Health effects of phloretin: from chemistry to medicine

Abstract

Dihydrochalcones are a class of secondary metabolites, whose demand in biological and pharmacological applications is rapidly growing. Phloretin is one of the best known and abundant dihydrochalcone characterized by the presence of 2,6-dihydroxyacetophenone pharmacophore. It is a versatile molecule with anticancer, antiosteoclastogenic, antifungal, antiviral, anti-inflammatory, antibacterial and estrogenic activities and able to increase the fluidity of biological membranes and penetration of administered drugs. In this review we have performed a critical evaluation of available literature as far as phloretin beneficial effects and activation/block of intracellular signal cascade are of concern. In addition, we supply useful information on its chemical properties, sources and bioavailability.

Full text

Health effects of phloretin: from chemistry to medicine
Sahar Behzad .Antoni Sureda .Davide Barreca .Seyed Fazel Nabavi .
Luca Rastrelli .Seyed Mohammad Nabavi
Received: 9 October 2016 / Accepted: 2 March 2017 / Published online: 7 March 2017
ÓSpringer Science+Business Media Dordrecht 2017
Abstract Dihydrochalcones are a class of secondary
metabolites, whose demand in biological and phar-
macological applications is rapidly growing. Phloretin
is one of the best known and abundant dihydrochal-
cone characterized by the presence of 2,6-dihydrox-
yacetophenone pharmacophore. It is a versatile
molecule with anticancer, antiosteoclastogenic, anti-
fungal, antiviral, anti-inflammatory, antibacterial and
estrogenic activities and able to increase the fluidity of
biological membranes and penetration of administered
drugs. In this review we have performed a critical
evaluation of available literature as far as phloretin
beneficial effects and activation/block of intracellular
signal cascade are of concern. In addition, we supply
useful information on its chemical properties, sources
and bioavailability.
Keywords Anticancer Dihydrochalcones 
Phenolic compound Phloretin
Introduction
Natural products supply inexhaustible sources of
molecules with remarkable biological properties and
functionalities. The properties of these molecules are
tightly related to the basic skeleton and to the presence
of specific substituents, which confer them, just to
mention a few, the ability to interact with macro-
molecules, modulated signal cascade, change perme-
ability and fluidity of membranes. Phloretin and its
derivatives (mainly glycosyl forms) are naturally
occurring dihydrochalcones identified in apple, kum-
quat, pear, strawberry and vegetables (Barreca et al.
2011,2013; Gosch et al. 2009; Hilt et al. 2003a; Tsao
et al. 2003). It is a phenylpropanoid lacking the
heterocyclic C ring and the double bond between aand
bpositions on the three carbon atoms bridge between
homocycles rings A and B. This former makes
phloretin a very flexible molecule, able to bind
S. Behzad
Department of Pharmacognosy, School of Pharmacy,
Shahid Beheshti University of Medical Sciences, Tehran,
Iran
A. Sureda
Grup de Nutricio
´Comunita
`ria i Estre
`s Oxidatiu,
CIBEROBN (Physiopathology of Obesity and Nutrition),
University of Balearic Islands, Palma, Illes Balears, Spain
D. Barreca
Dipartimento di Scienze Chimiche, biologiche,
farmaceutiche ed ambientali, University of Messina, Viale
F. Stagno d’Alcontres 31, 98166 Messina, Italy
S. F. Nabavi S. M. Nabavi (&)
Applied Biotechnology Research Center, Baqiyatallah
University of Medical Sciences,
P.O. Box 19395-5487, Tehran, Iran
e-mail: Nabavi208@gmail.com
L. Rastrelli
Dipartimento di Farmacia, University of Salerno, Via
Giovanni Paolo II, 84084 Fisciano, Italy
123
Phytochem Rev (2017) 16:527–533
DOI 10.1007/s11101-017-9500-x

efficiently with biological macromolecules. These
interactions and block/activation of intracellular sig-
naling pathways result in striking biological properties
(such us antifungal, anticancer, antioxidant, antibac-
terial, antiosteoclastogenic, estrogenic, antiviral, and
anti-inflammatory activities) (Calliste et al. 2000; Kim
et al. 2012;Rajaetal.2003; Stangl et al. 2005; Yang
et al. 2001). Phloretin can be utilized also as a
penetration enhancer of administered drugs. In fact,
after its binding to biological membranes, it increases
their fluidity (Nakamura et al. 2003; Rezk et al. 2002).
Moreover, it modulates Ca
2?
level and down-regu-
lates the secretion of IL-2 of human normal lympho-
cytes and counteracts advanced glycation end
products formation (Calliste et al. 2000; Fordham
et al. 2014; Kim et al. 2012; Nakamura et al. 2003;
Raja et al. 2003; Rezk et al. 2002; Stangl et al. 2005;
Yang et al. 2001). Recently, U
¨llen et al. (2012)
reported its cytoprotective activity in prevention and/
or treatment of acrolein-associated human diseases
and Barreca et al. (2014,2017a,b) described its
antiaggregation potentiality on the protein fibrillation,
neuroprotective properties and antimicrobial activity
against Staphylococcus aureus ATCC 6538, Listeria
monocytogenes ATCC 13932, methicillin-resistant S.
aureus clinical strains and Salmonella typhimurium
ATCC 13311. In particular in Staphylococcus aureus,
it modulates the activities of key enzymes, influencing
the energetic metabolism of the microorganism.
Overall the specific functions and potentialities of this
molecule are being revealed rapidly, especially taking
into account its low toxicity, high antioxidant activity
and potential health-promotion applications.
Chemistry
Dihydrochalcones (1,3-diaryl-2-propen-1-ones) are
phenolic compounds characterized by a flavonoid
skeleton, diphenylpropan (C6-C3-C6), with the
absence of heterocyclic C ring. Indeed, these sec-
ondary metabolites are mainly precursors of flavo-
noids in plants. Phloretin [20,40,60-trihydroxy-3-(4-
hydroxy phenyl)-propiophenone] (Fig. 1), a crys-
talline phenolic ketone and its most abundant glyco-
sylated products, phloridzin (phloretin-20-O-
glucoside) and phloretin-20-O-(20-O-xylosyl) gly-
coside are simple dihydrochalcones. Several other
derivatives such as 3-hydroxyphloretin, sieboldin (3-
hydroxyphloretin-40-O-glucoside), trilobatin (phlore-
tin-40-O-glucoside), phloretin-40-O-galloyl glucoside,
nothofagin (phloretin-30-C-glucoside) and glycy-
phyllin (phloretin-20-O-rhamnoside) have been iso-
lated from natural sources (Gaucher et al. 2013;
Harborne 2013; Iwashina et al. 2012). In phloretin,
two aromatic phenol rings (ring A and B), hydroxyl
groups and a carbonyl group are responsible for a wide
spectrum of pharmacological effects. The antioxidant
pharmacophore of phloretin is 20,60-dihydroxyace-
tophenone, in which the contribution of carbonyl and
OH groups of ring A enhances its activity, whereas, the
substitution of one hydroxyl moiety by a sugar (as in
the case of phloridzin) reduces the activity compared to
phloretin (Bentes et al. 2011; Rezk et al. 2002).
Sources and bioavailability
To date, about 200 dihydrochalcones have been
isolated from more than 300 plant families. Apple tree
(Malus spp.), belonging to the Rosaceae family, is the
predominant source of glycosylated phloretin deriva-
tives and aglycone. However, they are present in
several other genera like Symplocos spp. (Symplo-
caceae) (Polya, 2003), Kalmia spp. (Ma et al. 2016;
Polya 2003), Pieris japonica,Rhododendron spp.
(Ericaceae) (Polya 2003), Linderalucida (Lauraceae),
Fragaria x ananassa (Rosaceae) (Hilt et al. 2003b),
Balanophora spp. (Balanophoraceae) (de Bernonville
et al. 2010), Piper elongatum (Piperaceae), Lithocar-
puspolystachyus (Fagaceae) (Li et al. 2014), Lactuca
sativa (Asteraceae), Corylopsis spp. (Hamameli-
daceae) (Iwashina et al. 2012), Hovenia Lignum (An
et al. 2007), Ziziphus spp. (Rhamnaceae) (Pawlowska
et al. 2009), Smilax glyciphylla (Smilaceae) (Huang
et al. 2013), Fagopyrum esculentum (Polygonaceae)
(Nagatomo et al. 2014) and Aspalathuslinearis
OH
O
OH
HO
OH
Fig. 1 Chemical structure of phloretin
528 Phytochem Rev (2017) 16:527–533
123

(Fabaceae), as reported in Table 1. In Rosaceae family,
Malus domestica L. (apple) and Fragaria x ananassa
Duch. (strawberry) have widespread use in the food
market and are good sources of flavonoids and phenolic
compounds in human diet. Apple is a widely planted
fruit crop in the world and it has an important role in the
daily diet. Profiles of phloretin derivatives can vary
greatly in different parts of apple fruits in faction of the
cultivars. Approximately 838.0, 429.0, 59.0 and
4.1 mg/kg dry weight of phloridzin were reported in
unripe fruit, peel, pulp and apple juice, respectively
(Rana and Bhushan 2015). This content was signifi-
cantly decreased and ranged from *19.0
to *49.0 mg/kg of dry matter in strawberry (Hilt
et al. 2003a). Phloretin has been also isolated from
leaves, barks and roots of the apple trees. In contrast to
dessert fruits (which supply 1.0 mg phloretin starting
from 100 g of product), apple juice and cider would be
the main source of dihydrochalcones intake (which
supply *1.0–5.0 mg phloretin from 250.0 ml). Other
apple products, like jam and jelly, also provide less
than 1.0 mg/100 g. However, variable phloretin con-
tent could be clearly seen in industrial or domestic
apple juice products. In industrial process, whole parts
of fruits are used and oxidative enzymes are inactive
due to high temperature. Active forms of these
enzymes might degrade dihydrochalcones (Toma
´s-
Barbera
´n and Clifford 2000).
The bioavailability of the flavonoid is influenced by
the presence of sugar moieties, molecular weight,
metabolic conversion and gut microflora degradation.
Glycosylated flavonoid with complex skeleton may
have lower absorption (Thilakarathna and Rupasinghe
2013). Glycosides of phloretin are hydrolyzed by
small intestine microbial enzymes (LPH:lactase phlo-
ridzin hydrolase) and cytosolic b-glucosidases in the
enterocytes, producing phloretin aglycone and free
sugars. The reaction of deglycosylation of Phloretin-
20-O-glycoside is much more rapid than that of the
corresponding disaccharide substituents. Metabolic
conversion may occur in intestine or liver. A range of
simple phenols, such as 3-(40-hydroxyphenyl) propi-
onic acid (phloretic acid) and 1,3,5-trihydroxy ben-
zene (phloroglucinol), are generated after degradation
of phloretin by colon microflora. These results are in
agreement with the metabolism of other flavonoids
(Borges et al. 2013; Spencer and Crozier 2012;
Toma
´s-Barbera
´n and Clifford 2000).
Several studies have showed that after oral inges-
tion of phloretin, in the form of aglycone or as the
glycoside substutuents, it has been quickly absorbed in
the intestine and appeared in the plasma. Some
unconjugated forms, glucoronide and sulphurated
metabolites of phloretin could be also identified in
the plasma. At the first 10 h of oral consumption of
phloretin compounds, there is no significant difference
in plasma level of total phloretin, but it changes,
tending to go back to baseline, after 24 h due to urine
excretion (Crespy et al. 2001; Spencer and Crozier
2012).
Health effects of phloretin
In the past years, attentions have been focused on
flavonoids, indicating that they are a functionalized
chemical group of compounds with many biological
activities. The use of these compounds can be a
pharmacological strategy for different pathologies. As
other flavonoids, phloretin has been described to
display, among others, antioxidant, anti-inflammatory
and anticarcinogenic activities.
It is known that the action of endogenous antiox-
idant defense systems is completed together with
Table 1 Plants in which has been identified phloretin or its
glycosylated derivatives
Species Family
Malus spp. Rosaceae
Fragaria x ananassa Rosaceae
Symplocos spp. Symplocaceae
Kalmia spp. Ericaceae
Pieris japonica Ericaceae
Rhododendron spp. Ericaceae
Lindera lucida Lauraceae
Balanophora spp. Balanophoraceae
Piper elongatum Piperaceae
Lithocarpus polystachyus Fagaceae
Lactuca sativa Asteraceae
Corylopsis spp. Hamamelidaceae
Hovenia Lignum Rhamnaceae
Ziziphus spp. Rhamnaceae
Smilax glyciphylla Smilaceae
Fagopyrum esculentum Polygonaceae
Aspalathus linearis Fabaceae
Phytochem Rev (2017) 16:527–533 529
123

exogenous antioxidants, such as polyphenols, to
suppress oxidative stress. The antioxidant effects
induced by phloretin not only correlate with the
presence of hydroxyl moieties in its chemical struc-
ture, but it is also influenced by the presence of a
carbonyl group (Bors et al. 1990; Rezk et al. 2002).
Discrepancies in the obtained results are due to the use
of different concentrations of this flavonoid or to the
conditions applied. Many works have reported the
capacity of phloretin to scavenge different reactive
oxygen species (ROS), including peroxynitrite (Bors
et al. 1990), hydroxyl radical (Rezk et al. 2002)or
superoxide anion (Leu et al. 2006). Other works have
also described the capacity of phloretin to reduce the
lipid peroxidation caused by different agents (Liu et al.
2015; Nakamura et al. 2003; Ratty and Das 1988; Ren
et al. 2016; Zhu et al. 2009). Phloretin is also able to
activate transcription factors, inducing the expression
of antioxidant genes and improving enzymatic antiox-
idant defense system, through complex mechanisms
almost completely unknown (Fig. 2). Phloretin has
been described to increase the superoxide dismutase
(SOD) and glutathione peroxidase (GPx) activities in a
concentration-dependent manner (Liu et al. 2015; Ren
et al. 2016). Contrary to the above results, Galati and
collaborators (Galati et al. 2002) described a proox-
idative capacity of phloretin in hepatocytes of rats,
although this result could be related to the activation of
some transcription factors related with the anti-
tumoral activity of the flavonoid. Phloretin also
promotes the synthesis of non-enzymatic antioxidant
defenses, such as the reduced glutathione (GSH),
which is usually used as a marker of oxidative stress.
Moreover, some other works have also described the
ability of the above mention flavonoid to avoid GSH
depletion, such as in cortical brain of rats (Liu et al.
2015) or in keratinocytes (Shin et al. 2014).
Phloretin has anti-inflammatory effects, modulat-
ing the immune cell activity. The compound inhibits
the expression and secretion of diverse pro-inflamma-
tory agents including cytokines, such as IL-6, IL-8 and
TNF-a, chemokines and adhesion molecules (Huang
et al. 2015; Jung et al. 2009; Van Raemdonck et al.
2015). In addition, phloretin treatment decreases the
expression of other pro-inflammatory proteins such as
cyclooxigenase-2 (COX-2) and the inducible isoforms
of the nitric oxide synthase (iNOS) (Chang et al.
2012). In this way, phloretin treatment decreases the
synthesis of nitric oxide and prostaglandin E
2
(PGE
2
).
The mechanism of action seems to be related to the
Phloretin
Antioxidant
activity
Scavenger of ROS
Decrease level of:
Superoxide anion
Peroxynitrite
Hydroxyl radical
Increase level of :
Reduced
glutathione
Activation of
gene
transrtiption
involved in
antioxidant
system
Activator of
SOD and
GPx
activities
Reducer of lipid
peroxidation
Anti-inflammatory
activity
Decrease
level of :
Cytokines
Chemokines
Adhesion
molecules
Decrease expression
of COX-2 and iNOS
Suppression of NF-κβ
transcription
Reduction of
prostaglandin E2and
Nitric oxide level
Effect on cancer
cells
Cytotoxic and
Apoptotic activity
Up-regulation
of perforin or
granzyme B
Release of
Cytocrome C
Activation of :
Caspase 9,
Caspase 3,
PARP, Bax
Up-regulation
of p53
Decrease of
Bcl-2
Activation of
immune cells
against tumor
Fig. 2 Schematic representation of phloretin’s cellular effects and of its block/activation of protein activities and transcription factors
530 Phytochem Rev (2017) 16:527–533
123

suppression of the NF-jb transcription factor activa-
tion, a master regulator of the inflammatory process in
mammalian cells, through a mechanism involving
extracellular signal-regulated kinase 1/2 (ERK1/2),
p38 mitogen-activated protein kinase (p38 MAPK),
and c-Jun N-terminal kinase (JNK) (Gambhir et al.
2015; Hoesel and Schmid 2013). Several studies
evidenced a significant attenuation in the inflamma-
tory response induced by LPS, IL-1aor TNF-aby
phloretin treatment (Fordham et al. 2014). Related to
the phloretin anti-inflammatory effects, an inhibitory
activity against immunoglobulin E (IgE)-mediated
allergic responses has been evidenced (Chung et al.
2013).
Another important effect of phloretin is the asso-
ciation to the protective effects against tumor growing,
triggering cell death in malignant cells by either direct
or indirect mechanisms (de Oliveira 2016). Different
authors have investigated the capacity of phloretin to
potentiate the activity of immune cells against tumor
cells favoring cellular proliferation and differentiation
and enhancing the cytotoxic activity up-regulating
proteins such as perforin or granzyme B (Nusse and
Varmus 1992; Zhu et al. 2013). In other studies the
treatment of cancer cells with phloretin significantly
has suppressed the growth of these cancer cells. The
mechanisms of action of phloretin is related to the
increase of apoptotic rates (evidenced by cytochrome
c release in the cytosol), the activation of caspase-9
and caspase-3, the increase of poly (ADP-ribose)
polymerase (PARP) cleavage and Bax levels, the up-
regulation of P53, and the decrease of Bcl-2 amount
(Fig. 2), leading to DNA fragmentation and cell death
(Kim et al. 2009; Park et al. 2007; Yang et al. 2009). It
has been proposed that phloretin pro-apoptotic activity
could be mediated through the production of ROS and
the inhibition of glucose transporter 2 (GLUT2)
interfering with glucose uptake (Liu et al. 2016). This
is a well known role of phloretin; in fact, its naturally
occurring glucoside (phlorizin) and, to a lesser extent,
phloretin, for instance, have been an essential model to
reveal the role of sodium glucose co-transporter type 2
(SGLT2) inhibition in the treatment of hyperglycemia
(Bays 2013). This property has been confirmed also by
animal studies, affected by hyperglycemia and insulin
resistance. In fact, phlorizin is a competitive inhibitor
of both SGLT1 and SGLT2. The low selectivity for
SGLT2 versus SGLT1 is one of the reasons for its
unsuitable use for treatment of hyperglycemia.
Actually, researchers try to develop phlorizin deriva-
tives with more stability, higher bioavailability and
selectivity towards SGLT2 to overcome these prob-
lems (Bays 2013).
Finally, it is also important to note that phloretin has
been suggested to exert other activities including the
suppression of biofilm formation (Lee et al. 2011), the
modulation of lipid metabolism and adipocytes
metabolism, all element that open a potential use in
the treatment of obesity or insulin resistance (Hassan
et al. 2007; Shu et al. 2014), or in the regulation of
bone dynamics, increasing bone mineral density and
content (Feng 2005; Lee et al. 2014).
Conclusion and recommendations
In the last two decades, a great deal of attentions has
been focused on diet as source of nutraceuticals. The
useful and interesting biological activities of phloretin
make it a reference point as far asthe potentiality to exert
health promoting properties on human organism are of
concern. In particular, just to mention a few, the abilities
to modulate signal cascade and the energy metabolism,
to avoid the depletion of intracellular antioxidant system
and the growth of some cancer cell typologies have
attracted the attention of researchers to produce new
compounds with specific therapeutic targets, due to
phloretin remarkable involvement in organism wellness
and the almost completely absence of toxicity. Never-
theless, the in vivo studies focusing on its effects are
scarce and further studies are needed to better under-
stand its activities on human organisms and to promote
its development, as well as its use as nutraceutical in
food supplements and pharceutical products, which can
increase the potentiality of the administered drug and
decrease their potential side effects.
Acknowledgements A. Sureda was supported by the Spanish
Ministry of Health, Social Services and Equality (CIBEROBN -
CB12/03/30038).
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