Ci a ion: Esebe i, I.; T epiana, J.;
Léniz, A.; Gómez-Ga cía, I.;
Ca -Uga e, H.; González, M.;
Po illo, M.P. Va iabili y in he
Bene icial E ec s o Phenolic
Compounds: A Re iew. Nu ien s
2022,14, 1925. h ps://doi.o g/
10.3390/nu14091925
Academic Edi o :
F ancesca Giampie i
Recei ed: 30 Ma ch 2022
Accep ed: 2 May 2022
Published: 4 May 2022
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nu ien s
Re iew
Va iabili y in he Bene icial E ec s o Phenolic Compounds:
A Re iew
I zia Esebe i 1,2,3 , Jeni e T epiana 1,2,3,* , Asie Léniz 2,3,4 , Ike Gómez-Ga cía1, Helen Ca -Uga e 1,
Ma cela González 5and Ma ía P. Po illo 1,2,3
1Nu i ion and Obesi y G oup, Depa men o Pha macy and Food Sciences, Uni e si y o he Basque
Coun y (UPV/EHU) and Lucio Lasca ay Resea ch Ins i u e, 01006 Vi o ia-Gas eiz, Spain;
i zia [email p o ec ed] (I.E.); ike gomezga [email p o ec ed] (I.G.-G.); [email p o ec ed] (H.C.-U.);
ma iapuy[email p o ec ed] (M.P.P.)
2BIOARABA Heal h Resea ch Ins i u e, 01006 Vi o ia-Gas eiz, Spain; asie [email p o ec ed]
3CIBERobn Physiopa hology o Obesi y and Nu i ion, Ins i u e o Heal h Ca los III, 01006 Vi o ia, Spain
4School o Nu sing o Vi o ia-Gas eiz, Osakide za Basque Heal h Se ice, Uni e si y o he Basque
Coun y (UPV/EHU), 01006 Vi o ia-Gas eiz, Spain
5
Nu i ion and Food Science Depa men , Facul y o Biochemis y and Biological Sciences, Na ional Uni e si y
o Li o al and Na ional Scien i ic and Technical Resea ch Council (CONICET), San a Fe 3000, A gen ina;
[email p o ec ed]
*Co espondence: jeni e [email p o ec ed]; Tel.: +34-945013863; Fax: +34-945013014
Abs ac :
When analysing he bene icial e ec s o phenolic compounds, se e al ac o s ha exe
a clea in luence should be aken in o accoun . The con en o phenolic compounds in oods is
highly a iable, di ec ly a ec ing indi idual die a y in ake. Once inges ed, hese compounds ha e a
g ea e o lesse bioaccessibili y, de ined as he amoun a ailable o abso p ion in he in es ine a e
diges ion, and a ce ain bioa ailabili y, de ined as he p opo ion o he molecule ha is a ailable
a e diges ion, abso p ion and me abolism. Among he ex e nal ac o s ha modi y he con en o
phenolic compounds in ood a e he a ie y, he cul i a ion echnique and he clima e. Rega ding
unc ional oods, i is impo an o ake in o accoun he ole o he selec ed ood ma ix, such as dai y
ma ices, liquid o solid ma ices. I is also essen ial o conside he in e ac ions be ween phenolic
compounds as well as he in e play ha occu s be ween hese and se e al o he componen s o
he die (mac o- and mic onu ien s) a abso p ion, me abolism and mechanism o ac ion le els.
Fu he mo e, he e is a g ea in e -indi idual a iabili y in e ms o phase II me abolism o hese
compounds, composi ion o he mic obio a, and me abolic s a e o me abo ype o which he subjec
belongs. All hese ac o s in oduce a iabili y in he esponses obse ed a e inges ion o oods o
nu aceu icals con aining phenolic compounds.
Keywo ds: phenolic compounds; bioaccesibili y; bioa ailabili y; me abo ype; ch onobiology
1. In oduc ion
The bene icial e ec s o phenolic compounds on heal h ha e been demons a ed in
epidemiological and p eclinical s udies [
1
–
4
]. Howe e , when conside ing he posi i e
impac o phenolic compounds in humans, high in e -indi idual a ia ions in he bio-
logical esponses o die a y phenolic compound in ake and supplemen a ion ha e been
commonly epo ed [
5
]. This ac hampe s he ansla ion o cu en knowledge abou
hese compounds in o die a y ad ice and hinde s heal h claims o he gene al popula ion.
Consequen ly, mo e esea ch on he ac o s ha unde lie hese di e ences is needed.
Phenolic con en in oods is e y a iable, which di ec ly a ec s hei indi idual
die a y in ake [
6
,
7
]. Fu he mo e, ollowing o al in ake, he
in i o
e ec s o phenolic
compounds depend, in pa , on hei bioaccessibili y, which is de ined as he amoun ha is
a ailable o abso p ion in he gu a e diges ion [
8
]. They also es on hei bioa ailabili y,
Nu ien s 2022,14, 1925. h ps://doi.o g/10.3390/nu14091925 h ps://www.mdpi.com/jou nal/nu ien s
Nu ien s 2022,14, 1925 2 o 19
de ined as he p opo ion o he molecule ha is a ailable a e diges ion, abso p ion and
me abolism [9].
Among he ex e nal ac o s ha al e phenolic con en in oods u s, we ind plan o igin,
cul i a ion echnique, clima e and ype o ood ma ix. Chemical in e ac ions be ween phenolic
compounds and o he componen s o he die can ha e signi ican consequences. Mo eo e ,
he e is g ea in e -indi idual a iabili y in he esponse o phenolic compound in ake due
o pe sonal di e ences in me abolism (i.e., gene ic a ian s o enzymes in ol ed in phase II
me abolism), mic obio a composi ion, he indi idual me abolic s a us, o he me abo ype o
which he subjec belongs, among o he ac o s [10–12].
All hese elemen s cause an a ay o esponses a e he inges ion o oods o nu aceu-
icals con aining phenolic compounds. Consequen ly, i is e y di icul o o e p ecise
ecommenda ions abou hei consump ion. The p esen e iew does no in end o ca y
ou an exhaus i e eexamina ion o he epo ed pape s ha add ess he ole o all hese
ac o s on he e ec s o he main phenolic compounds inges ed by humans, because i is
no possible o e lec all his in o ma ion in a single pape . Fo his eason, we ha e de ined
wo aims: Fi s , o p o ide a gene al o e iew o he di icul ies ound in s anda dising he
ecommenda ions o phenolic compound in ake, by e ising he ac o s ha play a key
ole in he e ec s o hese molecules (Figu e 1). Second, o p o ide scien i ic e idence o
suppo his issue by desc ibing se e al epo ed s udies.
Nu ien s 2022, 14, x FOR PEER REVIEW 2 o 19
a ailable o abso p ion in he gu a e diges ion [8]. They also es on hei bioa ailabil-
i y, de ined as he p opo ion o he molecule ha is a ailable a e diges ion, abso p ion
and me abolism [9].
Among he ex e nal ac o s ha al e phenolic con en in oods u s, we ind plan
o igin, cul i a ion echnique, clima e and ype o ood ma ix. Chemical in e ac ions be-
ween phenolic compounds and o he componen s o he die can ha e signi ican conse-
quences. Mo eo e , he e is g ea in e -indi idual a iabili y in he esponse o phenolic
compound in ake due o pe sonal di e ences in me abolism (i.e., gene ic a ian s o en-
zymes in ol ed in phase II me abolism), mic obio a composi ion, he indi idual me a-
bolic s a us, o he me abo ype o which he subjec belongs, among o he ac o s [10–12].
All hese elemen s cause an a ay o esponses a e he inges ion o oods o
nu aceu icals con aining phenolic compounds. Consequen ly, i is e y di icul o o e
p ecise ecommenda ions abou hei consump ion. The p esen e iew does no in end
o ca y ou an exhaus i e eexamina ion o he epo ed pape s ha add ess he ole o
all hese ac o s on he e ec s o he main phenolic compounds inges ed by humans, be-
cause i is no possible o e lec all his in o ma ion in a single pape . Fo his eason, we
ha e de ined wo aims: Fi s , o p o ide a gene al o e iew o he di icul ies ound in
s anda dising he ecommenda ions o phenolic compound in ake, by e ising he ac o s
ha play a key ole in he e ec s o hese molecules (Figu e 1). Second, o p o ide scien i ic
e idence o suppo his issue by desc ibing se e al epo ed s udies.
Figu e 1. Fac o s a ec ing phenolic compound e ec i eness.
2. Chemis y o Phenolic Compounds
Phenolic compounds cons i u e a g oup o subs ances ha a e widely p esen in he
plan kingdom, whe e mo e han 8000 a e known, wi h di e en chemical s uc u es and
ac i i ies [13,14]. They can be ound in ege ables, seeds, ui s, nu s, ed wine, ea and
many o he ood sou ces. S uc u ally, phenolic compounds a e seconda y plan me abo-
li es cha ac e ised by a leas one a oma ic ing wi h one o mo e hyd oxyl g oups a -
ached [15]. The e a e wo basic pa hways in ol ed in he biosyn hesis o phenolic com-
pounds, he shikimic acid pa hway and he malonic acid pa hway. In plan s, he main
Figu e 1. Fac o s a ec ing phenolic compound e ec i eness.
2. Chemis y o Phenolic Compounds
Phenolic compounds cons i u e a g oup o subs ances ha a e widely p esen in
he plan kingdom, whe e mo e han 8000 a e known, wi h di e en chemical s uc u es
and ac i i ies [
13
,
14
]. They can be ound in ege ables, seeds, ui s, nu s, ed wine, ea
and many o he ood sou ces. S uc u ally, phenolic compounds a e seconda y plan
me aboli es cha ac e ised by a leas one a oma ic ing wi h one o mo e hyd oxyl g oups
a ached [
15
]. The e a e wo basic pa hways in ol ed in he biosyn hesis o phenolic
compounds, he shikimic acid pa hway and he malonic acid pa hway. In plan s, he main
pa hway is he o me . The shikima e pa hway consis s o se en eac ion s eps, beginning
Nu ien s 2022,14, 1925 3 o 19
wi h an aldol- ype condensa ion o phosphoenolpy u ic acid (PEP) om he glycoly ic
pa hway, and D-e y h ose-4-phospha e om he pen ose phospha e cycle, o p oduce
3-deoxy-D-a abino-hep ulosonic
acid 7-phospha e (DAHP). A key b anch-poin compound
is cho ismic acid, he inal p oduc o he shikima e pa hway. They a e gene ally p oduced
as de ence mechanisms agains pa hogens, p o ec ion om excess ul a iole adia ion and
as a ac an s o pollina o s. Complex phenolic compounds a e also impo an s uc u al
componen s o plan s [16].
Phenolic compounds wi h mo e han one phenolic g oup a e called polyphenols.
Gene ally, phenolic compounds a e ound in conjuga ed o m wi h one o mo e suga
moie ies, as glycosides, linked h ough OH g oup (O-glycosides) o h ough ca bon–ca bon
bonds (C-glycosides). The suga bonds could be monosaccha ides, disaccha ides o e en
oligosaccha ides, being he mos common glucose, al hough i could be bound o galac ose,
hamnose, a abinose, xylose o glucu onic acid [17].
Based on he s uc u e o he aglycones, hey a e i s di ided in o la onoids and
non- la onoids. Fla onoids a e 15 ca bon compounds con igu ed as C
6
-C
3
-C
6
, gene ally
as wo a oma ic ings, connec ed by h ee ca bons, and hey a e subdi ided in o se e al
g oups ( la onols, la ones, iso la ones, la anones, la an-3-ols and an hocyanidins) [
18
].
Non- la onoids a e composed o one o wo a oma ic ings and a e classi ied as phenolic
acids, which con ain a C
6
-C
1
ca bon skele on, hyd oxycinnama es wi h a s uc u e o C
6
-C
3
,
hyd olysable annins wi h one o wo a oma ic ings and s ilbenes, wi h a mo e complex
s uc u e o C
6
-C
2
-C
6
[
14
,
19
]. Some phenolic compounds wi h di e en chemical s uc u es
a e shown in Figu e 2.
Nu ien s 2022, 14, x FOR PEER REVIEW 3 o 19
pa hway is he o me . The shikima e pa hway consis s o se en eac ion s eps, beginning
wi h an aldol- ype condensa ion o phosphoenolpy u ic acid (PEP) om he glycoly ic
pa hway, and D-e y h ose-4-phospha e om he pen ose phospha e cycle, o p oduce 3-
deoxy-D-a abino-hep ulosonic acid 7-phospha e (DAHP). A key b anch-poin compound
is cho ismic acid, he inal p oduc o he shikima e pa hway. They a e gene ally p oduced
as de ence mechanisms agains pa hogens, p o ec ion om excess ul a iole adia ion
and as a ac an s o pollina o s. Complex phenolic compounds a e also impo an s uc-
u al componen s o plan s [16].
Phenolic compounds wi h mo e han one phenolic g oup a e called polyphenols.
Gene ally, phenolic compounds a e ound in conjuga ed o m wi h one o mo e suga
moie ies, as glycosides, linked h ough OH g oup (O-glycosides) o h ough ca bon–ca -
bon bonds (C-glycosides). The suga bonds could be monosaccha ides, disaccha ides o
e en oligosaccha ides, being he mos common glucose, al hough i could be bound o
galac ose, hamnose, a abinose, xylose o glucu onic acid [17].
Based on he s uc u e o he aglycones, hey a e i s di ided in o la onoids and
non- la onoids. Fla onoids a e 15 ca bon compounds con igu ed as C6-C3-C6, gene ally
as wo a oma ic ings, connec ed by h ee ca bons, and hey a e subdi ided in o se e al
g oups ( la onols, la ones, iso la ones, la anones, la an-3-ols and an hocyanidins)
[18]. Non- la onoids a e composed o one o wo a oma ic ings and a e classi ied as phe-
nolic acids, which con ain a C6-C1 ca bon skele on, hyd oxycinnama es wi h a s uc u e o
C6-C3, hyd olysable annins wi h one o wo a oma ic ings and s ilbenes, wi h a mo e
complex s uc u e o C6-C2-C6 [14,19]. Some phenolic compounds wi h di e en chemical
s uc u es a e shown in Figu e 2.
Figu e 2. Phenolic compounds showing di e en chemical s uc u es.
The chemical s uc u e o phenolic compounds can in luence hei bioa ailabili y and
biological ac ions. A good example is he sligh di e ences in he chemical s uc u e o
es e a ol, picea annol and p e os ilbene. Al hough hey a e chemical analogues,
picea annol and p e os ilbene ha e been shown o ha e g ea e ac i i y [19,20], p obably
due o hei highe esis ance o in es inal and hepa ic me abolism, gi en by he di e -
ences in he amoun o hyd oxyl and me hoxyl g oups among hem [21] (Figu e 3). In
addi ion, Rice-E ans and co-wo ke s (1996) hypo hesised ha he di e en an ioxidan
ac i i y o phenolic compounds could be ela ed o hei abili y o ac as adical sca enge s
in ela ion o hei chemical s uc u es [22].
Figu e 2. Phenolic compounds showing di e en chemical s uc u es.
The chemical s uc u e o phenolic compounds can in luence hei bioa ailabili y
and biological ac ions. A good example is he sligh di e ences in he chemical s uc u e
o es e a ol, picea annol and p e os ilbene. Al hough hey a e chemical analogues,
picea annol and p e os ilbene ha e been shown o ha e g ea e ac i i y [
19
,
20
], p obably
due o hei highe esis ance o in es inal and hepa ic me abolism, gi en by he di e ences
in he amoun o hyd oxyl and me hoxyl g oups among hem [
21
] (Figu e 3). In addi ion,
Rice-E ans and co-wo ke s (1996) hypo hesised ha he di e en an ioxidan ac i i y o
phenolic compounds could be ela ed o hei abili y o ac as adical sca enge s in ela ion
o hei chemical s uc u es [22].
Nu ien s 2022,14, 1925 4 o 19
Nu ien s 2022, 14, x FOR PEER REVIEW 4 o 19
Figu e 3. Chemical s uc u es o es e a ol, p e os ilbene and picea annol.
3. Fac o s ha A ec Phenolic Con en and Composi ion o Foods
The e a e nume ous ac o s ha ha e a clea in luence on he amoun and composi-
ion o phenolic compounds p esen in plan s (Figu e 4). Among hem, he e a e ac o s
in insic o he plan i sel (gene ic o igin) ha lead o in e species di e ences, and a ie-
ies o he same p oduc . Fo ins ance, in he case o he le uce a ie ies, whe eas oma-
nine, baby and icebe g ha e a poo con en o an ioxidan phenolic subs ances ( la anols
and de i a i es o ca eic acid), lea oak and lollo osso show high con en s [23].
Figu e 4. Main ac o s ha a ec phenolic con en and composi ion o oods.
The e a e also ac o s ex insic o he plan , linked o he g owing ci cums ances (ag i-
en i onmen al ac o s) and o he pos -ha es s o age condi ions. Rega ding g owing
condi ions, he p esence o absence o ce ain nu ien s in he soil can a ec he phy o-
chemical composi ion o ui s and ege ables, bo h quali a i ely and quan i a i ely. As
an example, i is known ha he con en o calcium in soil induces phenolic me abolism
and an hocyanin accumula ion in g apes [24]. Bo on a ailabili y also a ec s he phenolic
con en o plan s subs an ially. In ac , his mine al can inc ease he key enzyme phenyl-
alanine ammonia-lyase (PAL), which augmen s he an hocyanin biosyn hesis [25].
Clima e is ano he key aspec , and as a esul , ui s om he same a ie y cul i a ed
in di e en a eas p esen di e en con en s o phenolic compounds. I we ake g apes as
an example, i has been demons a ed ha high empe a u es du ing he g owing s ages
can dec ease an hocyanin syn hesis [26]. Con e sely, he wa e s a us a he lowe ing
s age o he g ape cycle has a posi i e e ec on phenolic compound syn hesis, whe eas
he syn hesis o an hocyanins and phenolic compounds inc eases wi h wa e de ici s du -
ing ma u i y s ages [27].
The in luence o seasonal a ia ions has been s udied in peach. Rahma i e al. (2014)
analysed he changes in peach componen s (ca bohyd a es, o ganic acids and phenolic
compounds) when exposed o long- e m d ough in semi-a id clima e condi ions du ing
Figu e 3. Chemical s uc u es o es e a ol, p e os ilbene and picea annol.
3. Fac o s Tha A ec Phenolic Con en and Composi ion o Foods
The e a e nume ous ac o s ha ha e a clea in luence on he amoun and composi ion
o phenolic compounds p esen in plan s (Figu e 4). Among hem, he e a e ac o s in insic
o he plan i sel (gene ic o igin) ha lead o in e species di e ences, and a ie ies o he
same p oduc . Fo ins ance, in he case o he le uce a ie ies, whe eas omanine, baby and
icebe g ha e a poo con en o an ioxidan phenolic subs ances ( la anols and de i a i es
o ca eic acid), lea oak and lollo osso show high con en s [23].
Nu ien s 2022, 14, x FOR PEER REVIEW 4 o 19
Figu e 3. Chemical s uc u es o es e a ol, p e os ilbene and picea annol.
3. Fac o s ha A ec Phenolic Con en and Composi ion o Foods
The e a e nume ous ac o s ha ha e a clea in luence on he amoun and composi-
ion o phenolic compounds p esen in plan s (Figu e 4). Among hem, he e a e ac o s
in insic o he plan i sel (gene ic o igin) ha lead o in e species di e ences, and a ie-
ies o he same p oduc . Fo ins ance, in he case o he le uce a ie ies, whe eas oma-
nine, baby and icebe g ha e a poo con en o an ioxidan phenolic subs ances ( la anols
and de i a i es o ca eic acid), lea oak and lollo osso show high con en s [23].
Figu e 4. Main ac o s ha a ec phenolic con en and composi ion o oods.
The e a e also ac o s ex insic o he plan , linked o he g owing ci cums ances (ag i-
en i onmen al ac o s) and o he pos -ha es s o age condi ions. Rega ding g owing
condi ions, he p esence o absence o ce ain nu ien s in he soil can a ec he phy o-
chemical composi ion o ui s and ege ables, bo h quali a i ely and quan i a i ely. As
an example, i is known ha he con en o calcium in soil induces phenolic me abolism
and an hocyanin accumula ion in g apes [24]. Bo on a ailabili y also a ec s he phenolic
con en o plan s subs an ially. In ac , his mine al can inc ease he key enzyme phenyl-
alanine ammonia-lyase (PAL), which augmen s he an hocyanin biosyn hesis [25].
Clima e is ano he key aspec , and as a esul , ui s om he same a ie y cul i a ed
in di e en a eas p esen di e en con en s o phenolic compounds. I we ake g apes as
an example, i has been demons a ed ha high empe a u es du ing he g owing s ages
can dec ease an hocyanin syn hesis [26]. Con e sely, he wa e s a us a he lowe ing
s age o he g ape cycle has a posi i e e ec on phenolic compound syn hesis, whe eas
he syn hesis o an hocyanins and phenolic compounds inc eases wi h wa e de ici s du -
ing ma u i y s ages [27].
The in luence o seasonal a ia ions has been s udied in peach. Rahma i e al. (2014)
analysed he changes in peach componen s (ca bohyd a es, o ganic acids and phenolic
compounds) when exposed o long- e m d ough in semi-a id clima e condi ions du ing
Figu e 4. Main ac o s ha a ec phenolic con en and composi ion o oods.
The e a e also ac o s ex insic o he plan , linked o he g owing ci cums ances (ag i-
en i onmen al ac o s) and o he pos -ha es s o age condi ions. Rega ding g owing
condi ions, he p esence o absence o ce ain nu ien s in he soil can a ec he phy o-
chemical composi ion o ui s and ege ables, bo h quali a i ely and quan i a i ely. As an
example, i is known ha he con en o calcium in soil induces phenolic me abolism and
an hocyanin accumula ion in g apes [
24
]. Bo on a ailabili y also a ec s he phenolic con-
en o plan s subs an ially. In ac , his mine al can inc ease he key enzyme phenylalanine
ammonia-lyase (PAL), which augmen s he an hocyanin biosyn hesis [25].
Clima e is ano he key aspec , and as a esul , ui s om he same a ie y cul i a ed
in di e en a eas p esen di e en con en s o phenolic compounds. I we ake g apes as an
example, i has been demons a ed ha high empe a u es du ing he g owing s ages can
dec ease an hocyanin syn hesis [
26
]. Con e sely, he wa e s a us a he lowe ing s age o
he g ape cycle has a posi i e e ec on phenolic compound syn hesis, whe eas he syn hesis
o an hocyanins and phenolic compounds inc eases wi h wa e de ici s du ing ma u i y
s ages [27].
The in luence o seasonal a ia ions has been s udied in peach. Rahma i e al. (2014)
analysed he changes in peach componen s (ca bohyd a es, o ganic acids and phenolic
compounds) when exposed o long- e m d ough in semi-a id clima e condi ions du ing
he sp ing and summe o 2011 in Golmakan (I an) [
28
]. The au ho s epo ed ha phenolic
compound concen a ion (mainly an hocyanin and chlo ogenic acid) inc eased unde
se e e d ough . When hey s udied he e ec o his se e e s ess ea men , hey obse ed
Nu ien s 2022,14, 1925 5 o 19
ha compa ed o low-s ess ea men , he phenolic compound concen a ions inc eased
abou 62–85%.
The e ec o clima e on phenolic compound composi ion in be ies has also been
s udied. González-Domínguez e al. (2020) analysed he chemical p o ile (suga s, o ganic
acids, phenolic compounds and mine al elemen s) o i e di e en a ie ies o s awbe ies
ha we e cul i a ed in wo consecu i e campaigns unde di e en clima ic condi ions [
29
].
They epo ed ha he con en o an hocyanins and he o al amoun o phenolic compounds
we e g ea e unde highe ain all and mo e ex eme empe a u es. Fe ei a e al. (2020)
pe o med a s udy o e alua e he composi ion o h ee Po uguese cul i a s o elde be y
o e he cou se o h ee yea s [
30
]. They obse ed ha he ha es ing yea had a s onge
in luence on he phenolic composi ion and an ioxidan ac i i y han he cul i a one.
They sugges ed ha he clima ic condi ions, especially he wa e s a us, ha dly modi ied
he chemical composi ion o he elde be ies. Rega ding sunligh exposu e, he g ea es
con en o o al la onoids and an hocyanins was ound in ui juices subjec ed o sou he n
exposu e, ollowed by no he n exposu e ui s [31].
Wi h ega d o cul i a ion condi ions, in he s udy p e iously desc ibed, and pub-
lished by González-Domínguez e al. (2020), he au ho s compa ed he composi ion o
s awbe ies g own in wo soilless sys ems: a closed sys em wi h eci cula ion o he
nu ien solu ion and an open sys em wi hou his eci cula ion [
29
]. A e de e mining
he phenolic con en in he ui s, hey only ound sligh di e ences in he concen a ion
o se e al an hocyanins and phenolic acids. Along his line, “Golden Delicious” apples
om o ganic cul i a s showed a g ea e phenolic con en han hose om con en ional
cul i a s [
32
]. I is impo an o men ion a s udy by Mule o e al. (2010), whe e he au ho s
claimed ha signi ican di e ences we e obse ed be ween un ipe o ganic and nono ganic
g ape cul i a s, hough hese di e ences disappea ed when g apes eached he ipening
s age [
33
]. Thus, al hough he a o emen ioned s udies ha e shown ha his ag icul u al
p ac ice could inc ease he amoun o phenols in he cul i a , Win e e al. (2006) did no
ind signi ican di e ences be ween o ganic and con en ional cul i a s [
34
]. Conside ing
ha his is an impo an ac o a ec ing phenolic composi ion, u he esea ch is equi ed.
The ma u i y s age o he di e en ui s and ege ables also exe s a signi ican
in luence on he phy ochemical composi ion. Al hough a gene al pa e n o all p oduc s
has no been ound, in gene al e ms, imma u e ui s show a lowe le el o phenolic
compounds. In a s udy ca ied ou wi h ou blackbe ies cul i a s om he ge mplasm
bank o he Na ional Ins i u e o Ag icul u al Resea ch (INIAP), Qui o (Ecuado ), he o al
con en o polyphenols dec eased du ing he ma u a ion p ocess o he ou blackbe ies
cul i a s. Ne e heless, no all he polyphenols ollowed he same pa e n. Thus, whe eas
he con en o la onoids dec eased wi h he ipening p ocess, he con en o an hocyanins
inc eased [
35
]. In ano he s udy ca ied ou wi h Cucu bi a moscha a Duchesne pumpkin
ha es ed a di e en ipening s ages (young, ma u e, ipened) in Alge ia, he au ho s
epo ed ha he amoun o phenolic acids was dependen on he ma u i y s age. The e o e,
acco ding o he esul s, ca eic acid, cinnamic acid, couma ic acid and dihyd o e ulic acid
inc eased om young o ma u e ui s. Ne e heless, a signi ican dec ease in he le els o
hese molecules occu ed a he end o he ipeness [
36
]. In he same line, couma ic acid
con en signi ican ly inc eased om g een o ma u e s ages in he juice o h ee di e en
pomeg ana e cul i a s o Tu key [37].
In addi ion, changes in he phenolic compound composi ion can also occu du ing
he p ocessing and conse a ion o oods. Conse a ion is gene ally ca ied ou a low
empe a u es, which induces he exp ession o enzymes esponsible o he biosyn hesis o
some phenolic compounds [
38
]. Fo his eason, he con en o some cons i uen s inc eases
occasionally du ing he conse a ion o ce ain ui s and ege ables. On he o he hand,
pos -ha es ea men s wi h ozone o i adia ions wi h UV ligh o gamma adia ion en ail
an inc ease in he biosyn hesis o phy ochemicals in mos cases. Thus, i adia ion wi h UV
ligh induces he accumula ion o es e a ol in g apes [
39
]. O acz e al. (2015) epo ed ha
Nu ien s 2022,14, 1925 6 o 19
echnological p ocesses applied o cocoa beans, including e men a ion, d ying and oas ing,
a ec he inal con en o phenolic compounds, leading o hei decomposi ion [40].
As a consequence o he a iabili y o he phenolic compound p o iles ound in ui s
and ege ables, impo an di e ences in phenolic compound in akes can be obse ed
among subjec s, e en when ollowing a simila die a y pa e n, and hus in he bene icial
e ec s on heal h de i ed om his in ake. This makes i di icul o o e p ecise ecommen-
da ions abou he mos ad isable oods u s aimed a eaching speci ic amoun s o phenolic
compounds. The g ea a iabili y poses an impo an limi a ion in e ms o compa ing he
e ec s o phenolic compound ex ac s and educing he e ec s o hese ex ac s.
4. Fac o s A ec ing Phenolic Compound Bioaccessibili y
Mos phenolic compounds a e glycosyla ed, and he a ached suga moie y is usually
eleased be o e abso p ion. The amoun o phenolic compounds a ailable o abso p ion
a e inges ion can be a ec ed by se e al ac o s, such as he p esence o o he compounds
in he die , such as ib e, lipids, p o eins and diges ible ca bohyd a es (Table 1). Soluble
die a y ib e can p olong gas ic emp ying ime, and hus delay he abso p ion o phenolic
compounds in he small in es ine. Die a y ib e may also educe he a e o he molecules
abso bed, by physically apping he phenolic compound wi hin he ib e ma ix due o he
in e ac ion be ween pola g oups om he phenolic compounds and he ib e polysaccha-
ides [
41
]. Along his line, Tew e al. (1996) obse ed ha a high whea - ib e die p oduced
lowe ed plasma genis ein (55%) 24 h a e ha ing aken a single soy- ich ood, p esumably
due o inc eased iscosi y and hyd ophobic in e ac ions be ween hem [
42
]. Mo eo e ,
Manach e al. (2005) epo ed ha phenolic compound abso p ion di e ed among adul s
a e he same in ake o aglycone equi alen s as a plan ex ac o as a whole ood [9].
Wi h ega d o he die a y lipids, i should be poin ed ou ha al hough he majo i y o
he phenolic compounds a e wa e -soluble, he apola ones, such as cu cumin, es e a ol,
xan hones and some la onoid aglycones, a e micella ised wi h die a y a . Acco dingly,
Guo e al. (2013) epo ed on he bioaccessibili y o que ce in, which p esen s lipophilic
p ope ies, ha i is inc eased a 45% in subjec s who consumed he aglycon supplemen
combined wi h a a - ich (15 g) b eak as , due o enhanced phenolic compound micel-
liza ion and abso p ion in he in es ine [
43
]. Lesse e al. (2004) showed inc eased (57%)
que ce in bioaccessibili y in pigs ed wi h a die ha p o ided 17% a , compa ed wi h
pigs ha ecei ed a die ha p o ided 3% a [
44
]. In he case o es e a ol, con adic-
o y esul s ha e been epo ed. Vaz-da-Sil a e al. (2008) ca ied ou a s udy whe e
subjec s, who ollowed ei he a high- a con en meal o eigh -hou as ing, we e ea ed
wi h
ans- es e a ol
[
45
]. They concluded ha , al hough a la ge in e -indi idual a iabil-
i y in he ans- es e a ol pha macokine ic pa ame e s was obse ed, he amoun o he
phenolic compound abso bed was simila unde bo h eeding condi ions. Con e sely, La
Po e e al. (2010) s udied he pha macokine ics o ans- es e a ol (2000 mg wice daily),
adminis e ed wi h a s anda d o a high- a b eak as o eigh heal hy subjec s, and epo ed
ha he high- a b eak as signi ican ly dec eased he ans- es e a ol abso p ion when
compa ed wi h he s anda d b eak as [46].
Rega ding die a y p o eins, i seems ha hose phenolic compounds ha con ain
a high numbe o hyd oxyl g oups display a s ong a ini y o hese molecules. I has
been sugges ed ha such in e ac ions consis o he o ma ion o hyd ogen bonds and
hyd ophobic ela ions be ween hyd oxyl g oups o he phenolic compounds and he
ca bonyl g oups o he p o eins [
47
]. The p o ein-phenolic compound complex o med
migh educe he abso p ion o he la e [
48
]. Howe e , Lang e al. (2021) in a s udy ca ied
ou in a s, epo ed ha bluebe y an hocyanin abso p ion could inc ease 1.5–10 imes
when adminis e ed in agas ically wi h
α
-casein [
49
]. Mo eo e , o he au ho s epo ed
ha p o ein- ich oods do no ha e an impac on phenolic compound bioaccessibili y.
Consequen ly, i is clea ha his emains a con o e sial issue.
In o he s udies, he au ho s used be e ages ich in p o eins ins ead o isola ed p o eins.
Along his line, D aije e al. (2016) ca ied ou a s udy whe e 35 heal hy males ecei ed a
Nu ien s 2022,14, 1925 7 o 19
g ape ex ac inco po a ed in o a dai y d ink, soy d ink (bo h con aining 3.4% p o eins)
o p o ein- ee d ink. The au ho s epo ed ha he in ake o phenolic compounds in
combina ion wi h hype p o eic d inks had no e ec on he bioa ailabili y o epica echin,
gallic acid, iso hamne in o es e a ol [
50
]. Keogh e al. (2007) s udied he e ec o
milk p o eins on he bioa ailabili y o cocoa phenolic compounds in humans. Fo his
pu pose, 24 subjec s consumed chocola e phenolic compounds wi h o wi hou milk, and
he au ho s epo ed ha p o eins did no modi y he a e age concen a ion o ca echins
and epica echins [
51
]. In he same line, i was epo ed ha he addi ion o milk had no
signi ican e ec on black ea ca echin bioaccessibili y [
52
]. By con as , Se a ini e al. (2009)
obse ed ha he abso p ion o bluebe y phenolic compounds (ca eic and e ulic acid)
was educed when hey we e inges ed wi h milk [
53
]. An impo an limi a ion o hese
s udies is ha , al hough he obse ed e ec could be he esul o an in e ac ion be ween
p o eins and phenolic compounds, he in ol emen o o he milk componen s such as
lipids o ca bohyd a es canno be disca ded.
Phenolic compound abso p ion can also be modi ied by die a y ca bohyd a es.
Sch amm e al. (2003) demons a ed in humans ha die a y ca bohyd a es inc eased
he abso p ion o cacao la anols by 40%, whe eas p o ein o lipid- ich meals did no in-
duce his e ec , pe haps because he glycoside up ake migh be enhanced by he suga s in
he die [
54
]. In his s udy, he au ho s sugges ed ha he inc eased abso p ion o phenolic
compounds, which we e consumed a e a ca bohyd a e- ich meal, could be due o he
in luence o ca bohyd a es on gas oin es inal mo ili y and/o enzyme sec e ion.
Table 1. E ec s o he die mac omolecules on he phenolic compound bioccessibili y.
Food Compound Type o In e ac ion E ec Re e ences
Die a y ib e
P olonga ion o gas ic emp ying (soluble ib es) ↑abso p ion ime [42]
Inc ease in iscosi y (soluble ib es) ↓% abso p ion [9]
Physical apping
Lipids
Micelliza ion o pola phenolic compounds ↑% abso p ion [43,44]
= % abso p ion [45]
↓% abso p ion [46]
P o eins
P o ein-phenolic compound complex o ma ion ↓% abso p ion [53]
↑% abso p ion [49]
= % abso p ion [50–52]
Diges ible ca bohyd a es Abso p ion acili a ion o phenolic compound glycosides
by suga s ↑% abso p ion [54]
Al oge he , hese esul s show he g ea in luence o he die a y pa e n on he bioac-
cessibili y o phenolic compounds. As a consequence, a simila in ake o hese compounds
can lead o impo an di e ences in blood concen a ions, and hus in biological e ec s,
depending on he composi ion o he die , o he ac ha phenolic compounds, p esen in
a nu aceu ical p oduc , a e inges ed in meals o ou o hem.
5. Fac o s A ec ing Phenolic Compound Bioa ailabili y
In addi ion o he ac o s ha a ec phenolic compound bioaccesibili y, and conse-
quen ly bioa ailabili y, he e a e o he elemen s desc ibed in his sec ion ha a ec he la e .
The as majo i y o phenolic compounds a e apidly and ex ensi ely me abolised a e
hei abso p ion (Figu e 5) [
14
]. In gene al, phenolic compounds appea in oods u s in
glycosyla ed o ms, and hey a e hyd olysed o he aglycone o m in he small in es ine by
wo mechanisms [
55
,
56
]. In he i s one, lac ase-phlo izin hyd olase (LPH) deglycosyla es
phenolic g oups, eleasing ee aglycones which a e eady o be abso bed by en e ocy es.
In he second mechanism, glycosides a e ca ied by he sodium-dependen glucose ans-
po e 1 (SGLT1) (Figu e 5) o be u he clea aged by cy osolic
β
-glucosidases [
57
]. Due
o hei as appea ance in plasma, i seems ha a pa o some phenolic compounds such
Nu ien s 2022,14, 1925 8 o 19
as an hocyanins, iso la onoids and phenolic acids, a e abso bed in he s omach, al hough
in es inal abso p ion is conside ed he main one.
Nu ien s 2022, 14, x FOR PEER REVIEW 8 o 19
5. Fac o s A ec ing Phenolic Compound Bioa ailabili y
In addi ion o he ac o s ha a ec phenolic compound bioaccesibili y, and conse-
quen ly bioa ailabili y, he e a e o he elemen s desc ibed in his sec ion ha a ec he
la e . The as majo i y o phenolic compounds a e apidly and ex ensi ely me abolised
a e hei abso p ion (Figu e 5) [14]. In gene al, phenolic compounds appea in oods u s
in glycosyla ed o ms, and hey a e hyd olysed o he aglycone o m in he small in es ine
by wo mechanisms [55,56]. In he i s one, lac ase-phlo izin hyd olase (LPH) deglyco-
syla es phenolic g oups, eleasing ee aglycones which a e eady o be abso bed by en-
e ocy es. In he second mechanism, glycosides a e ca ied by he sodium-dependen glu-
cose anspo e 1 (SGLT1) (Figu e 5) o be u he clea aged by cy osolic β-glucosidases
[57]. Due o hei as appea ance in plasma, i seems ha a pa o some phenolic com-
pounds such as an hocyanins, iso la onoids and phenolic acids, a e abso bed in he s om-
ach, al hough in es inal abso p ion is conside ed he main one.
Figu e 5. Schema ic ep esen a ion o phenolic compound me abolism. PC: phenolic compound;
LPH: lac ase-phlo izin hyd olase; SGLT1: sodium-dependen glucose anspo e 1; UGTs: u idine
5-diphospha e glucu onosyl ans e ases; COMT: me hyla ion by ca echol-O-me hyl ans e ase;
SULTs: sulpho ans e ases.
As p e iously men ioned, phenolic compounds unde go apid me abolism in bo h
en e ocy es and he li e . The cy och ome P450 (CYP) amily o enzymes ca alyse phase-
I eac ions, which include oxida ion, educ ion and hyd olysis [58]. Addi ionally, hey un-
de go ex ensi e phase-II de oxi ica ion eac ions, which include glucu onida ion by u i-
dine 5-diphospha e glucu onosyl ans e ases (UGTs), me hyla ion by ca echol-O-me hyl-
ans e ase (COMT) and sulphu a ion by cy osolic sulpho ans e ases (SULTs). These
phase II me abolic eac ions se e he o ganism o educe hei po en ial oxic e ec and
o acili a e hei bilia y and u ina y exc e ion by inc easing hei hyd ophilici y [59]. Non
abso bed phenolic compounds each he colon, whe e hey a e subjec ed o ex ensi e mi-
c obial me abolism [14,60].
As a esul o me abolism, he amoun s o me aboli es in plasma and issues a e o en
highe han hose o he pa en compounds [61]. Al hough, in gene al, phase II me abo-
lism is conside ed an impo an limi a ion o he use o phenolic compounds as he a-
peu ic ools, i is cu en ly known ha some me aboli es can be ac i e and esponsi e in
pa , o he e ec o he pa en compound [62–70].
Figu e 5.
Schema ic ep esen a ion o phenolic compound me abolism. PC: phenolic compound;
LPH: lac ase-phlo izin hyd olase; SGLT1: sodium-dependen glucose anspo e 1; UGTs: u i-
dine
5-diphospha e
glucu onosyl ans e ases; COMT: me hyla ion by ca echol-O-me hyl ans e ase;
SULTs: sulpho ans e ases.
As p e iously men ioned, phenolic compounds unde go apid me abolism in bo h en e-
ocy es and he li e . The cy och ome P450 (CYP) amily o enzymes ca alyse phase-I eac ions,
which include oxida ion, educ ion and hyd olysis [
58
]. Addi ionally, hey unde go ex ensi e
phase-II de oxi ica ion eac ions, which include glucu onida ion by u idine
5-diphospha e
glucu onosyl ans e ases (UGTs), me hyla ion by ca echol-O-me hyl ans e ase (COMT) and
sulphu a ion by cy osolic sulpho ans e ases (SULTs). These phase II me abolic eac ions
se e he o ganism o educe hei po en ial oxic e ec and o acili a e hei bilia y and u i-
na y exc e ion by inc easing hei hyd ophilici y [
59
]. Non abso bed phenolic compounds
each he colon, whe e hey a e subjec ed o ex ensi e mic obial me abolism [14,60].
As a esul o me abolism, he amoun s o me aboli es in plasma and issues a e o en
highe han hose o he pa en compounds [
61
]. Al hough, in gene al, phase II me abolism
is conside ed an impo an limi a ion o he use o phenolic compounds as he apeu ic
ools, i is cu en ly known ha some me aboli es can be ac i e and esponsi e in pa , o
he e ec o he pa en compound [62–70].
Takingin o accoun ha no allme aboli es canac asac i ecompounds[
64
,
68
,
70
–
72
], in e -
indi idual di e ences in he p oduc ion o phase II me aboli es and mic obial me aboli es
a e o g ea impo ance o assess he e ec i eness o phenolic compounds. Rega ding
his issue, a ia ions in he exp ession o genes coding o he enzymes in ol ed in phase
II me abolism ha e been desc ibed in animals and in humans su e ing some diseases.
Liu e al. (2012) obse ed ha he plasma a ea unde he cu e (AUC) o mangi e in was
signi ican ly highe in diabe ic a s han in he con ol g oup a e a single o al dose o
400 mg/kg [73]. The au ho s measu ed he gene exp ession o he main phase II enzymes
in he li e , and hey obse ed ha he exp ession o Ug 1a3,Ug 1a8,Ug 2b8 and Sul 1a1
was highe in diabe ic a s. By con as , Com ,Ug 2b6,Ug 2b12 and Sul 1c1 mRNA le els
we e lowe .
Dos alek e al. (2011) p o ided e idence ha diabe es in humans signi ican ly educed
he mRNA exp ession, p o ein le el and ac i i y o hepa ic UGT2B7, sugges ing ewe
Nu ien s 2022,14, 1925 9 o 19
glucu onida ion eac ions in he li e o diabe ic pa ien s [
74
]. Mo eo e , Yalcin e al.
(2013) s udied hepa ic sulpho ans e ase exp ession and ac i i y in heal hy subjec s and in
indi iduals diagnosed wi h s ea osis, diabe es, diabe ic ci hosis o alcoholic ci hosis [
75
].
They ound ha he capaci y o SULT1A1 diminished signi ican ly in li e s wi h s ea osis
and in mo e se iously diseased li e issue. This educ ion in SULT1A1 ac i i y could esul
in educed concen a ions o sulpha ed me aboli es and inc eased concen a ions o he
pa en compound. In addi ion, ega ding he iso o m SULT2A1, i s ac i i y was ound o
be signi ican ly dec eased only in he g oup showing ci hosis induced by alcohol, bu no
in s ea o ic o diabe ic ci ho ic li e s when compa ed wi h non- a y con ols.
Wi h e e ence o mic obial me aboli es, he in o ma ion abou hei ac i i y is sca ce .
Ou g oup has demons a ed ha , a physiological concen a ions, dihyd o- es e a ol
is as e ec i e as he pa en compound in p e en ing iglyce ide accumula ion in hep-
a ocy es [
69
]. Mic obial me aboli e p oduc ion can a y depending on he composi ion
o gu mic obio a, ha in u n is modi ied by a g ea numbe o ac o s such as sex, age,
e hnici y, die , physical ac i i y, s ess, d ugs o disease ea men and so on. The in e -
indi idual di e ences in me aboli es p oduced by gu mic obio a a e a e y in e es ing
issue. In his ield o esea ch, special a en ion should be paid o “me abo ypes”. These
a e me abolic pheno ypes iden i ied by he p esence o speci ic me aboli es de i ed om
he ca abolism o phenolic compounds by pa icula gu mic obio a, in e ms o compo-
si ion and unc ionali y. Acco ding o his de ini ion, wo me abo ypes which ha e been
unequi ocally iden i ied ha e been desc ibed: a) equol p oduce s s. equol non-p oduce s
in he me abolism o iso la ones and b) p oduce s o only U o-A (UM-A) s. p oduce s
o U o-A, isou oli hin-A (IsoU o-A) and s. u oli hin-B (U o-B) (UM-B) and s. u oli hin
non-p oduce s (UM-0) in he me abolism o ellagic acid [
76
]. Al hough he exis ence o
me abo ypes o o he phenolic compounds has been p oposed by se e al au ho s, hei
exis ence has no been adequa ely demons a ed.
Conce ning he me abolism o iso la ones, i has been epo ed ha , as opposed o
non-p oduce s, indi iduals who p oduce equol o O-desme hylangolensin as me aboli es
esul ing om daidzein me abolism show he bene icial e ec s on ca diome abolic ma ke s
a ibu ed o daidzein, one o he main phenolic compounds in soy [
77
]. Taking in o accoun
ha he pe cen age o equol p oduce s has been es ima ed o be a ound 30% in Caucasians,
and 50–60% in he Asian popula ion, his me abo ype can pa ly explain di e ences in he
e ec i eness o daidzein desc ibed in se e al s udies [5].
Wi h ega d o he me abolism o ellagi annins, González-Sa ias e al. (2017) epo ed
ha , whe eas he ch onic consump ion o an ellagi annin- ich pomeg ana e ex ac did no
induce bene icial e ec s on blood lipids in a coho o adul o e weigh -obese males and
emales when indi iduals we e dis ibu ed in di e en u oli hin me abo ypes, he subjec s
wi h UM-B me abo ype displayed a signi ican hypolipidemic e ec , as opposed o hose
showing UM-A o UM-0 me abo ypes [
78
]. The same g oup published a u he s udy
demons a ing, o he i s ime, ha indi iduals’ di e en ial capaci y o me abolise ellagic
acid de i a i es in o u oli hins depends mainly on age. In ac , aging leads o a p og essi e
educ ion in UM-A, a me abo ype concomi an wi h an inc ease in UM-B up o 30–40 yea s
o age, a e which he UM dis ibu ion emains cons an [79].
In conclusion, di e ences in he ac i i y o enzymes in ol ed in phase II me abolism,
as well as in mic obio a composi ion and unc ionali y can lead o disc epancies in he a io
o pa en compound/de i ed me aboli es ound in plasma and issues, which in u n can
ha e impo an consequences in e ms o phenolic compound e ec i eness. Mo eo e ,
he me abo ype o which each indi idual belongs de e mines he p esence o absence o
some speci ic me aboli es equi ed o obse e he bene icial e ec s o he pa en compound.
Consequen ly, his is one o he easons ha can help explain in e -indi idual a iabili y in
he esponse o phenolic compound in ake. Un o una ely, he e is no enough knowledge
conce ning he p esence o al e na i e me abo ypes o o he phenolic compounds, as well
as o he dis ibu ion o he me abo ypes acco ding o sex, age and e hnici y, o name bu
a ew. Mo eo e , i should be poin ed ou ha u u e s udies aimed a iden i ying new
Nu ien s 2022,14, 1925 16 o 19
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