Life Sciences 113 (2014) 16

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Life Sciences
journal homepage: www.elsevier.com/locate/lifescie

Review Article

Neuropharmacological properties and pharmacokinetics of the citrus

avonoids hesperidin and hesperetin A mini-review
Ali Roohbakhsh a, Hamideh Parhiz a,b, Fatemeh Soltani b,c, Ramin Rezaee a, Mehrdad Iranshahi c,
a
b
c

Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Biotechnology Research Center and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

a r t i c l e

i n f o

Article history:
Received 17 April 2014
Accepted 21 July 2014
Available online 7 August 2014
Keywords:
Flavonoid
Anti-nociceptive
Aliskiren
Cytochrome P450
Bioavailability
Fexofenadine

a b s t r a c t
Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two avonoids from citrus species that have various biological properties. Over the past decade, a large number of papers have been published regarding the biological
activities of these compounds and their molecular mechanisms. In this paper, we reviewed the neuropharmacology of Hsd and Hst as a recently emerged topic that has not been addressed in the past. Some of molecular targets
and signaling pathways for neuropharmacological effects of Hst and Hsd, including antidepressant, neuroprotective and the effects of Hsd/Hst on memory, have also been included in the review. We also discussed the mechanisms of actions for antidepressant activities of Hsd and Hst. In addition, pharmacokinetics of Hsd and Hst, their
interaction with some drugs such as atenolol, diltiazem, felodipine and verapamil, as well as related underlying
mechanisms have been discussed.
2014 Elsevier Inc. All rights reserved.

Contents
Introduction . . . . . . . . . . . . . . . . . .
Neuropharmacology of Hsd/Hst . . . . . . . . .
Neuroprotective effects . . . . . . . . . . .
Anxiolytic, sedative and anticonvulsant effects
Antinociceptive properties . . . . . . . . .
Antidepressant effects . . . . . . . . . . .
The effects on learning and memory . . . . .
Pharmacokinetics of Hst/Hsd . . . . . . . . . .
Conclusions and future perspectives . . . . . . .
Conict of interest . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . .

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Introduction
Flavonoids are a large group of phenolic compounds that are widely
distributed in plants. To date, a large number of these compounds have
been evaluated both in their free state and as glycosides. In addition to
this work, several biological properties have been reported from avonoids, including antioxidant, anticancer, cancer chemopreventive, and
Corresponding author. Tel.: +98 511 8823255; fax: +98 511 8823251.
E-mail address: Iranshahim@mums.ac.ir (M. Iranshahi).

http://dx.doi.org/10.1016/j.lfs.2014.07.029
0024-3205/ 2014 Elsevier Inc. All rights reserved.

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1
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5

anti-inammatory properties (Harborne and Williams, 2000; Pietta,

2000). Hesperidin (Hsd) is a avanone glycoside (a subclass of avonoids) that is found abundantly in citrus fruits. Its aglycone form is
called hesperetin (Hst). Hsd was rst isolated from citrus peel by the
French chemist Lebreton (Garg et al., 2001). Because of its various
biological activities, Hsd is also called a bioavonoid. Hsd is a -7rutinoside of Hst because it consists of an aglycone, Hst, and a disaccharide, rutinose (Fig. 1).
Both Hsd and its aglycone Hst have shown various biological activities (Garg et al., 2001). For example, Hsd possesses vitamin-like activity

A. Roohbakhsh et al. / Life Sciences 113 (2014) 16

Fig. 1. The chemical structures of hesperidin and hesperetin.

and can decrease capillary permeability (vitamin P), leakiness and fragility. It also showed antioxidant, anti-inammatory, anticarcinogenic
and antiallergic properties (Garg et al., 2001). The biological activities
of Hsd together with its physicochemical properties were reviewed in
a paper published by Garg et al., 2001. However, a large number of studies have been published since then describing its new pharmacological
activities, molecular targets and mechanisms of action. For example, the
effects of Hsd on the central nervous system have been a topic of research during the past decade, while they have not previously been investigated (Filho et al., 2013; Souza et al., 2013). New ndings also
revealed that the antioxidant activity of Hsd was not only limited to
its radical scavenging activity, but it augmented the antioxidant cellular
defenses via the ERK/Nrf2 signaling pathway as well (Chen et al., 2010;
Elavarasan et al., 2012). Recent studies showed that avonoids including Hsd and Hst enhanced learning and memory through various mechanisms such as elevating brain-derived neurotrophic factor (BDNF) and
reversing the disruptive effect of global cerebral I/R on memory (Gaur
and Kumar, 2010; Oztanir et al., in press). Hsd and Hst also showed antidepressant activities via mechanisms that, some of them, differ from
those of conventional antidepressant drugs (Donato et al., 2014).
This review addresses neuropharmacological properties of Hsd and
Hst that have been reported since 2001. Additionally, the current
paper provides a deeper insight into the mechanisms of action and molecular targets of Hsd and Hst and shows the gaps in our knowledge
about Hsd, which deserve further research.
All of the relevant databases were searched for the terms hesperidin, hesperetin and citrus avonoid without limitation from 2001
to 30th July 2014. Information on Hsd and Hst was collected via
electronic search by using Pubmed, Scopus, Web of Science and
ScienceDirect.
Neuropharmacology of Hsd/Hst
Neuroprotective effects
The ability of Hst and Hsd to cross the blood brain barrier has been
revealed (Dimpfel, 2006) and makes them ideal natural candidates in
the treatment of different CNS disorders. Therefore, the effects of both
compounds on the central nervous system have been the subject of
some previous studies. In general, studies showed that lower intake of
some avonoids may enhance the risk of Parkinson's disease in
human subjects (Gao et al., 2012). In addition, lower level of avonoids
has been connected to dementia. It was reported that one-fourth of patients with Alzheimer's disease had avonoid deciency (Gil Gregorio
et al., 2003).
The citrus avanones, Hsd, Hst, and neohesperidin, showed a neuroprotective effect and protected PC-12 cells against H2O2-induced cytotoxicity, likely by its radical scavenging property and via the attenuation of
the calcium level and also the caspase-3 activity (Hwang and Yen, 2008).
The Huang group's ndings revealed that Hsd and Hst could inhibit
amyloid -induced autophagy and improve glucose utilization in
Neuro-2A cells. This phenomenon is useful to prevent Alzheimer's disease through controlling the glucose metabolism in neuronal cells

(Huang et al., 2012). Previous studies showed that Hsd has neuroprotective effects both in vitro and in vivo. For example, it had neuroprotective effects on amyloid (Huang et al., 2012), 3-nitropropionic acidinduced (Menze et al., 2012) and H2O2-induced (Choi and Ahn, 2008)
neurotoxicity. However, it has been reported that Hst is more effective
than Hsd in preventing neurons from excitotoxic neuronal damage in
primary cultured rat cortical cells (Cho, 2006). The neuroprotective
effect of Hsd is mainly mediated by its antioxidant and antiinammatory activities (Menze et al., 2012). However, other biological
effects, such as the attenuation of caspase-3 activity, calcium ion regulation (Choi and Ahn, 2008), the improvement of neuronal energy metabolism (Huang et al., 2012) and reversing mitochondrial dysfunction
(Wang et al., 2013), have also been attributed to its neuroprotective effects. These avonoids may also have benecial effects on nervous system by the inhibition of nitrosative stress and nitrergic pathway. It has
been reported that lipopolysaccharide could increase serum level of nitrite up to 10 fold that was reversed by the administration of Hsd (Kaur
et al., 2006). Such results were conrmed by Viswanatha et al. (2012).
They showed that L-NAME as a nitric oxide synthase inhibitor, potentiated the protective effect of Hsd against acute immobilization-stressinduced anxiety-like behavior and mitochondrial dysfunction.
Based on the above evidence, one can assume that these compounds
possibly improve neuronal survival. In line with this hypothesis, Nones
et al. (2012a) showed that Hsd promotes neuronal crest survival without affecting the cell differentiation and proliferation. They also showed
that Hsd, through the activation of the PI3 and MAP kinase pathways,
protects neurons from death (Nones, 2011). At the same time, Hsd increases the neuronal population by neuronal progenitors via astrocytes
(Nones et al., 2012b). This latter effect is suggested for a new therapeutic strategy in the treatment of neurodegenerative diseases. The benecial effect of Hsd in the treatment of Huntington's disease as a
neurodegenerative illness in animals (Menze et al., 2012) further supports this idea.
In addition, Hsd and Hst augmented cellular antioxidant defense capacity through the induction of HO-1 (hemoxygenase-1) via ERK/Nrf2
signaling. This induction could also enhance the level of antioxidant enzymes, such as CAT, SOD, and GST (Chen et al., 2010). Therefore, Hsd
and Hst attenuate cell damage by augmenting cellular defenses. This
mechanism of action should also be considered for neuroprotective effects of Hst and Hsd (Fig. 2). Considering this opinion, the benecial actions of Hsd in an animal model of Parkinson's disease have been
attributed to this mechanism of action (Antunes et al., 2014). Administration of 6-hydroxydopamine (6-OHDA) into the striatum produced
motor and cognitive decits in aged mice that were improved following
the administration of Hsd. Hsd also attenuated the 6-OHDA-induced reduction in glutathione peroxidase and CAT activity, total reactive antioxidant potential and declined in dopamine and its metabolite levels
in the striatum (Antunes et al., 2014). The potential application of Hsd
in the treatment of Parkinson's disease was investigated against
rotenone-induced apoptosis in human neuroblastoma SK-N-SH cells.
Rotenone disrupted mitochondrial membrane potential, increased reactive oxygen species generation, depleted glutathione, enhanced activities of enzymatic antioxidants, up-regulated Bax, cytochrome c, and
caspases 3 and 9, and down-regulated Bcl-2 protein expression. The results showed that all these changes were attenuated in the presence of
Hsd (Tamilselvam et al., 2013). The neuroprotective effect of Hsd may
also be helpful in diabetes. Neuropathy is a common complication of diabetes. In a recent study, Hsd could reverse the decreased nociceptive
threshold, sensory nerve conduction velocity and motor nerve conduction velocity along with pro-inammatory cytokines such as TNF- and
IL-1 in diabetic rats (Visnagri et al., 2014).
Anxiolytic, sedative and anticonvulsant effects
The sedative effect of Hsd has been revealed in different studies
(Guzmn-Gutirrez and Navarrete, 2009; Loscalzo et al., 2008; Marder

A. Roohbakhsh et al. / Life Sciences 113 (2014) 16

Small intestine
Hst and Hst-7-glucoside are directly absorbed

Blood
Circulation

Hsd

Hst
Mircoflora

Liver

Hst

Hst glucuronide/sulfate metabolites

Fig. 2. An overview on hesperidin and hesperetin pharmacokinetics.

et al., 2003; Martinez et al., 2009; Wasowski et al., 2012). Moreover, a

synergistic interaction between Hsd and diazepam (Fernandez et al.,
2005) also implies that there are sedative effects. However, the central
depressant effects of Hsd could be dependent on the route of administration because it has been reported to be a sedative and anxiolytic following intraperitoneal and oral administration, respectively (Wasowski
et al., 2012). The anxiolytic effect of Hsd following oral administration
has also been reported in a recent study (Viswanatha et al., 2012). In
that study, Hsd attenuated immobilization-induced anxiety-like behaviors in the elevated plus-maze and mirror chamber tests of anxiety.
Marder et al. (2003) showed that the 2S form of Hsd is the CNS active
isomer that exists in Valeriana ofcinalis L., resulting in its sedative effects. They concluded that the failure in the discovery of the sedative effects of Hsd is related to the racemic nature of the mixture that is usually
provided by the citrus industry. However, their conclusion is in contrast
to the results of Guzmn-Gutirrez and Navarrete (2009), who showed
that the methanolic extract of Citrus sinensis owers has sedative properties and Hsd is its active principal sedative compound. The sedative
mechanism of Hsd has also been explored. Marder and co-workers,
using binding studies, showed that Hsd is not a ligand for benzodiazepine, serotonin (5-HT1A, 5-HT2), glutamate (AMPA) and adenosine
(A1) receptors. In addition, the sedative effect of Hsd is possibly not mediated by adrenergic (2, ), dopaminergic (D2) (Guzmn-Gutirrez
and Navarrete, 2009) or GABAergic (GABAA) (Fernndez et al., 2006) receptors and is A1 adenosine (despite Marder study) and opioid-receptor
dependent (Guzmn-Gutirrez and Navarrete, 2009; Loscalzo et al.,
2008). Regarding the central depressant effects of Hsd and Hst, similar
to many classical antiepileptic drugs, these compounds might have
anti-seizure effects.
In line with this hypothesis, Kumar and co-workers showed that Hsd
has anti-seizure effects in pentylenetetrazole (PTZ)-induced chemical
kindling. In this model, repeated administration of subconvulsive
doses of PTZ results in convulsion. Hsd increased glutathione, SOD,
CAT and mitochondrial complex (I, II, and IV) activities, and decreased
MDA and nitrite level in comparison with respective control group
(PTZ). The researchers also showed that the anticonvulsant effect of
Hsd is mediated by nitric oxide pathway (Gaur and Kumar, 2010).

Such results have also obtained following acute administration of PTZ

at the doses higher than those needed for kindling (Kumar et al.,
2014). Moreover, co-administration of low dose of Hsd with diazepam
or gabapentine, potentiated the neuroprotective effects of these drugs
(Kumar et al., 2014).
It should be pointed out, however, that both Hsd and Hst possessed
anticonvulsant effects with distinct modes of action (Dimpfel, 2006).
Antinociceptive properties
The deciency of Hsd in the diet has been linked to pain perception
in the extremities (Loscalzo et al., 2011). Thus, Hsd can be suggested as a
natural pain killer. Previous reports showed that this compound is effective in animal models of pain. In mouse writhing and hot plate tests, Hsd
caused antinociception after intraperitoneal administration and not
after oral administration (Loscalzo et al., 2011). These authors showed
that the antinociceptive effect is partially mediated by opioid receptors, while and opioid receptors are not involved. However, they
further showed that Hsd, despite its aglycone Hst, was not a ligand for
receptors (Loscalzo et al., 2011). It has been reported that coadministration of alprazolam (a benzodiazepine drug) and Hsd potentiates its antinociceptive effect (Loscalzo et al., 2008). Another study
showed an antinociceptive effect for Hsd in an arthritic gout-type pain
(Martinez et al., 2011). This effect was partially induced by TRPV1 receptors, which are new targets in the development of antinociceptive
and anxiolytic drugs (Hakimizadeh et al., 2012). The most famous natural ligand for TRPV1 receptors with analgesic effects is capsaicin, which
is a pungent component of hot chili peppers.
Antidepressant effects
The antidepressant-like effect of Hsd has been reported in both
swim and tail suspension tests of depression (Souza et al., 2013). Furthermore, Hsd could decrease depressive-like behaviors in tail suspension test exhibited by intra-striatal injection of 6-OHDA in an animal
model of Parkinson's disease (Antunes et al., 2014). Souza et al. showed
in their study that Hsd has an antidepressant-like effect that is mediated
by the serotonergic system mainly by the activation of 5-HT1A receptors.
In addition, but not opioid receptors participated in antidepressantlike effects of Hsd (Filho et al., 2013). Both ndings are in contrast to
previous reports that rule out the involvement of serotonin and opioid
receptors in the sedative and antinociceptive effects of Hsd (Fernndez
et al., 2006; Loscalzo et al., 2011). The involvement of serotonin in the
pharmacological effects of Hsd has also been reported outside the
CNS; Hsd suppressed the 5-HT-induced delayed gastric emptying,
being similar to ondansetron as a selective 5-TH3 receptor antagonist
(Tominaga et al., 2011). Therefore, we can suggest that Hsd is similar
to ondansetron and possibly has central anti-nausea and antivomiting effects through the inhibition of 5-HT3 receptors. Furthermore,
Hsd has antagonistic effects on 5-HT2B receptors (Takeda et al., 2008).
All of these ndings show that the effects of Hsd on the serotonergic system require further evaluation.
New ndings showed that the antidepressant effect of Hsd is a dependent NO/cGMP pathway (Donato et al., 2014). This nding is
based on the inhibitory effect of nitric oxide donor (L-arginine) and
phosphodiesterase 5 inhibitor (sildenal) on antidepressant-like effect
of Hsd in tail suspension test and the reduction of nitrate/nitrite levels
in the hippocampus of Hsd-treated mice. Interestingly, for the rst
time, the aforementioned study also evaluated the effect of Hsd on
BDNF as an important player in pathophysiology of depression
(Donato et al., 2014). The results showed that Hsd increased the BDNF
level in the hippocampus of mice (Donato et al., 2014). In this regard,
previous studies showed that the blood level of BDNF in patients with
major depressive disorder is lower than that of normal (Dwivedi,
2013). This nding also implies that avonoids with antidepressant-

A. Roohbakhsh et al. / Life Sciences 113 (2014) 16

like effects may have targets other than classical neurotransmitters involved in the depressive disorders.
The effects on learning and memory
The direct effects of Hsd/Hst on learning and memory have not been
evaluated yet. But there are evidences showing that these compounds
may have benecial effects on cognitive function.
Repeated administration of subconvulsive doses of PTZ induces seizure in rodents which is usually with impairment in memory function.
It is reported that Hsd is able to delay the impairment exhibited by
chronic administration of PTZ in passive avoidance learning paradigm
in mice (Kumar et al., 2013). Intra-striatum injection of 6-OHDA is a
valid animal model for Parkinson's disease. It selectively destroys dopaminergic neurons especially in the nigrostriatal pathway by induction of
oxidative stress and apoptosis and results in apparent motor and cognitive impairment. A recent study showed that Hsd reversed the memory
impairment of the rats in this model by dopamine and antioxidant enhancement (Antunes et al., 2014). Global cerebral I/R due to deteriative
effects on brain regions especially those involved in cognition, may disrupt learning and memory. A study showed that Hsd is able to reverse
the disruptive effect of global cerebral I/R on memory in rats (Gaur
and Kumar, 2010).
The memory-enhancing effect of Hsd/Hst may be explained by the
following mechanisms: As discussed previously, Hsd is able to increase
BDNF level in the hippocampus (Donato et al., 2014). Previous studies
have shown that BDNF receptor antagonists may disrupt learning
(Akhavan et al., 2013; Callaghan and Kelly, 2013). So, it is suggested
that a part of memory enhancing effect of Hsd may be mediated by increasing in BDNF levels. In addition, Hst is capable of activating ERK1/
2 signaling in cortical neurons (Vauzour et al., 2007). Activation of this
signaling pathway results in the activation of the cAMP response element binding protein that is responsible for increasing the expression
of a number of neurotrophins involved in dening memory (Xia and
Storm, 2012).
Pharmacokinetics of Hst/Hsd
Bioavailability is a key step in ensuring the bioefcacy of Hsd. Studies
showed that Hsd had limited bioavailability and required deglycosylation to be absorbed in the colon or intestine (Fig. 3). Hsd is converted
to Hst by the microora of the colon, and then, it is absorbed by
colonocytes via proton-coupled active transport and transcellular passive diffusion (colon). On the other hand, Hst and Hst 7-glucoside are directly absorbed by enterocytes (intestine) (Manach et al., 2003; Nielsen
et al., 2006). These ndings were supported by animal studies in rats
and clinical trials in healthy volunteers (Kanaze et al., 2007; Li et al.,
2008; Matsumoto et al., 2004; Yamada et al., 2006). According to
those investigations, the presence of the rutinoside moiety of Hsd led
to the poor bioavailability of Hsd, and the removal of either rutinoside

or rhamnose from Hsd to yield Hst (or Hst 7-glucoside) improved its
bioavailability (Londono-Londono et al., 2010). It should be noted, however, that Hst and Hst 7-glucoside not only had a better bioavailability
than that of Hsd but also had a much earlier tmax (0.6 h vs. 7 h), which
suggests that the site of absorption altered from the colon to the small
intestine. In addition, studies showed that, among the enantiomers of
Hst, R-(+)-Hst had higher plasma concentrations than S-()-Hst (the
natural form of Hst) following oral administration (Yanez et al., 2008).
The bioavailability of Hsd is affected by different physiological conditions. For example, Silberberg et al. (2006) showed that the bioavailability of avanones, including Hsd and naringin, was less in tumor-bearing
rats compared with healthy (Sham-operated) rats. In contrast, the conjugation of Hst was increased in tumor-bearing rats. However, the exact
reasons for the difference between the bioavailability of Hst in healthy
and tumor-bearing rats were not claried in the paper. In another
study, it was revealed that the co-administration of Hst with other avonoids, including quercetin, rutin, daidzein, and chrysin, increased
the bioavailability of Hst (Brand et al., 2010b). The possible underlying
mechanism of this increase could be related to the inhibition of phase
II metabolism (glucuronidation and sulfation of Hst) of Hst by other avonoids. However, it should be noted that this study was conducted on
the Caco-2 cell monolayer model and has not been conrmed by in vivo
or clinical studies (Brand et al., 2010b).
Considering the potential use of Hst for the treatment of diabetic retinopathy and macular edema, some investigations were undertaken to
clarify the pharmacokinetics of Hst in different parts of the eye. Briey,
Hsd, Hst and G-Hsd (containing an additional glucose attached to
rutinose) had poor permeability across the blood-retinal barrier, and
very small quantities of Hst reached the retina (Srirangam et al.,
2012a,b). The possible routes for the administration of suitable Hsd/
Hst concentrations in the retina include the invasive technique of intravitreal injection. On the other hand, Hst is capable of asymmetrical permeating (permeability of Hst from apical to basolateral is lower than in
the reverse direction) across the corneal tissue (Srirangam and
Majumdar, 2010). However, there is a need for further investigation to
prepare ophthalmic formulations.
Hst is an inhibitor of cytochrome P450 CYP1A and CYP1B1 (Doostdar
et al., 2000). This compound is a selective inhibitor of CYP1B1 at concentrations that are below 0.04 M. With respect to the possible role of
human CYP1B1 in activating carcinogens and the selectivity of Hst as
an inhibitor of this enzyme, this dietary compound might be protective
against certain cancers. In addition, the inhibition of cytochrome P450
by Hsd reduces the rst-pass metabolism of some drugs, such as diltiazem. Cho et al. (2009a) showed that Hsd enhanced the oral bioavailability of diltiazem in rats. They also showed that Hsd increased the
bioavailability of diltiazem via the inhibition of CYP3A4, the other isoform of cytochrome P450, as well as P-gp. The suggested mechanism
of Hsd for enhancing the bioavailability of diltiazem via P-gp efux inhibition was also in agreement with the results in which Hsd enhanced
the bioavailability of verapamil and vincristine (Mitsunaga et al., 2000;

5-HT1A
receptor

Nrf2/ERK1/2

Anti-depressant

Neuroprotective
BDNF

PI3/MAP
kinase

NO/cGMP
pathway

NO/cGMP
pathway
Sedative and
Anticonvulsant

TRPV1
Antinociceptive

Fig. 3. An overview on the targets of hesperetin for its neuropharmacological effects. It should be pointed out that neuroprotective effects of hesperidin and hesperetin were also exerted
via their direct radical scavenging and antioxidant activities.

A. Roohbakhsh et al. / Life Sciences 113 (2014) 16

Table 1
A tabulated overview of the pharmacokinetic interaction between Hsd/Hst and drugs.
Drug

Class

Interaction

Underlying mechanism

Ref.

Aliskiren

Renin inhibitor, antihypertensive

Absorption

Bailey et al. (2007)

Atenolol
Celiprolol

Beta blocker, antihypertensive

Beta blocker, antihypertensive

Absorption
Absorption

The inhibition of organic anion

transporting polypeptide (OATP2B1)
The inhibition of OATP2B1
The inhibition of OATP2B1

Diltiazem

Bioavailability

The inhibition of CYP3A4

Felodipine

Calcium channel blocker, antiarrhythmic,

antianginal, antihypertensive
Calcium channel blocker, antihypertensive

Bioavailability

The inhibition of CYP3A4

Fexofenadine
Vincristine and verapamil

Antihistamine
Mitotic inhibitor, anticancer

Absorption
Bioavailability

The inhibition of OATP2B1

The inhibition of CYP3A4

Piao and Choi, 2008). Recently, Sridhar et al. (Surya Sandeep et al., 2013)
indicated that the concurrent use of Hst and felodipine increased the
bioavailability of felodipine via the aforementioned mechanism, including the inhibition of CYP3A4 and P-gp. However, further studies are
needed to show if felodipine is a P-gp substrate (Table 1; a tabulated
overview of the pharmacokinetic interaction between Hsd/Hst and
drugs).
Hst is selectively metabolized by both cytochrome P450 isoforms
(CYP1A and CYP1B1) to eriodictyol, indicating that there is Odemethylation of Hst in liver. Subsequently, eriodictyol is methylated
and transformed to homoeriodictyol (3-O-methylated) or Hst (4-Omethylated). The other Hst metabolites include Hst glucuronides (7O-glucuronide and 3-O-glucuronide), Hst sulfates (7-O-sulfate and 3O-sulfate), Hst sulfoglucuronides and homoeriodictyol glucuronides. It
should be noted, however, that the rst-pass metabolism of Hst occurs
in intestinal cells and results in the formation of Hst 7-O-glucuronide
and 3-O-glucuronide, the major Hst metabolites in vivo (Brand et al.,
2010a; Matsumoto et al., 2004). The Hsd/Hst metabolites are detected
in urine but not in feces samples, which indicates that there is further
bacterial degradation to ring ssion products and phenolic acids in the
colon; these compounds can then reach the blood circulation. This nding is supported by the ndings of Honohan and his co-workers, who
showed that following oral administration, almost 40% of the radioactivity of Hst-3-14C was expired as carbon dioxide (Honohan et al., 1976).
Conclusions and future perspectives
Hst and Hsd are citrus avonoids that have various biological activities. Over the past decade, a large number of studies were conducted
to determine the molecular targets and underlying mechanisms of
Hst, Hsd as well as their metabolites. Some properties of these compounds include anticancer, cancer preventive, anti-inammatory, neuroprotective and antioxidant properties, which are well-known and
promising. In addition, some effects of these compounds on the central
nervous system have been a topic of research during the past decade,
and they were not previously investigated.
Hsd is converted to Hst by the microora of the colon, and then, it is
absorbed by colonocytes. Hst can directly be absorbed by enterocytes.
Hst is an inhibitor of cytochrome P450 and is able to affect metabolism
of some drugs such as diltiazem, verapamil and felodipine.
Although, polyphenols are considered as natural compounds with
low toxicity but depending on their chemical structure, for instance, in
terms of the presence of sugar moiety in their backbone, they might
have some side effects on benecial microbiota by altering microecology in the gut (Duda-Chodak, 2012). On the other hand, since
their bioavailability would be increased by commensally intestinal microbiota so that more investigations have to be conducted in this regard
to determine the suitable doses and structures to use in human.
Recent studies showed that avonoids including citrus avonoids
might have benecial neuropharmacological effects including antidepressant and anticonvulsant properties. They can also effectively protect

Bailey et al. (2007)

Bailey et al. (2007), Uesawa and
Mohri (2008)
Cho et al. (2009b)
Sridhar et al. (2013), Surya Sandeep
et al. (2013)
Bailey et al. (2007)
Mitsunaga et al. (2000)

neurons from damages induced by oxidative or nitrosative stress. Hsd

and Hst enhances cognitive functions through various mechanisms
such as elevating BDNF and reversing the disruptive effect of global cerebral I/R on memory (Gaur and Kumar, 2010; Oztanir et al., in press).
They also show antidepressant activities via mechanisms that, some of
them differ from those of conventional antidepressant drugs (Donato
et al., 2014). The aforementioned neuropharmacological mechanisms
of Hsd/Hst can be generalized to other avonoids and are, at least as a
part, considered for their mechanisms of actions.
In total, further studies are necessary to unravel more aspects of the
therapeutic effects of Hsd and Hst in human diseases. The lack of the
clinical data of the therapeutic effects of Hsd and Hst is an important
limitation that can be noted regarding most of the previous studies, deserving further research.
It is ultimately recommended that regarding the versatile biological
properties of Hsd and Hst, these compounds may have even a broader
range of biological applications in the future.
Conict of interest
The authors declare no conict of interest.

Acknowledgments
This study was partially supported by the Mashhad University of
Medical Sciences.
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