Role of honey polyphenols in health
Transcript of Role of honey polyphenols in health
REVIEW ARTICLE Role of honey polyphenols in health
Carlos A Uthurry1*, David Hevia1, Carmen Gomez-Cordoves1
1 Instituto de Ciencia y Tecnología de Alimentos y Nutrición, ICTAN Consejo Superior de Investigaciones Científicas (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain Received 26 May 2011, accepted subject to revision 20 June 2011, accepted for publication 16 August 2011 *Corresponding author: Email: [email protected].
Summary Many bioactive phenolic compounds have been reported in hive products. This review discusses the occurrence and putative therapeutic
applications of these phenolic compounds and is intended to be read by scientists, physicians, nutritionists, and other researchers interested in
the rapidly developing science of honey and related products. In view of the information presented here, honey can be regarded as a rich
source of phenolic bioactive molecules with promising potential benefits to health.
Keywords: Honey, polyphenols, cancer, antimicrobial, antioxidant, health.
Journal of ApiProduct and ApiMedical Science 3 (4): 141 - 159 (2011) © IBRA 2011 DOI 10.3896/IBRA.4.03.4.01
Introduction Honey is a sweet substance produced as a food source mainly from
the nectar and secretions of plants by honey bees (Codex Standard
for Honey, 2001). Honey is used to feed bees during the winter
(Jaganathan and Mandal, 2009). For centuries honey has been used
as food and as natural medicine, being prescribed by physicians of
many ancient cultures for the treatment of a wide variety of ailments
(Ransome, 1937). The art of apiculture and the benefits of honey
have been known since the Egyptian first dynasty (Nicholson and
Shaw, 2000), and ancient Greeks used honey as a sweetener
(Brothwell and Brothwell, 1969). In Classical Greece, laws
concerning apiculture were suggested and Plato included honey in
his concept of a healthy diet (Skiadas and Lascaratos, 2001). The
use of honey in folk medicine is thought to be as old as civilization,
but in recent times there has been a renaissance in interest in its
use as a medicinal product. The colour of honey can vary from clear
to dark amber according to its floral source and mineral content and
it has a close relationship with its flavour and quality (Jaganathan
and Mandal, 2009). Honeys may be viscous liquids or even solid with
differing honeys identifiable by their colour, flavour, crystallization,
and the presence of pollen grains in honey sediment (Alves da Silva
et al., 2006).
Honey is mainly composed of water and sugar (about 96%)
with the remainder being substances such as amino acids, enzymes,
minerals, flavonoids, phenolic acids, ascorbic acid, carotenoid-like
substances, organic acids, and several other compounds (White and
Subers 1963; Tan et al., 1989; Alves da Silva et al., 2006). D-fructose
and D- glucose are the predominant sugars but it is the former that
occurs at higher concentrations. Sucrose occasionally exceeds 1% of
the total sugar content while maltose may be found at levels three
times higher than that of sucrose. The mineral fraction of honey is
mainly composed of potassium and smaller amounts of magnesium,
sodium, calcium, phosphorous, iron, managanese, cobalt and copper
(Alves da Silva et al., 2006). Enzymes such as invertase, amylase,
catalase and glucose oxidase are also present, and proline is the
major amino acid constituent comprising about half the content of
total free amino acids (White and Subers, 1963).
Citric and gluconic acids are also present in honey though
malic, folic, lactic, succinic, butyric, acetic and formic acids have also
be identified (Tan et al., 1989). Honey, depending on variety, is a
poor source of vitamins with only a few honeys showing evidence of
vitamins A, B2, C and B6 and carotenoid- like substances (Alves da
Silva et al., 2006). Polyphenols, especially flavonoids and phenolic
acids, are known to play an important role as antioxidants and honey
is regarded as an important source of these compounds (Schramm et
al., 2003; Viuda Martos et al., 2008b). The presence and
concentrations of these phytochemicals in honeys can vary
depending upon the floral source, the geographical and the climatic
conditions. Consequently, polyphenols have been suggested as floral
markers for the botanical authentication of unifloral honeys (Amiot
et al., 1989; Jaganathan and Mandal, 2009). Pyrzynska and Biesaga
(2009) discussed the analytical procedures for the analysis of
phenolic acids and flavonoids in honey
Polyphenols are the most important group of plant secondary
metabolites and their chemical structures range from simple
phenolic molecules to high molecular weight polymers of
approximately 30000 Da (Bravo, 1998). All polyphenols have at least
one hydroxyl group bound to an aromatic ring in the molecule and
they are biosynthesised in plants by mainly the shikimate and the
acetate pathways (Harborne, 1989). In general, apart from their
ability to provide plants with colour, polyphenols have different
functions in plants that include their ability to act as antimicrobial,
antifungal, antioxidant activities, and chelation of toxic heavy metals
(Harborne, 1993; Gould and Lister, 2005). Furthermore, much of the
colours, flavour and taste of vegetable food and beverages are
associated with the presence of polyphenols (Bravo, 1998).
According to the classification of Harborne (1989) polyphenols
can be divided into at least ten different classes depending upon
their basic chemical structure, but in honey phenolic acids and
flavonoids are the most important. The flavonoid group may be
further divided into thirteen classes (Harborne, 1988; Harborne,
1993) and more than 5000 flavonoids have been described since the
late 1980s. Generally, polyphenols are divided into two major
groups, the low- molecular- weight polyphenols comprising simple
phenols and flavonoids, and the higher-molecular- weight
polyphenols represented by tannins.
Simple phenols (Fig.1 A) are those with a C6 carbon structure
(such as phenol itself, cresol and thymol). Some have a C6-C1
structure, such as phenolic acids (for example, gallic, vanillic and
syringic acids) and aldehydes (for example, vanillin). Those with a C6
-C2 structure such as phenylacetic acids and acetophenones and the
phenylpropanoid group with a C6-C3 structure are mainly
represented by the hydroxycinnamic acids such as p-coumaric, ferulic
and caffeic acids and their respective derivatives. Simple phenols,
phenolic and phenylacetic acids can be found free in a large variety
of plant species but their methyl and ethyl esthers and glycosides can
also occur in the free form and/or bound forms (Harborne, 1989;
Bravo, 1998).
Flavonoids with a C6-C3-C6 structure represent the most widely
distributed phenolic compounds in plants, and their carbon skeleton
consists of an aromatic ring (A) fused to a heterocyclic ring (C)
carrying an oxygen atom, and the other ring (B) is generally linked to
number two carbon atom of the ring C (Fig. 1 B). In nature, they can
be found as free aglycones although they usually occur as glycosides
and their derivatives. At the same time, flavonoids are further divided
and classified with respect to the degree of oxidation of the ring C
into flavones (such as apigenin, luteolin and diosmetin), flavonols,
(such as quercetin, myricetin and kaempferol), flavanones (such as
naringenin and hesperidin), flavan-3-ols, (such as catechin and
epicatechin), anthocyanidins and their glycosides (such as malvidin,
cyaniding and pelargonidin). It is important to mention that flavones,
flavonols and their glycosides are the most common flavonoids found
in the plant kingdom (Bravo, 1998).
On the other hand tannins are molecules of intermediate to
high molecular weight and have an important degree of
hydroxylation. They are typically found in plants and can be classified
in two large groups: hydolysable tannins and condensed tannins;
although there is a third group, the phlorotannins, which occurs in
brown algae but are not consumed by humans (Ragan and
142 Uthurry, Hevia, Gomez-Cordoves
Fig. 1. Basic structures of a simple phenol (A), a flavonoid showing the identification of its rings (B), and a condensed tannin or proanthocya-
nidin (C). NOTE: Fig. 1 (C) is based on one illustration appearing in: BRAVO, L (1998) Polyphenols: chemistry, dietary sources, metabolism and
nutritional significance. Nutrition Reviews 56 (11): 317-333.(Permission granted by: Blackwell Publishing Ltd., John Wiley & Sons Ltd.).
Glombitza, 1986). Hydrolysable tannins consist of molecules of
either gallic acid or ellagic acid esterified to a polyol molecule such
as glucose (Porter, 1989). These tannins can increase their
molecular weight by consecutive esterification with other galloyl or
ellagic molecules forming large polymers (Bravo, 1998). Further
esterification with more gallic acid molecules is also plausible. This
kind of tannin can be easily hydrolysed using diluted acids, alkalis,
water and enzymes. Condensed tannins or proanthocyanidins are
high-molecular-weight polymers, and the monomeric unit is a flavan
-3-ol molecule such as catechin or epicatechin (Fig. 1 C). Oligomers
such as dimers, trimers and tetramers of proanthocyanidins are well
described but there are molecules with a degree of polymerization
greater than 50. Molecular weights can reach values higher than
30000 Da (Würsch et al., 1984).
Since honey is a food product derived from plant nectar or
plant exudate, it is an excellent source of various polyphenols. This
review aims to clearly define the current state of knowledge of the
phenolic composition of honey and evaluate its relevance to human
health.
Benefits and therapeutic properties of polyphenols in honey
Preliminary scope
Studies into the biochemistry of polyphenols and their properties of
pharmacological and therapeutic interest have been extensive. For
example, flavonoids have important benefits in cardiovascular
health, mainly on blood pressure and in the prevention of the
damage due to lipid peroxidation of the low density proteins (Raj
Narayana et al., 2001). Other therapeutic aspects of polyphenols are
the protection of gastric mucus, liver mucus, anti-inflammatory and
anti-neoplasic behaviour, antimicrobial activity (including the
selective inhibition of some immunodeficiency viruses such as HIV-1
and HIV-2), and the biochemical effects on enzymes and hormones
(Raj Narayana et al., 2001). Flavonoids, the most typical plant
phenolics, have been the subject of many scientific researches.
Havsteen (2002) produced a valuable contribution towards
understanding the biochemistry and pharmacological potential of
flavonoids, highlighting their interesting antiviral properties. He also
remarked on current medical interest for the use of chemically pure
flavonoids in the treatment of certain diseases, based on their
effectiveness for inhibiting some enzymes, scavenging free radicals,
and simulating the behaviour of hormones and neurotransmitters.
Figure 2 shows some benefitial properties of the phenolic
compounds.
Polyphenols can behave as antioxidants in vivo and in vitro
because they function as terminators of free radicals and chelators of
metal ions which could catalyse the lipid peroxidation (Bravo, 1998).
The antioxidant activity of these molecules is due to a rapid donation
of hydrogen atoms to stabilise the free radicals and the remaining
phenoxy radicals can also react with any other radical to terminate
the propagation route (Shahidi and Wanasundara, 1992). The
chemical structure of polyphenols greatly influences their antioxidant
activity (Bravo, 1998). Flavonoids, have one or more of some
Honey and health 143
Fig. 2. Properties of polyphenols in health.
Fig. 3. The structure of some flavonoids found in honey and their features related to the antioxidant activity.
Flavonoid R3’ R4’ R3 R5 R7
Apigenin H OH H OH OH
Chrysin H H H OH OH
Galangin H H OH OH OH
Kaempferol H OH OH OH OH
Luteolin OH OH H OH OH
Quercetin OH OH OH OH OH
structural features involved in antioxidant activity such as: an o-
diphenolic group in the B ring, a 2-3 double bond conjugated with
the 4-oxo function (in ring C), hydroxyl groups in positions 5 and 7
(in ring A) (Ratty and Das, 1988; Bors et al., 1990; Manach et al.,
1996). Some flavonoids present in honey are shown in Figure 3.
Table 1 summarises some of the phenolic compounds identified in
different types of honey using either high-perfoemance liquid
chromatography (HPLC) or capillary electrophoresis (CE) techniques
with diode array detection (DAD) (Pyrzynska and Biesaga, 2009)
Generally, the antioxidant activity also correlates directly with
the degree of hydroxylation (Ratty and Das, 1988). In nature,
flavonoids usually occur as 3-O-glycosides and the presence of the
sugar moiety dramatically decreases the antioxidant activity of the
compound. Yet, free flavonoids, best known as aglycones, have
known antioxidant activity (Ratty and Das, 1988).
The role of polyphenols as antioxidant agents against radical
reactive species such as those belonging to the reactive oxygen
species (ROS) and reactive nitrogen species (RNS) groups is of
remarkable interest. Radicals belonging to ROS such as OH.
(hydroxyl), RCOO. (peroxyl) and RO. (alcohoxyl) are of major
concern in the study of the oxidative stress of living tissues (Ames et
al., 1993) since they can be scavenged by flavonoids (Shahidi and
Wanasundara, 1992). On the other hand, the highly reactive
nitrogen species peroxynitrite (ONOO-) has been investigated
regarding the ability of flavonoids, such as anthocyanins, to act as
scavengers (Haenen et al., 1997; Tsuda et al., 2000). Investigation
of the relationship between the chemical structure and the
antioxidant power (in terms of radical scavenging activity) of several
flavonoids demonstrated that this activity strongly depends on the
substitution pattern of the free hydroxyl groups in its base structure
(Ratty and Das, 1988; Bors et al., 1990; Manach et al., 1996; Bravo,
1998; Amic et al., 2003).
Kroon and Williamson (2005) discussed the benefits for health
connected to the intake of food rich in polyphenols and proposed
that the presence of polyphenolic substances in a balanced diet is
specially valuable. They further proposed that, just as recommended
daily intake values (RDI) exist for most micronutrients such as
vitamins and oligoelements, the evaluation of RDIs for various
polyphenols in food will also be possible in the not too distant future.
Functional foods, known as nutraceuticals, designed foods,
therapeutic foods and medicinal foods, fit the concept of optimal
nutrition (Berner and O’Donnell, 1998; Nagai and Inoue, 2004). In
fact, honey, propolis and royal jelly are considered among the foods
that possess the property of functionality, due to their naturally high
antioxidant potential and their anti-inflammatory properties (Ali et al.,
1991; Ali, 1995), associated with the presence of galangin (Raso et
al., 2001; Rosi et al., 2002a, 2002b), caffeic acid, phenethyl esters
(Ali, 1995), and chrysin (Mirzoeva and Calder, 1996; Martos et al.,
144 Uthurry, Hevia, Gomez-Cordoves
Type of honey Analytical technique Identified phenolic compounds References
Acacia, eucalyptus, lime, chestnut, heather, lavender, rosemary, orange, sunflower and rapeseed honeys.
HPLC-DAD 4-hydroxybenzoic acid, protocatechuic acid, gallic acid, syringic acid, vanillic acid, p-coumaric acid, caffeic acid, ferulic acid.
Dimitrova et al. (2007).
Australian Eucalyptus honey. HPLC-DAD Gallic acid, chlorogenic acid, caffeic acid,
p-coumaric acid, ferulic acid, ellagic acid. Yao et al. (2004 a).
Citrus, thyme, rosemary, lavender honeys. CE-DAD
Syringic acid, p-coumaric acid, caffeic acid, cinnamic acid, chlorogenic acid, ferulic acid, gallic acid.
Aljadi and Kamaruddin (2004).
Eucalyptus honey. HPLC-DAD
Myricetin, tricetin, quercetin, luteolin, quercetin-3-methyl ether, kaempferol, pinocembrin, chrysin, pinobanksin, isorhamnetin, genkwanin.
Yao et al. (2004 b).
New Zealand and Australian Leptospermum honeys.
HPLC-DAD
Myricetin, tricetin, quercetin, luteolin, kaempferol, kaempferol-8-methyl ether, pinocembrin, chrysin, gallic acid, ellagic acid, chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, syringic acid.
Yao et al. (2003).
Rosemary honey. CE-DAD Kaempferol, ferulic acid, chrysin, pinocembrin, p-coumaric acid.
Dimitrova et al. (2007).
Table 1. Some identified phenolic compounds occurring in honeys (Pyrzynska and Biesaga, 2009).
2000; Bruschi et al., 2003). Hive products have demonstrated
antiviral properties (Amoros et al., 1992), including the inhibition of
viral activation including HIV-1. This viral inactivation is thought to
be due to the chrysin, acacetin and apigenin components
(Critchfield et al., 1996). Other therapeutic properties of bee-
products that have been reported included their anti-ulcer and
antibacterial properties derived from the occurrence of flavonoids
such as galangin and quercetin (Mirzoeva et al., 1997; Cushnie and
Lamb, 2005). However, in honey there are other antimicrobial
factors apart from polyphenols, such as the recently discovered
methylglyoxal in manuka honey (Mavric et al., 2008; Adams et al.,
2008), sugar content, hydrogen peroxide and bee defensin-1
(Kwakman et al., 2010). Indeed, it is important to note that not all
antimicrobial properties can be attributed to polyphenols.
Paradoxically honeys with the same phenolic profiles can either
possess antibacterial activity or be totally devoid of any (Weston et
al., 2000). Henriques et al. (2006) also studied the antibacterial
activity of honeys that produce hydrogen peroxide. There is a
substantial body of research on the antiproliferative effect of honey
and its components on some cancers (Ghosh et al., 2005;
Jaganathan et al., 2010a; Pichichero et al., 2010; Jaganathan et al.,
2010b) .
Finally, it is important to be aware that the bioavailability of
dietary polyphenols is critical to realising their health benefits.
Manach et al. (2004, 2005) reported that polyphenol bioavailability is
dependant upon many variables including gut absorption,
glucuronide excretion to the intestinal lumen, microbiota
metabolism, liver and gut metabolism, plasma kinetics, a variety of
metabolites in the bloodstream, bonding to albumin, cell assimilation
and metabolism, accumulation in tissues and bile, and urinary
excretion. Proanthocyanidins are abundant in the human diet but
they are not well absorbed in the gut and the intake of flavonols,
flavones and flavanols remains relatively small. In addition to their
limited absorption and rapid elimination, final plasma concentrations
of procanthocyandins hardly ever exceed 1 µmol / L. Flavonoids with
the highest bioavailability are flavanones and isoflavones reaching
plasma concentrations in the vicinity of 5 µmol / L. Hydroxycinnamic
acids are widely distributed in the diet at substantial levels but their
bioavailability is poor due to estherification.
On account of these observations, honey has valuable
properties which make it considered as an irreplaceable source of
compounds with interesting therapeutic activities suitable to being
part of a healthy diet.
The radical scavenging and antioxidant activities of honeys Honey is regarded as a functional food largely due to the presence
of phenolic compounds that are able to act as free radical
scavengers, thus protecting cells and living tissues against oxidative
stress. This oxidative stress has been associated with enhanced
cellular ageing that is itself a feature of degenerative diseases such
as cancer, cardiovascular disease and related diseases (Kinsella et
al., 1993). Polyphenols in honey can scavenge hydroxyl, peroxyl and
alcohoxyl radicals through their ability to act as a hydrogen donor
and thus displaying their antioxidant properties.
Sánchez Moreno (2002) described diverse methods for the
assessment of the free radical scavenging activity in food and
biological systems. These reactive chemical species and free radicals
include superoxide (O2.), hydrogen peroxide (H2O2), hypochlorous
acid (HOCl), hydroxyl radical (HO.), peroxyl radical (ROO.) as
determined by the TRAP (Total Radical Trapping Antioxidant
Parameter), the ORAC (Oxygen Radical Absorbance Capacity)
methods, the ABTS [2,2-azinobis-(3-ethylbenzothiazoline-6-
sulphonate)], TEAC (Trolox Equivalent Antioxidant Capacity) method,
the DPPH (2, 2-dyphenyl-1-picrylhydrazyl) radical scavenging
capacity assay, and the DMPD (N-N-dimethyl-p-phenylendiamine)
method. Studies reporting the antioxidant power of honeys usually
depend on the use of the DPPH method, although the ORAC method
is increasing at a steady rate, together with those involving free
radical scavenging mechanisms.
Beretta et al. (2005) proposed a standard analytical platform for
the reliable assessment of the antioxidant activity of honey.
Significant correlations were recorded among the results of the
different methods used by the researchers. Principal component
analysis grouped the analysed samples according to their antioxidant
power and phenolic content. The authors emphasized the use of
combined methods to either foresee or confirm the health benefits of
honey in relation to their antioxidants´ concentration.
When the chemical composition and bioactivity of chestnut tree,
rhododendron and multifloral honeys from Anatolia (Turkey) was
investigated it was observed that chestnut-tree honey exhibited the
highest polyphenolic content, the highest radical scavenging activity
for superoxide, and the highest reducing power. Multifloral honey
exhibited the highest scavenging activity for the reactive nitrogen
species peroxynitrite (Küçük et al., 2007).
Baltrušaityté et al. (2007a) studied the radical scavenging
activity of Lithuanian honeys of different floral origin. Antioxidant
power of these samples was remarkably widespread. The beneficial
effects of bee products for health depend upon their source due to
the strong variability in the antioxidant power. Further investigations
have been recommended in order to elucidate connections between
floral origin, phenolic composition and antioxidant activity as
measures of the benefits of hive products on health.
The antioxidant activity of honey as phenolic content has been
extensively studied. Research on the antioxidant activity of honeys
from Yemen found that some Yemeni honeys contained significantly
higher phenolic contents than other honeys, and the percentage
antioxidant activities were higher than in the investigated non-
Yemeni honeys (Al-Mamary et al., 2002). Based on these results,
Yemeni honeys were found to be rich in antioxidant phenols with
Honey and health 145
antioxidant therapeutic potential (Al-Mamary et al., 2002).
Malaysian honeys were studied in relation to their polyphenolic
content and antioxidant properties (Aljadi and Kamaruddin, 2004).
Two of the most common Malaysian Apis mellifera honeys, namely
Gelam and Coconut honeys, were studied regarding their phenolic
content, radical scavenging activity (using the DPPH method), and
total antioxidant power (using the Ferric Reducing Ability Plasma
(FRAP) method). The data showed a significant correlation between
the antioxidant activity of the honeys and their total phenolic
contents. Gelam honey had a higher total phenolic content (21.4 μg/
g) than Coconut honey (15.6 μg/g), as well as greater radical
scavenging activity, water content and total antioxidant potential.
These observations supported those of Frankel and colleagues
(1998) that water content of honey and antioxidant activity were
correlated (Aljadi and Kamaruddin, 2004).
In a study of crude Italian honeys, Millefiori honeys showed a
higher flavonoid content than Acacia honeys in accordance with their
greater antioxidant power (Blasa et al., 2006). In another study, the
seven most common types of Slovenian honeys were studied in
terms of their total phenolic content, antioxidant activity and colour
(Bertoncelj et al., 2007). Honey samples were from acacia, lime,
chestnut, fir, spruce, multifloral and forest (honeydew honey from
coniferous trees). Analytical results showed that the total phenolic
content and the antioxidant activity varied greatly among the
different types of honey. Darker honeys (fir, spruce, forest) showed
higher total phenolic content and higher antioxidant capacity than
lightest honeys (acacia and lime). Total phenolic content ranged
from 44.8 mg. gallic acid/Kg in acacia honey to 241.1 mg. gallic
acid/Kg in fir honey. A significant correlation between the
antioxidant activity and the phenolic content was also found. In
accordance to these results, the polyphenolic composition and the
antioxidant activity of Czech honeys, Lachman et al. (2010)
suggested similarities between lime, rape and raspberry honeys,
followed by floral honeys, while multifloral and honeydew honeys
were remarkably different.
Oddo et al. (2008) studied the antioxidant activity of Australian
honeys from Trigona carbonaria, a stingless bee from Australia and
found that, when compared with honeys from different countries of
the world, the flavonoid content was high (about 10.0 mg quercetin
equivalents/100 g of honey). However, their phenolic content was
lower (about 55.74 mg gallic acid equivalents/100 g of honey) than
that recorded by Vit et al. (2008) for Czech A. mellifera honey. The
Australian honey also displayed a higher total antioxidant activity
than the Czech A. mellifera sample, while the radical scavenging
activity was similar to that reported for floral and honeydews blends
of Spanish honey (Oddo et al., 2008).
Honeys from the Czech Republic (Lachman et al., 2010)
evaluated for their antioxidant activity and total phenolic
composition. Forty honey samples of different types such as
multifloral, lime, rape, raspberry, mixture and honeydew were
studied. Total phenolics content ranged from 82.5 to 242.5 mg / Kg
honey, those with the lowest content were lime honeys, whereas
honeydew honeys exhibited the highest concentrations. The
antioxidant activity values recorded using the FRAP, DPPH. and ABTS.
methods demonstrated that floral honeys were the least active while
honeydew honeys had the highest activity. The authors noted that
the observed low activity of floral honeys was in accordance with the
results of Al-Mamary et al. (2002), and was indicative of the
presence of different phenolic compounds with different antioxidant
activity. Raspberry honeys showed marked antioxidant activity which
had also been reported by the results of Buřičová and Reblová
(2008).
Gheldof and Engeseth (2002) and Gheldof et al. (2002)
compared the scavenging activity of honey for oxygen radicals (3-17
Imol TE/g) to that of fruits and legumes (0.5-19 Imol TE/g).
The possible changes in the antioxidant power and the
polyphenolic composition of honey when fermented into mead were
another subject of research. It was found that pasteurisation of the
starting musts did not induce any significant change in the
antioxidant power of the resulting meads, although phenolic profiles
had changed due to temperature (Wintersteen et al., 2005).
Free-radical scavenging activities of bee hive products and
extracts, were examined from samples of multifloral honeys,
monofloral honeys and honeydews. A high variability of the phenolic
content was reported. Honeydew samples were the richest in
phenolic compounds and showed a significant radical scavenging
activity. However, it was observed that not all the activity of the
samples accounted for the phenolic content. In fact, correlation
between proline content and the radical scavenging capacity was
found to be greater than that indicated by their total phenolic
content. In this case scientists suggested giving more importance to
the amino acid composition of honeys when evaluating their
antioxidant power (Meda et al., 2005).
Kishore et al., (2011) evaluated the total phenolic content, the
antioxidant and the radical scavenging activity of Asian honeys. They
found a higher phenolic content in tualang honey (83.96 mg gallic
acid equivalent /100 g of honey) than in Gelam, Indian forest and
pineapple honeys, and observed strong correlations of the phenol
content with the antioxidant and radical scavenging activities. They
also observed a significant peroxynitrite and superoxide anion
scavenging ability from this honey.
Regarding research with cells, Blasa et al. (2007) studied the
role of Italian honey flavonoids as agents against the oxidative
damage to human red blood cells. This study investigated water and
ether phenolic fractions from honeys to assess their phenolic and
flavonoid contents and their antioxidant activities. Differences in their
FRAP values were noted and it was concluded that hydrophillic
polyphenols were mostly glycosides and water soluble high
molecular weight polymers, whereas the lipophillic polyphenols were
low-molecular weight flavonoids. The aqueous fractions showed the
146 Uthurry, Hevia, Gomez-Cordoves
highest antioxidant activity and the organic fraction showed activity
against haemolytic agents and radicals involved in the lipid
peroxidation of the cell membrane and this activity could in part be
explained due to the higher liposolubility of these compounds.
Beretta et al. (2007) studied the protective effect of honey
against hydrogen peroxide and peroxyl radicals able to damage
endothelial cells and highlighted the synergistic action of honey
antioxidants (mainly phenolic acids and flavonoids). This antioxidant
activity had the ability to remove ROS that lead to oxidative stress
of endothelial cells and thus lowering the risk of develpoing acute
and chronic free-radical mediated pathologies such as
atherosclerosis and cancer in vivo.
In the search of healing products based on honey, Van den
Berg et al. (2008) studied the antioxidant and anti-inflammatory
properties of honey in vitro, and found that buckwheat honey was
the most effective in reducing ROS such as hydroxyl radicals
(formed from superoxide anion produced by the polimorphonuclear
neutrophils) and reactive nitrogen species such as peroxynitrite
anion (formed from the nitric oxide released by macrophages)
frequently found in wounds. Thus, this honey can help to reduce
the inflammatory effects in a wound and the surrounding tissue, and
help to improve wound healing due to its antibacterial and
antioxidant properties.
The cytotoxic activity of Indian honey has recently been
studied (Jaganathan et al., 2010b). Apart from flavonoids, phenolic
acids such as di-hydroxybenzoic and cinnamic acids were found.
This study observed that honey with the highest phenolic content
and antioxidant activity increased numbers of 3T3 cells viability in a
dose-dependant manner when cells were oxidative-induced to
death. Moreover, it was found that this honey could induce
apoptosis in cultured breast cancer cells (MCF-7) by arresting the
cells at the sub-G1 phase (Jaganathan et al., 2010b).
It has also been demonstrated that an increase in the
concentration of human plasma antioxidants was verified after the
intake of food rich in them, such as buckwheat honey. Therefore,
the antioxidant and reducing power of plasma increased significantly
and it was advised to have a higher honey intake in order to
increase the antioxidant defences in healthy adults (Schramm et al.,
2003).
Gheldof and Engeseth (2002) found that honeys from different
floral sources can protect against the oxidation of lipoproteins in
human plasma. Their results suggested that darker honeys such as
buckwheat honey displayed more protection than lighter ones such
as clover and acacia honeys.
The maintenance of the redox status of human plasma by
flavonoids in Italian multifloral honeys was studied by Fiorani et al.
(2006). Hydrophillic flavonoids were found to be remarkably more
effective than lipophillic flavonoids in promoting the chemical
reduction of the anion ferricyanide. However, the content of
hydrophillic flavonoids was lower than that of lipophillic flavonoids,
suggesting the presence of water-soluble phenolic polymers and
sugars. HPLC-MS (liquid chromatography with mass detection)
analyses of lipophillic flavonoids revealed the presence of high
concentrations of the aglycones of quercetin, luteolin, kaempferol,
fisetin, isorhamnetin, acacetin, chrysin, apigenin, galangin and
tamarixetin. Cell-based assays demonstrated that lipophillic
flavonoids developed greater protection for erythrocytes than
hydrophllic ones, by passing through the cell membrane,
accumulating in the cell and readily binding to haemoglobin. The
antioxidant role of intracellular flavonoids was explained by a donor-
electron mechanism to a trans-plasma membrane oxidoreductase
(PMOR) which may consequently promote the reduction of
extracellular oxidants.
Gheldof et al. (2003) investigated whether the intake of honey
could improve the human serum antioxidant status. After volunteers
had consumed beverages of water, water with buckwheat honey,
black tea, black tea with buckwheat honey and black tea with a sugar
analogue of honey, it was found that those who had consumed water
with buckwheat honey, significantly increased their plasma
antioxidant capacity, when compared with subjects receiving the
other beverages. Nevertheless, further studies on the bioavailability
of honey phenolics and more long-term studies are required to better
assess in vivo honey inhibition of plasma lipid peroxidation.
The antimicrobial and antiviral activity of honeys
The antimicrobial properties of honey have been known for millennia.
Aristotle (384-322 BC) discussed the properties of different honeys
and indicated pale honey for the treatment of sore eyes and wounds,
while Dioscorides (ca. 50 AD) referred to a pale yellow honey form
Attica as being the best for treating rotten and hollow ulcers. Honey
has inhibitory effects against several types of bacteria such as Gram
positive, Gram negative, aerobic and anaerobic bacteria (Molan,
1992).
There are several studies investigating the antimicrobial activity
of honey. The antibacterial activity of honey is usually associated
with the release of hydrogen peroxide, from the oxidation of glucose
to glucolactone and then to gluconic acid in presence of the enzyme
glucose oxidase (Adock, 1962; White and Subers, 1963). This activity
is called peroxide-activity and constitutes, at variable extent, the
mode of action of some honeys (Henriques et al., 2006). However,
another antibacterial non--peroxide activity in honey is mainly due to
their polyphenol content, sugar and other recently discovered factors.
Firstly, non-peroxide antimicrobial activity of honey from stingless
honeybees (Meliponinae) has been demonstrated as being important
because antibacterial activity due to hydrogen peroxide might be
reduced by the action of catalase present in human serum. (Temaru
et al., 2007). Secondly, New Zealand manuka honey (Leptospermun
scoparium (Myrtaceae)) have been studied regarding their
antibacterial activity and its relationship with their phenolic
Honey and health 147
composition (Weston and Brocklebank, 2000), but in recent years
Mavric et al. (2008) and Adams et al. (2008) described
methylglyoxal as the dominant antibacterial compound of manuka
honey. Atrott and Henle (2009) proved the close relationship
between methylglyoxal content and the antibacterial activity in
manuka honey. Moreover, Kwakman et al. (2010) characterized
other antibacterial non-peroxide factors of honey such as bee
defensin-1 along with methylglyoxal and sugar. Therefore, the
antimicrobial activity of honey can have several explanations and not
all the honeys behave similarly.
Regarding polyphenols, Burdock (1998) attributed the
antibacterial properties of honey to the presence of aromatic acids
and esters, whereas Takaisi and Schilcher (1994) said that
pinocembrin, galangin and caffeic acid phenethyl ester can inhibit
bacterial RNA polymerase. Moreover, Cushnie and Lamb (2005)
suggested an antibacterial mechanism of action started by galangin;
this involves degradation of the cytoplasmic membrane causing loss
of potassium ions and the subsequent cell autolysis. Furthermore,
Mirzoeva et al. (1997) proposed another mechanism of action for
quercetin, a flavonoid that may occur in honeys. They suggested
that quercetin may increase bacterium membrane permeability
leading to electric potential dissipation and decrease in the synthesis
of ATP. Kirnpal-Kaur et al. (2011) fractionated tualang honey into
polar, acidic and basic fractions using the solid phase extraction
technique (SPE) in order to evaluate their antibacterial properties
against wound and enteric bacteria, and found that the acidic
fraction enhanced the antibacterial properties of this honey. In an
effort to identify the main phytochemicals with antibacterial activity
present in the acidic fraction, the need for further investigations was
acknowledged, although preliminary evidence indicted that these
compounds could be polyphenols.
The inhibition of microorganisms of clinical significance
The recorded antimicrobial properties of honeys against some of the
most important microorganisms from a clinical standpoint will now
be described. Antimicrobial activity derived from the occurrence of
polyphenols will be emphassised, although any other activity whose
cause is not clearly defined will also be included.
Gram positive bacteria such as Staphylococcus aureus, the
causal agent of a range of illnesses from skin infections to life-
threatening diseases such as pneumonia and meningitis, did not
grow in the presence of honeys produced by A. mellifera and
Tetragonisca angustula bees in the Brazilian states of Paraná and
Minas Gerais. In order to study this effect, honeys were analysed by
high performance liquid chormatography (HPLC) and the anti-
microbial activity was connected to phenolic compounds, such as 4-
hydroxybenzoic acid (HBEN). These compounds occur in higher
concentrations in propolis than in honey, and propolis was more
effective against S. aureus than honey (Miorin et al., 2003). This
bacterium has proved to be variable in susceptibility to different
honeys. Turkish honeys from Anatolia showed a moderate inhibition
towards some strains of S. aureus (Küçük et al., 2007), while Turkish
rhododendron honeys partially inhibited the growth of this bacterium
(Silici et al., 2010). Honey from stingless bees had powerful activity
against S. aureus when compared to that exhibited by manuka honey
produced by honeybees belonging to Apidae family (A. mellifera, A.
cerana) (Temaru et al., 2007). Argentinean honeys from the province
of Córdoba evidenced high activity against S. aureus, which was
considered to be of remarkable clinical importance, since an increase
in difficult-to-treat skin infections had been reported in the last
decade and resistance against several antibiotics had developed
(Basualdo et al., 2007). A study of the properties of several Cuban
honeys demonstrated that Gram positive bacteria are more sensitive
than Gram negative bacteria (Alvarez Suárez et al., 2010), with S.
aureus the most sensitive bacterium (Alvarez Suárez et al., 2010).
Honeys from A. mellifera produced in Thailand also showed inhibitory
effects (Srisayam and Chantawannakul, 2010). Strains of S. aureus
were found to be very sensitive to Spanish honeydew honeys (Pérez
Martín et al., 2008) whereas in other studies using honeys from
Galicia (northwest of Spain) two strains of the bacterium, including a
difficult-to-treat strain in humans such as the methicillin-resistant
Staphylococcus aureus (MRSA), exhibited different sensitivities
(Gallardo-Chacón et al., 2008). South African honeys from
indigenous Leucospermum cordifolium and Erica species showed
poor antibacterial activity against this Gram positive bacterium
(Basson and Grobler, 2008). Baltrušaityté et al. (2007b) observed
that Lithuanian honeys exhibited antibacterial effects on S. aureus
and concluded that this was mainly due to the presence of hydrogen
peroxide. Honeys produced in the Czech Republic are also
antimicrobially effective with some honeydew honeys possessing the
greatest effects (Vorlova et al., 2005). In a study with unifloral and
multifloral Portuguese honeys, Henriques et al. (2005) analysed their
antibacterial activity against a strain of S. aureus, and observed that
all of the samples tested possessed peroxide activity except some
honeys derived from Lavandula stoechas which revealed non-
peroxide antibacterial activity. Recently, Isla et al. (2011) observed
that algarrobo honey (Prosopis nigra) and a multifloral honey from
the northwestern provinces of Argentina had activity against S.
aureus. They identified at least five antibacterial compounds in the
algarrobo honey and four compounds in the multifloral honey and
found that most of them corresponded to flavonoids. One of these
flavonoids was identified as pinocembrin. The authors also pointed
out that the antibacterial activity of the analysed honeys might be
mainly due to their phenol content because of the significant
correlation observed between the phenolic content and the
antibacterial activity.
Among the Gram negative bacteria, Escherichia coli is of great
concern from a health point of view. It may cause life threatening
gastric infections and diarrhoea, following consumption of
148 Uthurry, Hevia, Gomez-Cordoves
contaminated food, as well as other infections such as cystitis,
meningitis, peritonitis and pneumonia. There are several studies on
the antibiotic effect of honey towards E. coli. E. coli exhibited
sensitivity to stingless honeybee honey (Temaru et al., 2007),
Spanish honeys (Gallardo-Chacón et al., 2008), Cuban honeys
(Alvarez-Suárez et al., 2010), and Thailand honeys (Srisayam and
Chantawanakul, 2010). Basualdo et al. (2007) demonstrated that E.
coli can be inhibited by some Argentinean honeys while, Fangio et
al. (2010) demonstrated the effectiveness of honeys produced in the
province of Buenos Aires (Argentina) against this enterobacterium.
The antimicrobial activity of these honeys was mainly non-peroxide
and the presence of phytochemicals such as phenolic compounds
was considered in the most active honeys (Fangio et al., 2010).
Nevertheless, rhododendron Turkish honeys showed no inhibitory
effect (Silici et al., 2010), and Basson and Grobler (2008) found poor
antibiotic activity of South African honeys from indigenous L.
cordifolium and Erica species. Some Czech Republican honeys were
also tested for their antibacterial activity against E. coli and
researchers concluded that honeydew honeys are the most effective
(Vorlova et al., 2005). Recently, Brudzynski and Miotto (2011), in an
investigation with twenty Canadian unheated honeys, quantified
Maillard reaction- like products (MRLPs) and total phenol contents,
apart from assessing the antioxidant activity using the ORAC
method. One of their results indicated that both the recorded
antioxidant activity and the content of MRLPs of these honeys
mainly contributed to the antibacterial activity against E. coli. This
antibacterial activity confirms the work of Rufian-Henares and de la
Cueva (2009) who suggested that the antibacterial activity of coffee
melanoidins against E. coli is due to their behavior as metal-
chelators
Pseudomoma aeruginosa, an important pathogenic bacterium
which can cause several health disorders in humans including lung,
urinary, tissue, blood and wound infections was studied in many
published reports. Silici et al. (2010) showed that rhododendron
honeys from Turkey have antimicrobial activity against P. aeruginosa
when diluted at 50% and 75% in water. A. mellifera honeys
produced in Thailand also inhibited the growth of this bacterium
(Srisayam and Chantawannakul, 2010). Honey from stingless
honeybees showed significant inhibitory effects on the growth of P.
aeruginosa (Temaru et al., 2007). The bactericidal potency of
Saharan honey against this pathogen was studied by Boukraa and
Niar (2007) who reported that Saharan honey showed higher
potency than Algerian honeys, probably due to antibacterial
substances from the botanic flora ocurring in the Sahara. This Gram
negative and aerobic micro-organism was sensitive to some honeys
produced in the province of Córdoba (Argentina) (Basualdo et al.,
2007), but was the least sensitive in comparison with other bacteria
Alvarez-Suárez et al., 2010), while not sensitive to honey samples
evaluated by Gallardo-Chacón et al. (2008).
Helicobacter pylori, can occur in the stomach, and is linked to
the development of ulcers and many types of gastritis. There is
evidence that honey can have inhibitory effects against this
bacterium. Küçük et al. (2007) reported a moderate inhibitory effect
by honeys harvested in Anatolia (Turkey), and studies conducted
with manuka (L. scoparium) honey showed interesting antibacterial
activity. We must remember that, as previously described,
antibacterial activity of manuka honey is now mainly attributed to the
occurrence of methylglyoxal (Mavric et al., 2008, Adams et al., 2008;
Attrot and Henle, 2009). It has been suggested that this honey can
also act by healing the gastric mucosa and stimulating epithelial cells
growth.
Bacillus cereus, a Gram positive, aerobic and beta-haemolytic
bacterium, is a food-borne pathogen for humans, whose growth
results in the production of enterotoxins causing nausea, vomiting,
abdominal cramps and diarrhoea. There are reports of the sensitivity
of the bacterium towards some honeys. For example, some Thai
honeys can inhibit growth of the bacillus (Srisayam and
Chantawannakul, 2010), and similar activity was observed in studies
using different honeys which included honey from Galicia (Spain)
(Gallardo-Chacón et al., 2008). In contrast, Bacillus cereus was
found to be resistant when rhododendron Turkish honeys were
tested for their antibacterial activity (Silici et al., 2010).
Honeys produced in Anatolia (Turkey), in Cuba and in the
Turkish Black Sea Region showed inhibition effects on strains of
Bacillus subtilis (Küçük et al., 2007; Silici et al., 2010; Alvarez-Suárez
et al., 2010), a Gram positive sporing bacterium occurring in soil
which can contaminate food but rarely causes infections in humans.
Some other honey sensitive-pathogens described in the
literature are Bacillus anthracis (anthrax), Corynebacterium
diphtherine (diphtheria), Klebsiella pneumoniae (pneumonia),
Mycobacterim tuberculosis (tuberculosis), Salmonella typhi (typhoid
fever), Vibrio cholerae (cholera) and different streptococci, among
others. For example, Klebsiella pneumoniae was found to be sensitive
to Argentinean (Basualdo et al., 2007), and Thai honeys (Srisayam
and Chantawannakul, 2010). The growth of Enterococcus faecalis
was inhibited by stingless honeybee honey (Temaru et al., 2007),
and this bacterium also showed sensitivity to honey according to the
research performed by Gallardo-Chacón et al. (2008).
In addition, other bacteria sensitive to different types of honey
are Staphylococcus epidermidis (Basualdo et al., 2007; Baltrušaityté,
2007b), S. uberis (Basualdo et al., 2007), Pediococcus mirabilis (Silici
et al., 2010), Aeromonas hydrophila (Silici et al., 2010), Micrococcus
luteus (Srisayam and Chantawannakul, 2010), Streptococcus oralis
(Basson and Grobler, 2008), Streptococcus anginosus (Basson and
Grobler, 2008), Salmonella enterica ser. Typhimurium (Vorlova et
al., 2005; Gallardo-Chacón et al., 2008), Shigella sonnei (Gallardo-
Chacón et al., 2008), Listeria monocytogenes (Vorlova et al., 2005;
Gallardo-Chacón et al., 2008) and Streptococcus mutans (Basson
and Grobler, 2008). Among yeasts, some Candida species were
inhibited by Turkish honeys (Küçük et al., 2007).
Honey and health 149
The initial event in the development of bacterial infections of
the gastrointestinal gut is the attachment of bacteria to the mucosal
epithelial cells (Raupach et al., 1999) and the blocking of this event
represents an interesting strategy for the prevention of diseases
(Sherman et al., 1983; Leung and Finlay, 1991; O´Farrelly et al.,
1992; Peralta et al., 1994). Alnaqdy et al. (2005) studied the
antimicrobial activity of Omani honeys against Salmonella interitidis
and the ability of these honeys to prevent the bacterium from
adhering to intestinal epithelial cells in vitro.
However, in spite of the antimicrobial activity, there are yeasts
like Candida albicans and Saccharomyces cereviseae which showed
resistance towards some honeys (Silici et al., 2010; Srisayam and
Chantawannakul, 2010), while rhododendron honeys were not
effective against strains of B. cereus, E. coli and Yersinia
enterocolítica (Silici et al., 2010).
The bactericidal properties of honey led researchers to
investigate its applications on cutaneous wound healing and the
treatment of burns. Mohd Nasir et al. (2010) and Kirnpal-Kaur et al.,
(2011) found that tualang honey (Koompassia excelsa) had
important bactericidal and bacteriostatic effects in the treatment of
burns by using dressings soaked with this honey. Also, non-toxicity
of honey against tissue cell cultures of human keratinocyte and
fibroblasts has recently been found in vitro. This kind of evidence
may positively influence the choice of wound dressings in clinical
prescriptions (Du Toit and Page, 2009).
Inhibition of viruses
Antiviral properties of honeys are also of great concern from a
therapeutic point of view. Chritchfield et al. (1995) showed that
some important flavonoids of honey such as chrysin, acacetin and
apigenin can inhibit the human immunodeficiency virus (HIV-1)
activation, via a probable mechanism involving the inhibition of viral
transcription. Other researchers have demonstrated the inhibitory
effects of chrysin against herpes simplex virus type 1 (HSV-1) (Lyu
et al., 2005). Hu et al. (1994) observed that chrysin and apigenin
have a significant antiviral activity against HIV-1 in acutely infected
H9 lymphocytes. Apigenin also exhibited antiviral activity against
influenza virus (H3N2) in vitro (Liu et al., 2008).
Molecular biological processes at DNA level are responsible for
cell events that lead to the development of some phenomena such
as carcinogenesis, and, in this line, binding studies of different
flavonoids were undertaken. Apigenin, a cancer chemopreventive
agent, has the highest affinity of ligand-DNA binding when
compared to those of morine and naringin (Nafisi et al., 2008).
Chiang et al. (2005) observed that apigenin behaves as a
potent antiviral substance against herpes virus type-2 (HSV-2),
adenovirus (ADV-3), hepatitis B surface antigen (HBsA) and hepatitis
B e antigen (HBeA).
Al-Waili (2004) studied the activity of honey on two types of
herpes: labial and genital herpes. His results demonstrated that the
topic application of honey on recurrent attacks of this viral disease
was effective. This study reported that in the labial herpes the mean
time of healing was 43% better than with the conventional treatment
with acyclovir, while for genital herpes the mean healing time was
improved around 59%. The authors remarked that some cases
remitted completely after treatment with honey, although none of
the attack remitted when using acyclovir. Honey has also
demonstrated anti-Rubella activity in experiments performed on
monkey kidney cell cultures infected with the Rubella virus (Zeina et
al., 1996).
Finally, further investigations are required to study the
relationship between the phenolic composition of honeys and their
therapeutic properties, now that it is has been proposed that honey
from stingless bees may be used to manufacture pharmaceuticals, as
well as nutritional supplements and cosmetics (Temaru et al., 2007).
Antitumour properties
Honey and its components have several applications in cancer
therapy. There are a number of reports focusing on honey and some
individual components undertaken in cell cultures, animal models and
humans (Fig. 4) as described later in the text. So, for instance, the
use of honey has revealed a significant inhibition of the proliferation
in three human bladder cancer cell lines (T24, 253J and RT4) and
one murine bladder cancer cell line (MBT-2). When researchers used
between 1 and 25% of honey BrdU labelling index was significantly
lower and the same was observed for the S-phase fraction when
compared with control cells. In the in vivo studies, cancer cells were
implanted subcutaneously in the abdomens of mice and tumour
growth was significantly inhibited after intralesional injection of 6 and
12% of honey as well as after oral ingestion of honey (Swellam et
al., 2003). In other research, honey was used in solution as
treatment in W256 mammary carcinoma implants in Wistar rats, and
a decrease in relative tumour weight was observed suggesting that
honey modulated tumour growth (Tomasin and Cintra Gomes-
Marcondes, 2011). Honey not only has antitumour properties, but
has protective effects on the oxidative stress and carcinogenesis
induced by carcinogenic compounds as methylnitrosourea (MNU). In
fact, one week after Sprague Dawely rats were injected with
methylnitrosourea one group of rats were given orally 5 g honey
(containing 0.2 g of ground Nigella sativa seeds) per rat, per day.
After six months the methylnitrosourea injected in the control group
produced a variety of oxidative stresses ranging from severe
inflammatory reaction in lung and skin to colon adenocarcinoma,
whereas honey and Nigella sativa together protected 100% (12/12)
against effects of methylnitrosourea (Mabrouk et al., 2002).
The antitumour effects of eugenol, chrysin and galangin have
demonstrated antitumoural activity (Jaganathan et al., 2011)
Eugenol, a natural compound available in honey, has antiproliferative
150 Uthurry, Hevia, Gomez-Cordoves
effects in colon cancer cells (HT29, HT15) and increased the
accumulation of cells at sub-G1 phase. Eugenol increased levels of
ROS, DNA fragmentation and decreases mitochondrial membrane
potential (MMP). Eugenol was found to be a potential
chemopreventive agent against colon cancer cells (Jaganathan et
al., 2011). Eugenol has not only antitumoural properties in this cell
type, but also it has antiproliferative effects in other cells such as
prostate or melanoma cancer cells (Ghosh et al., 2005, 2009). In
animal models, this compound has demonstrated interesting
results. So, when Ehrlich ascites carcinoma (EAC) cells were injected
in female mice and then, either 0,2 ml (25% v/v) of honey or
eugenol (from 80 to 120 mg/Kg) were administered
intraperitoneally, an inhibitory effect in tumour growth was reported
of 30% with eugenol and close to 40% with honey. Another
important compound with antitumoural properties is chrysin. This
compound and honey (acacia honey) have antiproliferative effects in
human (A375) and murine (B16-F1) melanoma cell lines. In this
case honey and chrysin induced G 0/G 1 cell cycle arrest, and hence,
chrysin has been considered as a potential candidate for cancer
prevention and treatment (Pichichero et al., 2010). In other
research, cell viability assay and flow cytometric analysis suggested
that chrysin exhibited a dose-dependent and time-dependent ability
to block, in G1 phase, rat C6 glioma cell line. It was demonstrated
that expression of cyclin-dependent kinase inhibitor, p21, was
significantly increased, and both cyclin-dependent kinase 2 and 4
(CDK2, CDK4) kinase activities were reduced by chrysin in a dose-
dependent manner (Weng et al., 2005). Several individual
compounds of honey have shown apoptotic effects. For instance,
galangin is effective as an anti-proliferative and apoptotic agent in
human myeloid cell lines (K562 and KCL22) and in imatinib mesylate-
resistant myeloid cells (K562-R and KCL22-R). Galangin induced a
decrease in Bcl-2 levels and markedly increased the apoptotic activity
of imatinib in both imatinib sensitive and imatinib-resistant Bcr-Abl+
cell lines. These observations suggest that galangin is an interesting
candidate for a combination therapy in the treatment of imatinib-
resistant leukemias (Tolomeo et al., 2008). The honey components
quercetin (Murakami et al., 2008), caffeic acid (Nagaoka et al.,
2003), acacetin (Shen et al., 2010), kaempferol (Luo et al., 2010),
and apigenin (Shukla and Gupta, 2010) have all been studied in
relation to cancer.
Not all studies have been conducted on cell and animal models;
in fact honey has also been evaluated in clinical cancer cases and
with beneficial effects. Honey has been evaluated as a treatment for
radiotherapy or chemotherapy, induced mucositis in humans
(Motallebnejad et al., 2008; Rashad et al., 2009). Mucositis is a
frequently encountered oral complication of both radiation and
Honey and health 151
Fig. 4. The benefits of honey against cancer at cell, animal and human levels.
chemotherapy of head and neck cancers. In the case of the research
to assess the effect of honey against radiation-induced mucositis,
Motallebnejad et al. (2008) performed a single blind clinical trial with
forty patients with head and neck cancer and under radiotherapy
treatment. Twenty of them were administered honey before, during
and after radiation and the rest saline before and after radiation.
Then, patients were evaluated weekly for mucositis and an
important reduction in mucositis among honey-treated patients was
found. In view of this result, it can be concluded that honey is an
effective treatment in mucositis derived from cancer treatments.
Another possible clinical use of honey is in the management of
radiation-induced burns in women treated for breast cancer. In this
case, women were treated with honey and pentoxifylline and so the
area of burned skin was reduced by more than 25% with honey, so
that patients underwent shorter radiotherapy treatments (Shoma et
al, 2010).
Life Mel honey is a natural honey produced by bees that are fed
a blend of different therapeutic herbs such as Calendula, Avena
sativa, Echinacea, nettles, ginseng, red clover, Melissa and
dandelion, among others. Their flavonoids, vitamins and minerals
enrich Life Mel honey and each herb has a specific function to offset
the adverse effect of drugs used in cancer patients undergoing
chemotherapy. Neutropenia is a common side effect affecting cancer
patients under chemotherapy treatments, consisting in a decrease of
neutrophils in blood. The low levels of these blood cells put these
patients at risk of infections. In fact, Zidan et al. (2006) observed
that intake of Life Mel honey helped to prevent neutropenia induced
by chemotheraphy, and haemoglobine levels were high in 64% of
the cases.
If we gather all of these results it is possible to believe that
honey is an important source of interesting compounds for the
treatment of cancer, and that it can be regarded as a functional food
in the cancer field.
Antiulcer and cardioprotective properties
Of great interest are the antiulcer properties of honey and, also of
propolis, described by Viuda Martos et al. (2008a, 2008b). These
authors cited several sources regarding the relationship between the
antiulcer action of honeys and their flavonoid content. The antiulcer
capacity of honeys has been attributed to their many flavonoids
(Gracioso et al., 2002, Batista et al., 2004, Hiruma-Lima et al, 2006).
Flavonoids in beehive products may inhibit the formation of gastric
ulcers via various suggested mechanisms. For example, Speroni and
Ferri (1993) deduced that these compounds increased the level of
mucosal prostaglandins; Vilegas et al. (1999) added that apart from
the formation of these prostaglandins, honey flavonoids can also
inhibit acid secretions thus preventing ulceration. Another proposed
theory to explain the development of gastric ulcers argues that the
lesions are provoked by reactive oxygen species, and that the
flavonoids in honey scavenge them and thus inhibit lipid peroxidation
and so prevent tissue damage (Martin et al., 1998, Young et al.,
1999, Duarte et al., 2001). Some studies confirmed the antiulcer
activity of some flavonoids found in honey, such as kaempherol and
quercetin (Leite et al., 2001, Yao et al., 2004 b, Orsolic and Basic,
2005, Fiorani et al., 2006), also hesperitin and naringin which were
both found in orange honey (Ferreres et al., 1993, 1994; Kanaze et
al., 2003).
The cardioprotective role of natural honey was studied by
Rakha et al. (2008) in relation with the decrease of the vulnerability
of the heart to several kinds of cardiac disorders and vasomotor
dysfunction associated with hyperadrenergic activity.
Hyperadrenergic activity may be caused by stress, emotion, and
among physiological causes, there is evidence of a close association
between palpitation, tachycardia, arrythmia, and the
pheochromocytoma (an adrenaline-secreting tumour of adrenal
medullary tissue). Adrenaline (epinephrine), a well-known drug
widely used to maintain blood pressure, may cause side effects such
as tachycardia, arrythmias, hypertension and oxidative stress. Natural
wild honey can ameliorate the cardiac disorders induced by
adrenaline injected in urethane-anestethised rats probably thanks to
its total antioxidant capacity and its great pool of enzymatic and non-
enzymatic antioxidants involved in cardiovascular defense
mechanisms.
The cardiovascular benefits of various flavonoids, their effects
on blood pressure and the role played by some molecules such as
quercetin and its glycosides in the prevention of the oxidative
damage of low density lipoproteins (LDL) are fully described in the
literature (Raj Narayana et al., 2001). Some honeys can protect LDL
from oxidative damages (Gheldof and Engeseth, 2002; Gheldof et al.,
2003), and it is important from a clinical aspect , since oxidative
modifications of LDL are considered critical in the onset of
atherosclerosis (Esterbauer et al., 1992 ).
Conclusions
The phenolic composition of honey appears to have an important role
in the health giving properties of bee hive products. Honey, together
with other natural foods, seems to be an important component of the
human diet.
Increasingly the amount of honey consumed in a well-balanced
diet could help to improve the prevention of free radical related-
diseases, as well as contributing to the management of more
common infective disorders. Honey can also be considered as a
natural alternative in the treatment of some herpes, and increasing
interest amongst clinicians of the effects of flavonoids such as
chrysin, acacetin and apigenin on HIV-1 virus is important.
In the cancer field, honey and some of its compounds, such as
eugenol, chrysin and galangin have demonstrated prevention and
treatment potential.
152 Uthurry, Hevia, Gomez-Cordoves
On account of its historical background of healthy properties
and the increasing experimental knowledge, honey can be regarded,
as a functional food which might be reasonably consumed
throughout life. Nevertheless, further studies are required to
determine and explore the mechanisms of flavonoid/polyphenol
derived benefits and to possibly discover new and as yet unreported
benefits of this natural product.
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