anthocyanins were
conditions that prevail in the gastric compartment anthocya- detected in the plasma or urine of the fasted animals, intact
nins are in the positively charged flavylium form, whilst all anthocyanins were detected in the liver, eye, cortex, and cer-
the other dietary flavonoids remain neutral. ebellum. The results suggest that anthocyanins can accumu-

Fig. 3 – Chemical structures of anthocyanin derivatives: malvidin-3-glucoside pyruvic acid adduct, vinylpyranomalvidin-3-
glucoside-catechin and (+)-catechin-(4,8)-malvidin-3-glucoside.
JOURNAL OF FUNCTIONAL FOODS 7 (2 0 14 ) 5 4–66 57

late in tissues, including tissues beyond the blood–brain bar- Upstream to gastrointestinal absorption, a variety of bind-
rier (Kalt et al., 2008). ing processes can take place, namely interaction with food
In a more recent work, anthocyanin metabolites (methyl- proteins or with salivary proteins and digestive enzymes
ated anthocyanins and glucurono-conjugated derivatives) (Matsui et al., 2001; Walle, Browning, Steed, Reed, & Walle,
were identified in various organs (bladder, prostate, testes, 2005; Wiese, Gärtner, Rawel, Winterhalter, & Kulling, 2009).
heart and adipose tissue) in rats fed with a blackberry antho- In a recent work with healthy volunteers, black raspberry
cyanin-enriched diet for 12 days (Felgines et al., 2009). In that anthocyanins could be detected as their hydrolyzed aglycone
study, the bladder contained the highest levels of anthocya- form in the oral cavity, resulting from the activity of b-glyco-
nins, followed by the prostate. Prostate, testes and heart con- sidase derived both from bacteria and oral epithelial cells
tained native cyanidin 3-glucoside and a small proportion of (Mallery et al., 2011). In the same study, parent anthocyanins
cyanidin monoglucuronide. Cyanidin 3-glucoside and methyl- and protocatechuic acid, a cyanidin-3-glucoside microbiota
ated derivatives were present in adipose tissue. Moreover, two metabolite, were detected in the saliva. Furthermore, saliva
recent works reported the capacity of dietary anthocyanins samples revealed the presence of glucuronidated anthocya-
from grapes and berries to reach the brain (Passamonti, nin conjugates, consistent with intracellular uptake and
Vrhovsek, Vanzo, & Mattivi, 2005; Talavéra et al., 2005). phase II conversion of anthocyanins (Mallery et al., 2011).
Still, whether these oral transformation reactions will be
4.1. Oral cavity absorption of anthocyanins of importance for local effects in the oral epithelium is diffi-
cult to assess considering the relatively short residence time
Studies involving individual anthocyanins revealed that their of most foods in the oral cavity.
amount in plasma is generally 1% of the consumed quanti-
ties, due to limited intestinal absorption, although additional 4.2. Gastric absorption of anthocyanins – a new approach
factors may contribute to the proposed low anthocyanin bio-
availability such as high rates of cellular uptake, metabolism Until the beginning of the twenty first century the study of
and excretion (Fig. 5) (Manach, Williamson, Morand, Scalbert, fast kinetics of plasma appearance of anthocyanins in rats
& Remesy, 2005). and humans was a challenging field (Cao & Prior, 1999; Mil-

Fig. 4 – Hypothetic pathways of anthocyanins absorption, distribution, metabolism and excretion based on current
information.
58 JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

4 approximately 30 min after ingestion. In the meanwhile, all


other flavonoid glycoside compounds are still in their journey
3 towards the circulation. There are some few references con-
cerning the gastric absorption of flavonoid aglycones. Querce-
Cmax (µM )

2
tin, but not quercetin 3-O-glucoside nor quercetin 3-O-
rutinoside, was found to be absorbed in rat stomach (Crespy
et al., 2001). Similarly, the isoflavones genistein and daidzein,
1
but not their glucosides, were also found to be absorbed in the
rat stomach (Piskula, Yamakoshi, & Iwai, 1999). Finally, some
0
phenolic acids were also found to be absorbed at the gastric
s

ls

ls

ns
s
epithelium (Konishi, Zhao, & Shimizu, 2006; Lafay et al.,
ne

ne

id
no
no

ni
ac
vo

no

a
av

cy
av

ic
la

2006; Vanzo et al., 2007; Zhao, Egashira, & Sanada, 2004).


av

l
Fl

ho
of

Fl

no
Fl
Is

nt
e

The main conclusion common to all the authors is the


Ph

high content of anthocyanins in the stomach, but the possible


Fig. 5 – Maximum plasma concentration of anthocyanins
mechanism of anthocyanin gastric absorption remains
compared to other flavonoid classes adapted from (Manach
unknown.
et al., 2005).
On this matter, the bioavailability of cyanidin-3-glucoside
in rats that were fed a red orange extract with or without glu-
cose by gastric intubation was not significantly affected by
bury et al., 2002; Murkovic, Mülleder, Adam, & Pfannhauser, simultaneous ingestion of glucose (Felgines et al., 2008). This
2001; Tsuda, Horio, & Osawa, 1999). fact may suggest that the glucose transporters are not in-
In 2003, Passamonti and co-workers performed an in vivo volved in anthocyanin gastric absorption.
experiment in rats that suggested the ability of anthocyanins Information regarding the kinetic flux of anthocyanins in
to cross the gastric mucosa (Passamonti, Vrhovsek, Vanzo, & the GI is critical for understanding anthocyanin absorption.
Mattivi, 2003). After feeding rats with black raspberry extract by stomach
Later, Talavéra et al., 2003 extended their research to struc- tube, anthocyanin content in the gastric lumen was found
turally related anthocyanins and demonstrated that anthocy- to decrease linearly during 180 min (He, Wallace, Keatley, Fail-
anin glycosides were quickly and efficiently absorbed in the la, & Giusti, 2009). The estimated time to deplete half of the
stomach (approximately 25%). However their absorption var- anthocyanin content in the gastric lumen of the fasted rat
ied greatly according to the anthocyanin structure and they was approximately 120 min, suggesting that minimal
were rapidly excreted into bile as intact and metabolized amounts of anthocyanins would still be present in the stom-
forms. ach after 4 h. In the same work, the authors highlighted an-
In 2005, the same authors investigated anthocyanin other important factor that may contribute to the
metabolism and distribution in different rat organs (stomach, underestimated anthocyanin quantification. Anthocyanins
jejunum, liver, kidney and brain). The only additional infor- appeared to bind to unidentified protein in the stomach tissue
mation of this work concerning the stomach absorption was and thus could not be quantified as free anthocyanins by
its incapacity of metabolizing anthocyanins, since no metab- HPLC. Such binding may be attributed to nonspecific binding
olites were detected in this organ. or perhaps specific binding to some protein transporter.
Moreover, El Mohsen et al. (2006) have analyzed pelargoni- The organic anion carrier bilitranslocase is expressed in
din gastric absorption in rats having detected the presence of the stomach (Battiston, Macagno, Passamonti, Micali, & Luigi
p-hydroxybenzoic acid in stomach 2 h after ingestion. This re- Sottocasa, 1999; Nicolin, Grill, Micali, Narducci, & Passamonti,
sult is not indicative of anthocyanin transformation in gastric 2005). Its, in vitro, normal transport activity is competitively
cavity but rather of the instability and degradation of the inhibited by quinoidal forms of dietary anthocyanins (Fig. 6),
anthocyanidin. suggesting that bilitranslocase could promote the facilitated
The absorption of red orange anthocyanins was studied in diffusion of anthocyanins (Passamonti, Vrhovsek, & Mattivi,
both rat stomach and intestine using in situ models (Felgines 2002). Nevertheless, it should be noted that those in vitro as-
et al., 2006). A high proportion (about 20%) of red orange says performed were conducted at pH 8.0, which is far from
anthocyanins was absorbed from the stomach and again no the gastric conditions here no quinoidal forms could be de-
anthocyanin metabolite was observed in the stomach after tected (Fig. 2). Therefore, bilitranslocase may be involved in
30 min of incubation. anthocyanin quinoidal forms absorption in the liver (Fig. 6).
The earliest reference on anthocyanin absorption in stom- On the other hand, the administration of high amounts of
ach is from 2007. In that work the authors examined the gas- anthocyanins, far from diet levels, could induce saturation of
tric absorption of pelargonidin-3-glucoside using rat models. this transport and contribute to the lower anthocyanin bio-
Once more, a high proportion of pelargonidin-3-glucoside availability reported in those particular studies (Talavéra
was found to be rapidly absorbed from the stomach (23%) (Fel- et al., 2003).
gines et al., 2007). Other transporter candidates may include GLUT1, OAT2,
Bearing all the above data, it appears that these amazing SMCT1 and SMCT2, since the expression of these transporters
compounds could entirely ‘‘jump’’ the gastric system and has already been detected in stomach tissue (Eraly, Bush,
reach the systemic circulation in their native or metabolized Sampogna, Bhatnagar, & Nigam, 2004; Garcia, Brown, Pathak,
forms, being available to exert their biological activities & Goldstein, 1995; Yoshikawa et al., 2011).
JOURNAL OF FUNCTIONAL FOODS 7 (2 0 14 ) 5 4–66 59

The stomach has been widely ignored as a metabolizing manner with no statistically differences in their transport
organ although it has been identified as a site of absorption efficiency according to the pH. Attending to the results ob-
for different compounds (Crespy et al., 2001; Piskula et al., tained, a saturable transport for these compounds was thus
1999). The contribution of the gastric mucosa to the metabo- proposed.
lism of anthocyanins should not be ruled out because the Considering the previously reported implication of glucose
stomach possesses conjugative enzyme activities (UDP-glu- transporters in the absorption of anthocyanins at the intesti-
curonosyltransferase, sulphotransferase, and catechol-O- nal level (Faria, Pestana, Azevedo et al., 2009) the effect of
methyl transferase) (Harris, Picton, Singh, & Waring, 2000; anthocyanins on the uptake of 3H-DG was proposed. Preli-
Karhunen, Tilgmann, Ulmanen, Julkunen, & Panula, 1994; minary studies on this field indicated that the anthocyanins
Strassburg, Nguyen, Manns, & Tukey, 1998; Strassburg, Oldha- tested did not affected glucose uptake in MKN-28 cell line
fer, Manns, & Tukey, 1997). Besides, in vitro studies showed (Fig. 7).
that some flavonoids could be metabolized into glucuronidat-
ed and sulphated metabolites by the gastric wall (Déchelotte, 4.3. Intestinal absorption of anthocyanins
Varrentrapp, Meyer, & Schwenk, 1993; Piskula et al., 1999).
As it can be easily perceived, there is too much ambiguous The anthocyanin fraction that is not absorbed in the stomach
information on the literature concerning anthocyanin gastric reaches the small intestine. Once anthocyanins enter more
absorption. basic conditions in the small intestine the carbinol pseudo-
Working with animal models or human volunteers is obvi- base is likely to predominate. Unlike flavonoids where glyco-
ously an important vehicle for obtaining new insights on sides are hydrolyzed, anthocyanin glycosides are rapidly and
anthocyanin bioavailability. In the meantime, a gastric cell efficiently absorbed in the small intestine (Miyazawa, Nakag-
barrier model would be extremely useful similarly to what awa, Kudo, Muraishi, & Someya, 1999; Talavéra et al., 2004;
was gained with the studies with caco-2 cell line that mimics Tsuda et al., 1999). Furthermore, anthocyanins are quickly
the intestinal barrier. metabolized and appear in the circulation or are excreted into
The methods available to evaluate the absorption of drugs bile and urine as both intact and metabolized forms (glucu-
at the gastric level make use of isolated gastric epithelial cells, ronidated, sulfated or methylated derivatives) (Fig. 4) (Ichi-
which are both time and labour consuming. yanagi, Shida, Rahman, Hatano, Matsumoto et al., 2005;
A critical feature of such a model is that it has to work in Ichiyanagi, Shida, Rahman, Hatano, et al., 2005; Ichiyanagi
the presence of a reduced pH. A recently published work re- et al., 2004; McGhie, Ainge, Barnett, Cooney, & Jensen, 2003;
ported the development of a biologically relevant in vitro mod- Miyazawa et al., 1999; Talavéra et al., 2003; Talavéra et al.,
el of moderately differentiated adenocarcinoma stomach 2004).
cells (MKN-28) to be used as a gastric barrier model (Fernan- The potential mechanisms of anthocyanin glycosides
des, de Freitas, Reis, & Mateus, 2012). In that work, the absorption in the small intestine may involve a specific glu-
absorption and metabolism of anthocyanins through gastric cose transporter, such as SGLT1, as previously suggested for
epithelium cells was evaluated over time in the presence of other flavonoids (Hollman et al., 1999).
proton gradient. A recent work points for the putative involvement of
By using this model, it was possible to study different pH GLUT2 transporter in anthocyanins absorption at the intesti-
conditions that correspond to the fed and unfed stage, pH nal level (Faria et al., 2009).
of 3.0 or 5.0, respectively (Dressman et al., 1990; Russell Another possible mechanism may involve the hydrolyza-
et al., 1993). It was also possible to conclude that anthocya- tion of anthocyanins by brush border enzymes such as lactase
nins could cross the gastric epithelium in a time dependent phloridzin hydrolase, prior to passive diffusion of the agly-

Fig. 6 – Schematic representation of the in vitro studies conducted to prove the involvement of bilitranslocase in anthocyanin
absorption.
60 JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

150

H-2-deoxi-D-glucose uptake
100

(% control)
*

*
50
*

0
3

µM

M
ol

lc

ol

M
gl

gl

m
g

m
tr

tr
50

p3
y3

v3
on

on

2
1
C

D
C

tin
n
B

zi
in

re
rid
as

lo
al

lo

Ph
Ph
oc
yt
C

3
Fig. 7 – Effect of anthocyanins (100 lM) for 30 min on the uptake of H-DG (100 lM) by MKN-28 cells. MKN-28 cells were
incubated at 37 °C with 3H-DG, for 1 min. MKN-28 cells were preincubated for 30 min with cytochalasin B (50 lM), phloretin
(2 mM) and phloridzin (1 mM) and incubated with 3H-DG (100 lM), for 1 min. Each value represents the mean ± SEM (n = 6).
Significantly different from the respective control (*p < 0.05).

cone, as already proved for other flavonoids (Gee et al., 2000; their putative role in physiological functions and health out-
Hollman et al., 1999). comes. It is known that flavonoids may directly interact with
Unabsorbed anthocyanins reach the colon where they un- membrane lipids altering membrane physical properties, li-
dergo substantial structural modifications. Previous studies gand–receptor interactions, modulate signal transduction,
have suggested that this is likely due to the spontaneous deg- transport and enzyme activity (Verstraeten, Fraga, & Oteiza,
radation under physiological conditions (Woodward, Kroon, 2010).
Cassidy, & Kay, 2009) or following microbial metabolism. In Some of the human studies investigating anthocyanin bio-
fact, colonic microbiota hydrolyses glycosides into aglycones availability were recently revised (Faria, Fernandes, Mateus, &
and degrades them to simple phenolic acids. Calhau, 2013).
According to Vitaglione and co-workers protocatechuic The overall analysis of the biokinetic parameters of those
acid is the major human metabolite of cyanidin-3-glucoside studies has facilitated some main assumptions in what
in humans (Vitaglione et al., 2007). In particular, proto- anthocyanin bioavailability is concerned. The most important
catechuic acid accounts for almost 73% of the ingested antho- one is that although there is a considerable variability in the
cyanins. This metabolite was detected in plasma 2 h after values for the biokinetic parameters, anthocyanins appear
orange juice ingestion, indicating that it was possibly formed to be rapidly absorbed and eliminated, reaching low maximal
through chemical degradation at the physiological conditions concentrations in plasma and urine.
of the systemic circulation or in the intestinal mucosa. This Several factors including variations in the dose, anthocya-
metabolite is recovered in fecal samples, which suggests that nin chemical composition in the different sources, food or
the gut extensively metabolizes anthocyanins (Riso et al., beverage matrix or processing, age and gender of the individ-
2005). uals and the analytical methodology used can have a huge ef-
The metabolism of berry anthocyanins resulting in pheno- fect on the bioavailability and metabolism of anthocyanins.
lic acids in humans was recently studied (Nurmi et al., 2009).
The main anthocyanin metabolites detected were homovani- 5. Microbiota impact on anthocyanins
lic and vanilic acids. availability and bioactivity
In another fresh study, blueberry anthocyanin absorption
and metabolism in rats was accomplished and the main Microbiota has been considered a metabolizing ‘‘organ’’ with a
metabolite detected in urine was hippuric acid, which may role in human metabolism through endo- and xenobiotic
be produced in liver through a conjugation of glycine with metabolism, vitamin B12 synthesis, carbohydrate breakdown,
aromatic phenolic acids (Del Bò et al., 2009). between other important functions.
Since anthocyanin phenolic acids can be further absorbed Besides the obvious role of the gut in normal digestive pro-
in colon (Williamson & Clifford, 2010) it is possible that they cesses, the community of microorganisms in the human GI
are additionally metabolized by hepatic cells (Woodward, tract is now being considered as a ‘‘microbial organ’’.
Needs, & Kay, 2011). Health benefits associated with anthocy- The human gut is composed of a bacterial ecosystem of
anin rich foods may also be explained by a slow and continu- around 1013–1014 bacterial cells, despite not being fully de-
ous release of phenolic compounds through the gut into the scribed. Microorganisms living inside humans are estimated
bloodstream. to be more than 10 times human cells, and the microbiome
Despite their low apparent bioavailability, plasma concen- represent more than 100 times the human genome (Cani &
trations of anthocyanins appear sufficient to induce changes Delzenne, 2009). It has been described a key metabolic role
in signal transduction and gene expression in vivo (DeFuria for microbiota on diabetes and obesity morbilities (Ley et al.,
et al., 2009; Karlsen et al., 2007) in a manner that suggests 2005).
JOURNAL OF FUNCTIONAL FOODS 7 (2 0 14 ) 5 4–66 61

The chemical forms of anthocyanins ingested in the diet The major route of entry of phytochemicals, polyphenols
are not the ones that reach microbiota but instead their and, in particular, flavonoids is by oral ingestion, as they are
respective metabolites that were excreted in the bile and/or consumed as part of a normal diet. The bioavailability of
from the enterohepatic circulation. In colon, anthocyanins these xenobiotics can be influenced by several factors, simi-
are broadly metabolized by bacteria originating more simple larly to what happens with other compounds ingested orally.
compounds. All the way through the absorption, distribution, biotransfor-
Anthocyanins metabolization includes methylation, sulfa- mation and elimination processes, the movement through
tion and conjugation with glucuronic acid but also the break biological membrane is implied. Nevertheless, the ability of
of glycoside linkages and cleavage of the anthocyanin hetero- a compound to cross membranes can be determined by its
cycle (Goldberg, Yan, & Soleas, 2003; Rechner et al., 2004; physicochemical characteristics such as size, lipid/water sol-
Slimestad, Fossen, & Vagen, 2007). For these reactions to take ubility or pKa. Usually, larger, hydrophilic or ionic charged
place, the involvement of beta-D-glucosidases, beta-D-glucu- molecules cannot freely cross membranes and a transporter
ronidases and alfa-L-rhamnosidases that release aglycones must be implicated.
from their glycoside or glucuronidate forms is necessary Regarding the gastrointestinal (GI) tract several other fac-
(Aura et al., 2005; Gonthier et al., 2003; Selma, Espin, & To- tors may also influence xenobiotics absorption such as pH,
mas-Barberan, 2009). Bacteroides could be the genera mostly food, digestive enzymes, biliary acids, microbiota and the
involved in these reactions as they express these enzymes. motility and permeability of the GI tract. The passage
Because of this and, based on substrate specificity, anthocya- through GI is extremely important concerning anthocyanins
nins may be responsible for the prebiotic benefits associated absorption since these compounds have a complex chemis-
with red wine ingestion, in particular for Bacteroides (Que- try responsible for their attractive colours but also for their
ipo-Ortuno et al., 2012). This is a new, but growing, concept, instability, which will influence all the biokinetics processes,
especially taken into consideration that dysbiosis occurs in and thus, the bioactivity. Its structure is pH-sensitive,
the occidental diet pattern and evidence exists that the Bacte- becoming unstable at higher pH (McGhie & Walton, 2007).
roides number needs to grow. Studies comparing microbiota The most common methodologies to detect anthocyanins
from lean and obese individuals have shown an increase on are centered on their colour in a cationic form and are based
Firmicutes genera and a decrease in Bacteroides (about 50% on the total conversion of anthocyanins to this form in
reduction) in the obese population (Ley et al., 2005). acidic medium. However, the conversion of anthocyanins
The structure of the metabolites produced in colon are not to a cation form may not be complete leading to an underes-
dependent on sugar moieties but on the structural features of timated quantification of these compounds (Fernandes et al.,
the polyphenols. As already referred, protocatechuic acid has 2012). In addition, it is usually not considered that anthocy-
been reported as the main metabolite, after anthocyanin con- anins may be metabolized/biotransformed and, thus, the
sumption (Goldberg et al., 2003; Selma et al., 2009; Slimestad conversion back to the cationic form after acidification is
et al., 2007). A recent work confirmed the degradation of no longer a possibility, contributing to this underestimation.
cyanidin-3-glucoside to protocatechuic acid after incubation Further, whether the biological effects attributed to anthocy-
with gut bacteria (Hanske et al., 2013). Curiously, it has been anins are due to their cationic form, their hemiacetal
described that protocatechuic acid improves spatial working form or a metabolite of one of these two forms is still
memory (Corona, Vauzour, Hercelin, Williams, & Spencer, uncertain.
2013). Another important factor affecting anthocyanins bioavail-
The individual characteristics of microbiota strongly de- ability is their possible ingestion as pigments (anthocyanin
pend on the dietary habits (Cani & Delzenne, 2011), which derivatives), especially when considering wine consumption
in turn influence anthocyanins bioavailability. (Fig. 7). A recent work had already indicated that anthocyanin
pyruvic-acid adducts can rapidly reach rat plasma 15 min
after oral administration of 400 mg/kg bw (21.1 nM kg/lmol
6. Factors affecting anthocyanins and 28.8 nM kg/lmol, of malvidin-3-glucoside-pyruvic acid
bioavailability adduct and malvidin-3-glucoside, respectively) (Faria et al.,
2009). The possible absorption of other forms of anthocyanin
The basic kinetic concepts used to study drug actions or phar- derivatives has also been recently explored in a study that
macokinetics are usually applied to study or predict the showed that flavanol–anthocyanin pigments presented a
movement of other substances in the organism, such as tox- higher absorption efficiency in caco-2 cell model than procy-
ins, environmental pollutants or even phytochemicals. anidin B3 (Fernandes, Nave, Gonçalves, de Freitas, & Mateus,
Biokinetic or disposition is the term used to describe the 2012). This work showed that not only anthocyanins and flav-
path of a xenobiotic in the body and is defined as the compos- anols may cross the caco-2 cell barrier model with similar
ite actions of its absorption, distribution, biotransformation efficiency, but also dimeric structures containing both antho-
and elimination. The bioactivity of a substance is directly cyanins and flavanols, although with a lower efficiency than
dependent on its concentration, making the disposition of the respective monomers.
any compound a major contributor to its potential bioactivity. Based on the reported studies, a new field of interest that
Therefore, because the disposition of a chemical determines is often overlooked arises: the anthocyanin absorption as
its concentration at the site of action, the concerted action anthocyanin-derived pigments.
of absorption, distribution and elimination dictates the po- Therefore, the overall anthocyanin bioavailability should
tential for biological events to occur. result from the contribution of the amount that crosses all
62 JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

Fig. 8 – Schematic representation of the different anthocyanin forms that could contribute to the net bioavailability and
biological effects of these food components.

physiological barriers in all their possible forms: native, deg- interfering with these molecules absorption, e.g., organic cat-
radation products, metabolites and anthocyanin derivatives ions, glucose (Faria, Mateus, de Freitas, & Calhau, 2006; Faria
(Fig. 8). et al., 2009; Keating, Lemos, Goncalves, & Martel, 2008).
The availability of phenolic compounds can be also depen- Recently, the frequency of the consumption has also been
dent on the food matrix where they are inserted. A more lipo- a point of discussion since cells long-term exposed to antho-
philic environment may facilitate flavonoids solubilization cyanins demonstrated to be more prone to their transport
and absorption. Additionally, the presence of ethanol can also (Faria et al., 2009). This point is of specifical importance as it
be determinant on the extent of anthocyanins absorption may be the first step to justify dietary recommendations
(Faria et al., 2009), promoting their transport across intestinal and emphasizes the importance of a fruit and vegetable-rich
epithelia. Another factor to take into consideration is the diet.
interaction between polyphenolic compounds and the other Different animal and human studies in the past decade
compounds present during a meal: it is well known the ability have related anthocyanin-rich foods with health beneficial ef-
of these compounds to interact with proteins (Bras et al., fects (Andres-Lacueva et al., 2005; Krikorian et al., 2010). For
2010; Goncalves, Mateus, & de Freitas, 2010), modifying or this to happen, bioavailability of these compounds is pre-
changing their biological function and limiting and/or inter- sumed but whether the effect is due to the native compounds
fering with both protein and phenolic absorption; moreover, or its metabolites, which mechanism are involved or which
because the cell does not have specific mechanisms for phen- factors have crucial impact on bioavailability still remains
olics entry, they use the cell machinery for other substances, underexplored.
JOURNAL OF FUNCTIONAL FOODS 7 (2 0 14 ) 5 4–66 63

7. Conclusion in aged blueberry-fed rats are found centrally and may


enhance memory. Nutritional Neuroscience, 8, 111–120.
Aura, A. M., Martin-Lopez, P., O’Leary, K. A., Williamson, G.,
Overall, anthocyanins are found in diverse food sources, with
Oksman-Caldentey, K. M., Poutanen, K., et al. (2005). In vitro
berries and red wine as main sources, they are gastric and metabolism of anthocyanins by human gut microflora.
intestinally absorbed, but they could also reach the colon European Journal of Nutrition, 44, 133–142.
and undergo microbiota metabolization. Content of anthocy- Battiston, L., Macagno, A., Passamonti, S., Micali, F., & Luigi
anins may vary considerably between food sources, environ- Sottocasa, G. (1999). Specific sequence-directed anti-
mental conditions, as a direct result of sun exposure, bilitranslocase antibodies as a tool to detect potentially
cultivars, etc. This fact is often neglected in studies, probably bilirubin-binding proteins in different tissues of the rat. FEBS
Letters, 453, 351–355.
justifying the results variability and the, still existing, gap in
Bras, N. F., Goncalves, R., Mateus, N., Fernandes, P. A., Ramos, M.
knowledge. J., & de Freitas, V. (2010). Inhibition of pancreatic elastase by
The interest in anthocyanins has been driven primarily by polyphenolic compounds. Journal of Agricultural and Food
epidemiological studies that have suggested that diets rich in Chemistry, 58, 10668–10676.
these phytochemicals are beneficial to human health. Brouillard, R., & Delaporte, B. (1977). Chemistry of anthocyanin
There is a real possibility that some dietary anthocyanins pigments. 2. Kinetic and thermodynamic study of proton
transfer, hydration, and tautomeric reactions of malvidin 3-
or derived pigments contribute positively to health and
glucoside. Journal of the American Chemical Society, 99,
well-being. Healthy known effects associated with consump-
8461–8468.
tion of anthocyanin-rich foods should be attributed to: (i) di- Brouillard, R., & Dubois, J. E. (1977). Mechanism of structural
rect effects of the absorbed parent compounds (or their transformations of anthocyanins in acidic media. Journal of the
metabolites); (ii) indirect effects mediated by non-absorbed American Chemical Society, 99, 1359–1364.
entities that, probably, induce modifications on microbiota Brouillard, R., & Lang, J. (1990). The hemiacetal-cis-chalcone
environment and, consequently, on human metabolism or equilibrium of malvidin, a natural anthocyanin. Canadian
Journal of Chemistry-Revue Canadienne De Chimie, 68, 755–761.
could act at the membrane border inducing signal transduc-
Cani, P. D., & Delzenne, N. M. (2009). The role of the gut microbiota
tion pathways. in energy metabolism and metabolic disease. Current
The health benefits associated in epidemiologic studies Pharmaceutical Design, 15, 1546–1558.
with the consumption of anthocyanin-rich foods contradict Cani, P. D., & Delzenne, N. M. (2011). The gut microbiome as
the apparent low bioavailability of these compounds. therapeutic target. Pharmacology & Therapeutics, 130, 202–212.
Nevertheless, the biological activity of absorbed parent Cao, G., Muccitelli, H. U., Sanchez-Moreno, C., & Prior, R. L. (2001).
compounds, their metabolites and microbial catabolites and Anthocyanins are absorbed in glycated forms in elderly
women: A pharmacokinetic study. The American Journal of
the potential synergy between them could be the answer to
Clinical Nutrition, 73, 920–926.
the anthocyanin paradox bioactivity. Cao, G., & Prior, R. L. (1999). Anthocyanins are detected in human
More studies should be carried out in what concerns plasma after oral administration of an elderberry extract.
anthocyanin or derived pigments transport across biological Clinical Chemistry, 45, 574–576.
membranes. There are studies announcing gastric absorption Clifford, M. N. (2000). Anthocyanins – nature, occurrence and
and neuroprotective effects of anthocyanin-rich foods, but dietary burden. Journal of the Science of Food and Agriculture, 80,
1063–1072.
there is a gap in the knowledge concerning, for example,
Corona, G., Vauzour, D., Hercelin, J., Williams, C. M., & Spencer, J.
anthocyanin transport across gastric or blood–brain barrier.
P. (2013). Phenolic acid intake, delivered via moderate
On top of this, it is urgent to know dietary factors able to champagne wine consumption, improves spatial working
modulate anthocyanin bioavailability, helping health profes- memory via the modulation of hippocampal and cortical
sionals to make dietary recommendations. These recommen- protein expression/activation. Antioxidants and Redox Signaling
dations will be relevant for a healthy life but, also, to alert [Epub ahead of print].
medical doctors as to possible pharmacological interactions Crespy, V., Morand, C., Besson, C., Manach, C., Demigne, C., &
Remesy, C. (2001). Quercetin, but not its glycosides, is absorbed
with anthocyanins.
from the rat stomach. Journal of Agricultural and Food Chemistry,
50, 618–621.
Acknowledgements Davies, K. (2009). Modifying anthocyanin production in flowers. In
K. Gould, K. Davies, & C. Winefield (Eds.), Anthocyanins –
This work was supported by FCT (Fundação para a Ciência e Biosynthesis, functions, and applications (pp. 49–84). Springer.
Déchelotte, P., Varrentrapp, M., Meyer, H. J., & Schwenk, M. (1993).
Tecnologia) (POCI, FEDER, POPH, QREN) by studentship grants
Conjugation of 1-naphthol in human gastric epithelial cells.
(SFRH/BPD/75294/2010 and SFRH/BPD/86173/2012) and one
Gut, 34, 177–180.
project grant (PTDC/AGR-TEC/2227/2012). DeFuria, J., Bennett, G., Strissel, K. J., Perfield, J. W., Milbury, P. E., &
Greenberg, A. S. (2009). Dietary blueberry attenuates whole-
body insulin resistance in high fat-fed mice by reducing
R E F E R E N C E S
adipocyte death and its inflammatory sequelae. The Journal of
Nutrition, 139, 1510–1516.
Del Bò, C., Ciappellano, S., Klimis-Zacas, D., Martini, D., Gardana,
Andersen, O. M., & Jordheim, M. (2005). The anthocyanins. In O. M. C., Riso, P., et al. (2009). Anthocyanin absorption, metabolism,
Andersen & K. R. Markham (Eds.), Flavonoids: Chemistry, and distribution from a wild blueberry-enriched diet
biochemistry and applications (pp. 471–552). CRC Press. (vaccinium angustifolium) is affected by diet duration in the
Andres-Lacueva, C., Shukitt-Hale, B., Galli, R. L., Jauregui, O., Sprague Dawley rat. Journal of Agricultural and Food Chemistry,
Lamuela-Raventos, R. M., & Joseph, J. A. (2005). Anthocyanins 58, 2491–2497.
64 JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

Deroles, S. (2009). Anthocyanin biosynthesis in plant cell cultures: Goncalves, R., Mateus, N., & de Freitas, V. (2010). Study of the
A potential source of natural colourants. In K. Gould, K. interaction of pancreatic lipase with procyanidins by optical
Davies, & C. Winefield (Eds.), Anthocyanins – Biosynthesis, and enzymatic methods. Journal of Agricultural and Food
functions, and applications (pp. 107–169). Springer. Chemistry, 58, 11901–11906.
Dressman, J. B., Berardi, R. R., Dermentzoglou, L. C., Russell, T. L., Gonthier, M. P., Cheynier, V., Donovan, J. L., Manach, C., Morand,
Schmaltz, S. P., Barnett, J. L., et al. (1990). Upper C., Mila, I., et al. (2003). Microbial aromatic acid metabolites
gastrointestinal (GI) ph in young, healthy men and women. formed in the gut account for a major fraction of the
Pharmaceutical Research, 7, 756–761. polyphenols excreted in urine of rats fed red wine
El Mohsen, M. A., Marks, J., Kuhnle, G., Moore, K., Debnam, E., Srai, polyphenols. The Journal of Nutrition, 133, 461–467.
S. K., et al. (2006). Absorption, tissue distribution and Hanske, L., Engst, W., Loh, G., Sczesny, S., Blaut, M., & Braune, A.
excretion of pelargonidin and its metabolites following (2013). Contribution of gut bacteria to the metabolism of
oral administration to rats. British Journal of Nutrition, 95, cyanidin 3-glucoside in human microbiota-associated rats. The
51–58. British Journal of Nutrition, 109, 1433–1441.
Eraly, S. A., Bush, K. T., Sampogna, R. V., Bhatnagar, V., & Nigam, S. Harris, R. M., Picton, R., Singh, S., & Waring, R. H. (2000). Activity of
K. (2004). The molecular pharmacology of organic anion phenolsulfotransferases in the human gastrointestinal tract.
transporters: From dna to fda? Molecular Pharmacology, 65, Life Sciences, 67, 2051–2057.
479–487. He, J., Wallace, T. C., Keatley, K. E., Failla, M. L., & Giusti, M. M.
Faria, A., Fernandes, I., Mateus, N., & Calhau, C. (2013). (2009). Stability of black raspberry anthocyanins in the
Bioavailability of anthocyanins. In K. Ramawat & J.-M. Merillon digestive tract lumen and transport efficiency into gastric and
(Eds.). Handbook of natural products (Vol. 2). Germany: Springer. small intestinal tissues in the rat. Journal of Agricultural and
Faria, A., Mateus, N., de Freitas, V., & Calhau, C. (2006). Modulation Food Chemistry, 57, 3141–3148.
of MPP+ uptake by procyanidins in Caco-2 cells: Involvement Hollman, P. C., Bijsman, M. N., van Gameren, Y., Cnossen, E. P., de
of oxidation/reduction reactions. FEBS Letters, 580, 155–160. Vries, J. H., & Katan, M. B. (1999). The sugar moiety is a major
Faria, A., Pestana, D., Azevedo, J., Martel, F., Freitas, V., Azevedo, determinant of the absorption of dietary flavonoid glycosides
D., et al. (2009). Absorption of anthocyanins through intestinal in man. Free Radical Research, 31, 569–573.
epithelial cells - Putative involvement of GLUT2. Molecular Ichiyanagi, T., Rahman, M. M., Kashiwada, Y., Ikeshiro, Y., Shida,
Nutrition & Food Research, 53, 1430–1437. Y., Hatano, Y., et al. (2004). Absorption and metabolism of
Faria, A., Pestana, D., Monteiro, R., Teixeira, D., Azevedo, J., Freitas, delphinidin 3-O-b-glucopyranoside in rats. Free Radical Biology
V. D., et al. (2009). Bioavailability of anthocyanin-pyruvic acid and Medicine, 36, 930–937.
adducts in rat. In International conference on polyphenols and Ichiyanagi, T., Shida, Y., Rahman, M. M., Hatano, Y., et al. (2005).
health (pp. 170–171). Yorkshire: Leeds. Extended glucuronidation is another major path of cyanidin 3-
Felgines, C., Talavera, S., Texier, O., Besson, C., Fogliano, V., O-b-D-glucopyranoside metabolism in rats. Journal of
Lamaison, J. L., et al. (2006). Absorption and metabolism of red Agricultural and Food Chemistry, 53, 7312–7319.
orange juice anthocyanins in rats. The British Journal of Ichiyanagi, T., Shida, Y., Rahman, M. M., Hatano, Y., Matsumoto,
Nutrition, 95, 898–904. H., Hirayama, M., & Konishi, T. (2005). Metabolic pathway of
Felgines, C., Texier, O., Besson, C., Lyan, B., Lamaison, J.-L., & cyanidin 3-O-b-D-glucopyranoside in rats. Journal of
Scalbert, A. (2007). Strawberry pelargonidin glycosides are Agricultural and Food Chemistry, 53, 145–150.
excreted in urine as intact glycosides and glucuronidated Kalt, W., Blumberg, J. B., McDonald, J. E., Vinqvist-Tymchuk, M. R.,
pelargonidin derivatives in rats. British Journal of Nutrition, 98, Fillmore, S. A. E., Graf, B. A., et al. (2008). Identification of
1126–1131. anthocyanins in the liver, eye, and brain of blueberry-fed pigs.
Felgines, C., Texier, O., Besson, C., Vitaglione, P., Lamaison, J.-L., Journal of Agricultural and Food Chemistry, 56, 705–712.
Fogliano, V., et al. (2008). Influence of glucose on cyanidin 3- Karhunen, T., Tilgmann, C., Ulmanen, I., Julkunen, I., & Panula, P.
glucoside absorption in rats. Molecular Nutrition & Food (1994). Distribution of catechol-O-methyltransferase enzyme
Research, 52, 959–964. in rat tissues. Journal of Histochemistry & Cytochemistry, 42,
Felgines, C., Texier, O., Garcin, P., Besson, C., Lamaison, J.-L., & 1079–1090.
Scalbert, A. (2009). Tissue distribution of anthocyanins in rats Karlsen, A., Retterstøl, L., Laake, P., Paur, I., Kjølsrud-Bøhn, S.,
fed a blackberry anthocyanin-enriched diet. Molecular Nutrition Sandvik, L., et al. (2007). Anthocyanins inhibit nuclear factor-
& Food Research, 53, 1098–1103. kappaB activation in monocytes and reduce plasma
Fernandes, I., de Freitas, V., Reis, C., & Mateus, N. (2012). A new concentrations of pro-inflammatory mediators in healthy
approach on the gastric absorption of anthocyanins. Food & adults. The Journal of Nutrition, 137, 1951–1954.
Function, 3, 508–516. Keating, E., Lemos, C., Goncalves, P., & Martel, F. (2008). Acute and
Fernandes, I., Nave, F., Gonçalves, R., de Freitas, V., & Mateus, N. chronic effects of some dietary bioactive compounds on folic
(2012). On the bioavailability of flavanols and anthocyanins: acid uptake and on the expression of folic acid transporters by
Flavanol–anthocyanin dimers. Food Chemistry, 135, 812–818. the human trophoblast cell line BeWo. The Journal of Nutritional
Francis, F. J. (1989). Food colorants: Anthocyanins. Critical Reviews Biochemistry, 19, 91–100.
in Food Science and Nutrition, 28, 273–314. Konishi, Y., Zhao, Z., & Shimizu, M. (2006). Phenolic acids are
Garcia, C. K., Brown, M. S., Pathak, R. K., & Goldstein, J. L. (1995). absorbed from the rat stomach with different absorption
CDNA Cloning of MCT2, a Second Monocarboxylate rates. Journal of Agricultural and Food Chemistry, 54, 7539–7543.
Transporter Expressed in Different Cells than MCT1. Journal of Krikorian, R., Shidler, M. D., Nash, T. A., Kalt, W., Vinqvist-
Biological Chemistry, 270, 1843–1849. Tymchuk, M. R., Shukitt-Hale, B., et al. (2010). Blueberry
Gee, J. M., DuPont, M. S., Day, A. J., Plumb, G. W., Williamson, G., & supplementation improves memory in older adults. Journal of
Johnson, I. T. (2000). Intestinal transport of quercetin Agricultural and Food Chemistry, 58, 3996–4000.
glycosides in rats involves both deglycosylation and Lafay, S., Gil-Izquierdo, A., Manach, C., Morand, C., Besson, C., &
interaction with the hexose transport pathway. The Journal of Scalbert, A. (2006). Chlorogenic acid is absorbed in its intact
Nutrition, 130, 2765–2771. form in the stomach of rats. The Journal of Nutrition, 136,
Goldberg, D. M., Yan, J., & Soleas, G. J. (2003). Absorption of three 1192–1197.
wine-related polyphenols in three different matrices by Ley, R. E., Backhed, F., Turnbaugh, P., Lozupone, C. A., Knight, R. D.,
healthy subjects. Clinical Biochemistry, 36, 79–87. & Gordon, J. I. (2005). Obesity alters gut microbial ecology.
JOURNAL OF FUNCTIONAL FOODS 7 (2 0 14 ) 5 4–66 65

Proceedings of the National Academy of Sciences of the United States Passamonti, S., Vrhovsek, U., Vanzo, A., & Mattivi, F. (2005). Fast
of America, 102, 11070–11075. access of some grape pigments to the brain. Journal of
Mallery, S. R., Budendorf, D. E., Larsen, M. P., Pei, P., Tong, M., Agricultural and Food Chemistry, 53, 7029–7034.
Holpuch, A. S., et al. (2011). Effects of human oral mucosal tissue, Perez-Jimenez, J., Fezeu, L., Touvier, M., Arnault, N., Manach, C., &
saliva and oral microflora on intraoral metabolism and bioactivation Hercberg, S. (2011). Dietary intake of 337 polyphenols in French
of black raspberry anthocyanins. Cancer Prevention Research. adults. The American Journal of Clinical Nutrition, 93, 1220–1228.
Manach, C., Williamson, G., Morand, C., Scalbert, A., & Remesy, C. Perez-Jimenez, J., Neveu, V., Vos, F., & Scalbert, A. (2010).
(2005). Bioavailability and bioefficacy of polyphenols in Systematic analysis of the content of 502 polyphenols in 452
humans. I. Review of 97 bioavailability studies. The American foods and beverages: An application of the phenol-explorer
Journal of Clinical Nutrition, 81, 230–242. database. Journal of Agricultural and Food Chemistry, 58,
Matsui, T., Ueda, T., Oki, T., Sugita, K., Terahara, N., & Matsumoto, 4959–4969.
K. (2001). a-Glucosidase inhibitory action of natural acylated Piskula, M. K., Yamakoshi, J., & Iwai, Y. (1999). Daidzein and
anthocyanins. 1. Survey of natural pigments with potent genistein but not their glucosides are absorbed from the rat
inhibitory activity. Journal of Agricultural and Food Chemistry, 49, stomach. FEBS Letters, 447, 287–291.
1948–1951. Pissarra, J., Lourenco, S., Gonzalez-Paramas, A. M., Mateus, N.,
Mazza, G., & Miniati, E. (1993). Anthocyanins in fruits, vegetables, Buelga, C. S., Silva, A. M. S., et al. (2004). Structural
and grains. In Anthocyanins in fruits, vegetables, and grains. Boca characterization of new malvidin 3-glucoside-catechin aryl/
Raton: CRC Press. alkyl-linked pigments. Journal of Agricultural and Food Chemistry,
Mazza, G., & Velioglu, Y. S. (1992). Anthocyanins and other 52, 5519–5526.
phenolic-compounds in fruits of red-flesd apples. Food Queipo-Ortuno, M. I., Boto-Ordonez, M., Murri, M., Gomez-
Chemistry, 43, 113–117. Zumaquero, J. M., Clemente-Postigo, M., Estruch, R., et al.
McGhie, T. K., Ainge, G. D., Barnett, L. E., Cooney, J. M., & Jensen, D. (2012). Influence of red wine polyphenols and ethanol on the
J. (2003). Anthocyanin glycosides from berry fruit are absorbed gut microbiota ecology and biochemical biomarkers. The
and excreted unmetabolized by both humans and rats. Journal American Journal of Clinical Nutrition, 95, 1323–1334.
of Agricultural and Food Chemistry, 51, 4539–4548. Rechner, A. R., Smith, M. A., Kuhnle, G., Gibson, G. R., Debnam, E.
McGhie, T. K., & Walton, M. C. (2007). The bioavailability and S., Srai, S. K., et al. (2004). Colonic metabolism of dietary
absorption of anthocyanins: Towards a better understanding. polyphenols: Influence of structure on microbial fermentation
Molecular Nutrition & Food Research, 51, 702–713. products. Free Radical Biology & Medicine, 36, 212–225.
Milbury, P. E., Cao, G., Prior, R. L., & Blumberg, J. (2002). Riso, P., Visioli, F., Gardana, C., Grande, S., Brusamolino, A.,
Bioavailablility of elderberry anthocyanins. Mechanisms of Galvano, F., et al. (2005). Effects of blood orange juice intake on
Ageing and Development, 123, 997–1006. antioxidant bioavailability and on different markers related to
Miyazawa, T., Nakagawa, K., Kudo, M., Muraishi, K., & Someya, K. oxidative stress. Journal of Agricultural and Food Chemistry, 53,
(1999). Direct intestinal absorption of red fruit anthocyanins, 941–947.
cyanidin-3-glucoside and cyanidin-3,5-diglucoside, into rats Russell, T. L., Berardi, R. R., Barnett, J. L., Dermentzoglou, L. C.,
and humans. Journal of Agricultural and Food Chemistry, 47, Jarvenpaa, K. M., Schmaltz, S. P., et al. (1993). Upper
1083–1091. gastrointestinal pH in seventy-nine healthy, elderly, North
Mulleder, U., Murkovic, M., & Pfannhauser, W. (2002). Urinary American men and women. Pharmaceutical Research, 10,
excretion of cyanidin glycosides. Journal of Biochemical and 187–196.
Biophysical Methods, 53, 61–66. Scalbert, A., & Williamson, G. (2000). Dietary intake and
Murkovic, M., Mülleder, U., Adam, U., & Pfannhauser, W. (2001). bioavailability of polyphenols. The Journal of Nutrition, 130,
Detection of anthocyanins from elderberry juice in human 2073S–2085S.
urine. Journal of the Science of Food and Agriculture, 81, 934–937. Selma, M. V., Espin, J. C., & Tomas-Barberan, F. A. (2009).
Nave, F., Petrov, V., Pina, F. R., Teixeira, N., Mateus, N., & de Freitas, Interaction between phenolics and gut microbiota: Role in
V. (2010). Thermodynamic and kinetic properties of a red wine human health. Journal of Agricultural and Food Chemistry, 57,
pigment: Catechin-(4,8)-malvidin-3-O-glucoside. The Journal of 6485–6501.
Physical Chemistry B, 114, 13487–13496. Silberberg, M., Morand, C., Mathevon, T., Besson, C., Manach, C.,
Neveu, V., Perez-Jimenez, J., Vos, F., Crespy, V., du Chaffaut, L., Scalbert, A., et al. (2006). The bioavailability of polyphenols is
Mennen, L., et al. (2010). Phenol-explorer: An online highly governed by the capacity of the intestine and of the
comprehensive database on polyphenol contents in foods. Oxford: liver to secrete conjugated metabolites. European Journal of
Database [bap024]. Nutrition, 45, 88–96.
Nicolin, V., Grill, V., Micali, F., Narducci, P., & Passamonti, S. (2005). Slimestad, R., Fossen, T., & Vagen, I. M. (2007). Onions: A source of
Immunolocalisation of bilitranslocase in mucosecretory and unique dietary flavonoids. Journal of Agricultural and Food
parietal cells of the rat gastric mucosa. Journal of Molecular Chemistry, 55, 10067–10080.
Histology, 36, 45–50. Sousa, C., Mateus, N., Silva, A. M. S., Gonzalez-Paramas, A. M.,
Nurmi, T., Mursu, J., Heinonen, M., Nurmi, A., Hiltunen, R., & Santos-Buelga, C., & de Freitas, V. (2007). Structural and
Voutilainen, S. (2009). Metabolism of berry anthocyanins to chromatic characterization of a new malvidin 3-glucoside-
phenolic acids in humans. Journal of Agricultural and Food vanillyl-catechin pigment. Food Chemistry, 102, 1344–1351.
Chemistry, 57, 2274–2281. Strassburg, C. P., Nguyen, N., Manns, M. P., & Tukey, R. H. (1998).
Oliveira, J., de Freitas, V., Silva, A. M. S., & Mateus, N. (2007). Polymorphic expression of the UDP-glucuronosyltransferase
Reaction between hydroxycinnamic acids and anthocyanin- UGT1A gene locus in human gastric epithelium. Molecular
pyruvic acid adducts yielding new portisins. Journal of Pharmacology, 54, 647–654.
Agricultural and Food Chemistry, 55, 6349–6356. Strassburg, C. P., Oldhafer, K., Manns, M. P., & Tukey, R. H. (1997).
Passamonti, S., Vrhovsek, U., & Mattivi, F. (2002). The interaction Differential expression of the UGT1A locus in human liver,
of anthocyanins with bilitranslocase. Biochemical and biliary, and gastric tissue: Identification of UGT1A7 and
Biophysical Research Communications, 296, 631–636. UGT1A10 transcripts in extrahepatic tissue. Molecular
Passamonti, S., Vrhovsek, U., Vanzo, A., & Mattivi, F. (2003). The Pharmacology, 52, 212–220.
stomach as a site for anthocyanins absorption from food. FEBS Talavéra, S., Felgines, C., Texier, O., Besson, C., Gil-Izquierdo, A.,
Letters, 544, 210–213. Lamaison, J. L., et al. (2005). Anthocyanin metabolism in rats
66 JOURNAL OF FUNCTIONAL FOODS 7 ( 2 0 1 4 ) 5 4 –6 6

and their distribution to digestive area, kidney, and brain. activated in the oral cavity in humans. The Journal of Nutrition,
Journal of Agricultural and Food Chemistry, 53, 3902–3908. 135, 48–52.
Talavéra, S., Felgines, C., Texier, O., Besson, C., Lamaison, J. L., Wiese, S., Gärtner, S., Rawel, H. M., Winterhalter, P., & Kulling, S. E.
et al. (2003). Anthocyanins are efficiently absorbed from the (2009). Protein interactions with cyanidin-3-glucoside and its
stomach in anesthetized rats. The Journal of Nutrition, 133, influence on a-amylase activity. Journal of the Science of Food and
4178–4182. Agriculture, 89, 33–40.
Talavéra, S., Felgines, C., Texier, O., Besson, C., Manach, C., Williamson, G., & Clifford, M. N. (2010). Colonic metabolites of
Lamaison, J. L., & Remesy, C. (2004). Anthocyanins are berry polyphenols: The missing link to biological activity?
efficiently absorbed from the small intestine in rats. The British Journal of Nutrition, 104, S48–S66.
Journal of Nutrition, 134, 2275–2279. Woodward, G., Kroon, P., Cassidy, A., & Kay, C. (2009). Anthocyanin
Tsuda, T., Horio, F., & Osawa, T. (1999). Absorption and stability and recovery: Implications for the analysis of clinical
metabolism of cyanidin 3-O-b-D-glucoside in rats. FEBS Letters, and experimental samples. Journal of Agricultural and Food
449, 179–182. Chemistry, 57, 5271–5278.
Vanzo, A., Cecotti, R., Vrhovsek, U., Torres, A. M., Mattivi, F., & Woodward, G. M., Needs, P. W., & Kay, C. D. (2011). Anthocyanin-
Passamonti, S. (2007). The fate of trans-caftaric acid derived phenolic acids form glucuronides following simulated
administered into the rat stomach. Journal of Agricultural and gastrointestinal digestion and microsomal glucuronidation.
Food Chemistry, 55, 1604–1611. Molecular Nutrition & Food Research, 55, 378–386.
Verstraeten, S., Fraga, C., & Oteiza, P. (2010). Flavonoids– Yoshikawa, T., Inoue, R., Matsumoto, M., Yajima, T., Ushida, K., &
membrane interactions: Consequences for biological actions. Iwanaga, T. (2011). Comparative expression of hexose
In C. Fraga (Ed.), Plant phenolics and human health (pp. 107–136). transporters (SGLT1, GLUT1, GLUT2 and GLUT5) throughout
John Wiley & Sons, Inc.. the mouse gastrointestinal tract. Histochemistry and Cell Biology,
Vitaglione, P., Donnarumma, G., Napolitano, A., Galvano, F., Gallo, 135, 183–194.
A., Scalfi, L., et al. (2007). Protocatechuic acid is the major Zhao, Z., Egashira, Y., & Sanada, H. (2004). Ferulic acid is quickly
human metabolite of cyanidin-glucosides. The Journal of absorbed from rat stomach as the free form and then
Nutrition, 137, 2043–2048. conjugated mainly in liver. The Journal of Nutrition, 134,
Walle, T., Browning, A. M., Steed, L. L., Reed, S. G., & Walle, U. K. 3083–3088.
(2005). Flavonoid glucosides are hydrolyzed and thus

Potrebbero piacerti anche