Biologically Active Compounds from Hops

and Prospects for Their Use

Marcel Karabı́n, Tereza Hudcová, Lukáš Jelı́nek, and Pavel Dostálek

Abstract: Although female cones of the hop plant (Humulus lupulus) are known primarily as raw material supplying
characteristic bitterness and aroma to beer, their equally significant health-promoting effects have been known to mankind
for several thousand years and hop is a plant traditionally utilized in folk medicine. This paper summarizes the scientific
knowledge on the effects of all 3 major groups of secondary metabolites of hops; polyphenols, essential oils, and resins.
Because of their chemical diversity, it is no coincidence that these compounds exhibit a wide range of pharmacologically
important properties. In addition to antioxidant, anti-inflammatory, and anticancer-related properties, particular attention
is being paid to prenylflavonoids that occur almost exclusively in hops and are considered to be some of the most active
phytoestrogens known. Hop oils and resins are well known for their sedative and other neuropharmacological properties,
but in addition, these compounds exhibit antibacterial and antifungal effects. Recently, alpha bitter acids have been
shown to block the development of a number of complex lifestyle diseases that are referred to by the collective name
“metabolic syndrome.” Information presented in this review confirms the significant potential for the use of hops in the
pharmaceutical industry and provides an understanding of beer as a natural drink that, although moderately consumed,
may become a source of many health-promoting compounds.
Keywords: biologically active compounds, bitter acids, essential oils, hops, polyphenols

Introduction mentioning hops focused more on their brewing applications.

Hop (Humulus lupulus Linnaeus) is a dioecious, perennial plant
belonging to the Cannabaceae family of the Urticales order
(Roberts and Wilson 2006). Besides the common hop, the Hu-
mulus genus includes 2 other species, Humulus japonicus Siebold &
Zucc and Humulus yunnanensis Hu, but only Humulus lupulus is of
industrial/medical importance (Van Cleemput and others 2009a).
The Humulus genus probably originated in China, from where it
migrated to the vast areas of the moderate climatic zones of the
northern and southern hemispheres (Zanoli and Zavatti 2008).
Nowadays, the world’s greatest hop producers are Germany, the
U.S., China, and the Czech Republic (U.S.A. Hops 2014).
The use of hops as a medicinal plant has more than 2000 y
of history (Koetter and Biendl 2010). The ancient healers used
hops against leprosy, foot odor, constipation, and for blood pu-
rification (Karabin and others 2015). The earliest writings that
mention hops date back to the 11th century, when the Arabic
medicus Mesue described their anti-inflammatory effects. Later,
in 1158, the German abbess and botanist, Hildegard von Bingen,
indirectly confirmed the antimicrobial properties of hop when
she recommended adding this plant to beverages so as to prolong
their shelf-life. From the 13th century, the majority of writings
MS 20151837 Submitted 3/11/2015, Accepted 2/2/2016. Authors are with Dept.
of Biotechnology, Faculty of Food and Biochemical Technology, Univ. of Chemistry and ties of hop substances (Koch and Heim 1953). Nowadays, hops or
Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic. Direct inquiries special phytoestrogen-rich hop materials are common components
to author Dostálek (E-mail: Pavel.Dostalek@vscht.cz).
However, several medical documents from this period have been
preserved. One of the most valuable scientific manuscripts of the
15th century, the Garden of Health (Anonymous 1485), describes
the effect of hops in combating ear infections. In the 16th cen-
tury, the German botanist Hieronymus Bock documented the 1st
application of hop in gynecology, Paracelsus used the hop plant
against indigestion, and the Italian doctor Matthiolus mentioned
its diuretic and bile-increasing effects (Biendl 2009; Koetter and
Biendl 2010). From the 19th century, phytotherapy has focused
on the effects of hop against sleeplessness. The combination of
hop extract and valerian (Valeriana officinalis, Valerianaceae) has long
been known and is the most frequently administered form of herb-
based sleeping agent and sedative (Dimpfel and Suter 2008). Hops
and their bitter components have also traditionally been used to
stimulate gastric secretion in a similar way as caffeine. A study
using the rat pylorus-ligation model confirmed that hops taken
orally will clearly increase gastric juice volume without affecting
acidity and this was mediated by the cholinergic nervous system
(Kurasawa and others 2005). Until the 1st half of the last century,
the majority of hop crops was harvested and processed manually.
At that time, female hop-pickers complained of menstrual distur-
bances that appeared at the time of harvest. Not long after that,
in 1953, Koch and Heim demonstrated strong estrogenic proper-
of commercial dietary supplements for women with menopausal
symptoms or hormonal disturbances.


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542 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016 doi: 10.1111/1541-4337.12201
Biologically active compounds from hops . . .
Figure 1–Chemical structures of main hop bitter acid analogues: (A) α-bitter acids and (B) β-bitter acids.
It is of no surprise that the majority of the hop crop is used in the
brewing industry. Hydrophobic compounds from hop cones are
responsible for bitterness (α- and β-bitter acids) and the character-
istic hoppy aroma (essential oils) of beer (Van Opstaele and others
2010). In addition, hop cones contain many biologically active
phenolic compounds and other constituents that have attracted
the attention of many phytopharmaceutical companies.
The α-bitter acids are the most important fraction of hop resins.
They are secreted from the lupulin glands of hop cones in the form
of a yellow powder (Okada and Ito 2001). The α-bitter acids
are a mixture of 6 humulone analogues (Figure 1A) that can be
found in all hop varieties, the major ones being humulone (35%
to 70% of total α-bitter acids), cohumulone (20% to 55%), and
adhumulone (10% to 15%; Briggs and others 2004). In addition,
hop cones contain small amounts of posthumulone, prehumulon,
and adprehumulone (Verzele and De Keukeleire 1991; Smith and
others 1998). The most important reaction of the α-bitter acids
is their isomerization to their corresponding iso-α-bitter acids
(Figure 2), which occurs more favorably at higher temperatures
(100 to 130 °C) and pH (8 to 10; Malowicki and Shellhammer
2005). In brewing technology, isomerization occurs during hop
boiling (100 °C, atmospheric pressure, 90 min), but not very
efficiently. According to Bamforth (2000), no more than 50%
of total α-bitter acids are converted in this way to the strongly
bitter tasting iso-α-bitter acids. Analogous to the α-bitter acids,

C 2016 Institute of Food Technologists®
the β-bitter acids (Figure 1B) also consist of several analogues:
lupulone (30% to 55% of total β-bitter acids), colupulone (20%
to 55%), adlupulone (5% to 10%), prelupulone, and postlupulone
(Verzele 1986). These compounds are virtually insoluble in water
and therefore they are only of minor importance in the brewing
process. However, because of their biological activities, they are in
the forefront for many potential biomedical applications.
Hop oils or essential oils are a very diverse group of several hun-
dred compounds with different physicochemical, biological, and
organoleptic properties. These compounds are secreted from the
lupulin glands, along with bitter acids, when the biosynthesis of
bitter acids is complete (Briggs and others 2004). In 1981, Sharpe
and Laws (1981) introduced a classification system where all
known hop oils were divided into 3 fractions: hydrocarbons (con-
tain monoterpenes, sesquiterpenes, and aliphatic hydrocarbons),
oxygenated compounds (terpene alcohols, sesquiterpene alco-
hols, and other oxygenated compounds), and sulfur-containing
compounds (thioesters, sulfides, and other sulfur compounds).
The most abundant representatives of the hydrocarbon fraction
(50% to 80% of total oil) are the monoterpenes α- and β-pinene,
myrcene, and limonene (Figure 3A), and the sesquiterpenes α-
humulene, β-farnesene, β-caryophyllene, α- and β-selinene, and
γ -muurolene (Figure 3B). Other components of the hydrocarbon
fraction are present in hop cones in only small amounts. The
oxygenated fraction (up to 30% of total oil) is formed during
Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 543
Biologically active compounds from hops . . .
Figure 2–Isomerization of hop α-bitter acids.
hop ripening, processing, and storage (Howard and Slater 1957).
It is a complex mixture of terpenic alcohols, aldehydes, ketones,
epoxides, acids, and esters (Sharpe and Laws 1981). The most
extensively studied compounds from the oxygenated fraction are
linalool, geraniol, caryophyllene oxide, and farnesol (Figure 3C).
The sulfur-containing fraction represents a minor part of total
oils (up to 1%); however, many of these compounds have a very
low flavor threshold (Peppard 1981). This fraction has little or no
biological activity; therefore, we will not pay any special attention
to them in this review.
Hop polyphenolic compounds are another large group of bi-
ologically active secondary metabolites that comprise 3% to 6%
of the dry weight of hop cones (Moir 2000). The majority of
polyphenols are located in the strig and bract, with the excep-
tion of the prenylflavonoids, which are secreted from lupulin
glands together with the bitter acids and essential oils (Almaguer
and others 2014). Biendl (2009) split the hop polyphenols into
4 groups: flavonols, flavan-3-ols, phenolic carboxylic acids (deriva-
tives of benzoic acid and cinnamic acid), and other phenolic
compounds (prenylflavonoids, stilbenoids and so on). The dom-
inant hop flavonols are quercetin, kaempferol, and myricetin
(Figure 4A); however, the majority of these compounds are present
in the form of glycosides, where D-glucose and L-rhamnose are
the most frequent sugar groups. However, flavan-3-ols such as (+)-
catechin, (−)-epicatechin, and (+)-gallocatechin (Figure 4A) are
relatively highly abundant hop phenolic monomers that are able
to form dimers, trimers, and oligomers (up to 20 monomeric
units) known as proanthocyanidins or condensed tannins
(Almaguer and others 2014). The phenolic carboxylic acids are
a group of single aromatic polyphenols substituted with hydroxyl
and methoxyl groups. The most abundant compounds belonging
to this group are gallic, protocatechuic, 4-hydroxybenzoic, vanil-
lic, p-coumaric, caffeic, ferulic, and sinapic acids (Figure 4C).
The most discussed class of hop polyphenols, over the past
20 y, is indisputably the prenylflavonoids. These compounds dis-
play strong biological activities and have proven benefits for human
health (Karabin and others 2015). The major prenylflavonoids of
hop are xanthohumol, isoxanthohumol, desmethylxantohumol,
and 6- and 8-prenylnaringenin (Figure 4B).
General Health-Promoting Effects
Antioxidant properties
In recent years many methods for determining antioxidant activ-
ity of hop constituents have been developed. The most commonly
used are chemical methods such as lipid peroxidation inhibitory
activity (LIA), ferric ion-reducing antioxidant power (FRAP),
544 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
2,2-diphenyl-1-picrylhydrazyl (DPPH), radical-scavenging activ-
ities (RSA), total reactive antioxidant potential (TRAP), the thio-
barbituric acid-reactive species (TBARS) assay, determination of
xanthine oxidase activity, and hydrogen peroxide hemolysis. Very
often a combination of methods is used for more precise charac-
terization of antioxidant activities (Karabin and others 2006; Van
Cleemput and others 2009b).
Polyphenols
Through numerous animal and clinical experiments it has been
assumed that most of the beneficial effects of polyphenols are re-
lated to their antioxidant properties. Polyphenols have been shown
to be effective antioxidants in a wide range of chemical oxida-
tion systems, as demonstrated by their ability to scavenge reactive
oxygen (ROS) or nitrogen species such as hydroxyl, peroxyl, su-
peroxide, hydrogen peroxide, or singlet oxygen (Ross and Kasum
2002; Nemzer and others 2011; Sandoval-Acuna and others 2014).
These radicals are involved in oxidative stress and may play cru-
cial roles in the development of tumors, atherosclerosis, diabetes,
Alzheimer’s disease, Parkinson’s disease, or in the entire ageing
process (Mladenka and others 2010; Nemzer and others 2011).
Antioxidant effects of polyphenols are also characterized by their
ability to suppress some specific enzymes involved in the gener-
ation of reactive oxygen species (Pietta 2000), such as NADPH
oxidase (Schramm and others 2012), cyclooxygenases, xanthine
oxidase (Masuda and others 2014), or lipoxygenases. Inhibition
of these enzymes by polyphenolic substances also contributes to
a reduction in antioxidant stress (Stoclet and others 2004). In ad-
dition, phenolic compounds can chelate trace metals (copper and
iron ions), which, like tert-butyl hydroperoxide (Alia and others
2006), play crucial roles in the oxidation of low-density lipopro-
tein (LDL), and thus in the development of atherosclerosis (Lind
2003; Porfirio and others 2014).
The antioxidant potential of specific polyphenols is determined
by their chemical structure and the number and position of OH
groups on the aromatic nucleus. Significant polyphenolic struc-
tural determinants of antioxidant activity are OH groups in the
C4 and C3 positions (o-dihydroxy) bonded on the B ring and
the 4-oxo group on the C ring, especially together with a double
bond between C2 and C3 (Nowak and others 2014). The addi-
tion of other OH groups on the aromatic nucleus in the C4 posi-
tion appears to further enhance antioxidant activities. Among the
flavonoids, quercetin, myricetin, and kaempferol possess the most
significant free radical–neutralizing effects (Quinones and others
2013). Of the compounds derived from phenolic acids, hydrox-
ylated esters of cinnamic acid have more significant antioxidant

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Biologically active compounds from hops . . .

Figure 3–Chemical structures of main hop essential oils: (A) monoterpenes, (B) sesquiterpenes, and (C) oxygenated terpenes.


C 2016 Institute of Food Technologists® Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 545
Biologically active compounds from hops . . .
Figure 4–Chemical structures of main hop polyphenols: (A) flavonoids, (B) prenylflavonoids, and (C) phenolic acids.
potential than compounds derived from benzoic acid. In addition,
flavonoid aglycones are more effective compared to their corre-
sponding glycosides (Nowak and others 2014). Gerhäuser (2009a)
compared radical scavenging capacity of hop phenolic compounds
and showed that catechins, proanthocyanidins, flavonols, and gal-
lic acid were the most potent with SC50 values of 16.9, 7.6, 8.6,
and 8.5 μM for (+)-catechin, procyanidin B3, quercetin, and gal-
lic acid, respectively. Using an oxygen radical-absorbance capacity
546 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
(ORAC) assay, cinnamic, caffeic, and ferulic acids, gallocatechin,
xanthohumol, and myricetin were described as the most active
in hydroxyl and peroxyl radical-scavenging (Gerhauser 2009a).
Kim and others (2002) compared phenolic compounds with vita-
min C, using ABTS and DPPH-scavenging assays, and expressed
their antioxidant activities as vitamin C equivalent antioxidant ca-
pacity (VCEAC). VCEAC results for phenolic compounds were
as follows: gallic acid > quercetin > epicatechin > catechin >

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Biologically active compounds from hops . . .
vitamin C > rutin. It was proposed that monomeric and
oligomeric flavonols have the ability to limit LDL oxidation
(Quinones and others 2013). It was demonstrated that among
phenolic compounds, flavonoids with a prenyl group are more
effective as inhibitors of LDL oxidation (Bartmanska and others
2013).
In addition, hop prenylflavonoids, especially xanthohumol, have
significant antioxidant potential. Gerhäuser and others (2002)
found that xanthohumol exerts 9 times higher antioxidant activity,
as determined by ORAC, than the reference compound Trolox, a
derivative of vitamin E that was used as a reference. Miranda and
others (2000b) tested the inhibitory effects of prenylflavonoids on
LDL oxidation induced by copper ions, where xanthohumol was
shown to be the most effective, having an antioxidant potential
greater than α-tocopherol.
Essential oils
Compared to hop polyphenols, the antioxidant properties of
hop essential oils and other constituents are much more complex.
The majority of hop polyphenols exhibit lower or higher activities
regardless of the analytical methods used. In contrast, antioxidant
properties of terpene compounds can vary; the same compound
can behave neutrally, exhibit relatively strong antioxidant proper-
ties, or, in many cases, may also acts as a pro-oxidant.
For example, linalool is able to reduce oxidative stress from
H2 O2 -induced lipid oxidation in the brain of guinea pigs (Celik
and Ozkaya 2002). The effect of intraperitoneally administered
linalool (120 mg/kg body weight [b.w.]) was comparable with the
effects of vitamin E and lipoic acid. Studies based on the abil-
ity to scavenge the 2,2-diphenylpicrylhydrazyl (DPPH) radical,
however, gave contradictory results. Hussain and others (2008)
showed relatively strong (IC50 = 16.4 μg/mL) antioxidant prop-
erties of linalool, whereas in another study (de Lima Guimaraes
and others 2014) linalool and another monoterpenic alcohol, ter-
pineol, showed no DPPH radical-scavenging properties, even at
a concentration of 500 μg/mL. Moderate antioxidative effects of
these compounds were demonstrated in both studies using the
β-carotene/linoleic acid assay in amounts from 50 to 200 μg/mL
(Hussain and others 2008; de Lima Guimaraes and others 2014).
Completely different results were obtained using the TBARS assay,
which attributed prooxidant effects to linalool at concentrations
ranging from 100 to 1000 μg/mL. For other monoterpenic alco-
hols, such as geraniol and terpineol, prooxidant effects were not
proven and the sesquiterpenic alcohol farnesol showed even mod-
erate antioxidant properties (Ruberto and Baratta 2000). The most
significant hop monoterpene myrcene, at a dose of 7.5 mg/kg b.w.,
was able to prevent oxidative damage of Wistar rat cells by increas-
ing the activities of the antioxidant enzymes superoxide dismutase
and glutathione peroxidase, possibly enabling a future application
in the prevention of peptic ulcer disease (Bonamin and others
2014). Antioxidant effects were also confirmed by various meth-
ods for other minor monoterpenic hydrocarbons occurring in hop,
such as β-pinene and γ -terpinene (Ruberto and Baratta 2000; de
Lima Guimaraes and others 2014), which, at concentrations rang-
ing from 50 to 1000 μg/mL, exhibited different effects when using
the β-carotene/linaloic acid assay and the DPPH method (Chen
and others 2014a) and limonene (Roberto and others 2010; Singh
and others 2010).
The sesquiterpene hydrocarbons α-humulene and β-caryo-
phyllene are among the technologically most important com-
ponents of hop essential oils. Considerable attention is now
being paid to their antioxidant properties, which have been

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confirmed using a variety of methods. In the study of Callejo
and others (2013), these sesquiterpenes were tested for their
radical-scavenging properties and their ability to prevent lipid
oxidation. Caryophyllene showed stronger antioxidant properties
than humulene, and its ability to prevent lipid oxidation was
higher than for the antihyperlipidemic drug Probucol and the
natural antioxidant α-tocopherol. At micromolar concentrations,
caryophyllene was a strong scavenger of hydroxyl radicals and su-
peroxide anions, but not the DPPH radical (IC50 = 132 μg/mL).
Contrary to this, in another study (Dahham and others 2015),
caryophyllene showed significantly lower IC50 values by DPPH
(0.25 μg/mL) and FRAP (0.66 μg/mL) methods, and these
values were comparable with the IC50 of ascorbic acid.
The acyclic sesquiterpene β-farnesene, a substance characteris-
tic for hop varieties genetically related to Saaz hops, was also tested
in vitro for its antioxidant properties. Testing on human blood tis-
sue (Celik and others 2014) showed a slight increase in antioxidant
capacity after 24 h of exposure to farnesene (10 to 25 μg/mL) and
application of farnesene to rat cerebral cortex neurons showed a
reduction in H2 O2 -induced oxidative stress, suggesting the pos-
sibility of its use for the prevention of certain neurodegenerative
diseases (Turkez and others 2014). Similar effects, in this case re-
lating to a reduction in 1,2-dimethylhydrazine-induced oxidative
stress in rat colon cells was also shown for farnesol, which was
able to potentiate the activity of antioxidant enzymes at a level of
40 mg/kg b.w. (Khan and Sultana 2011).
Bitter acids
Humulone and lupulone were tested as potent antioxidant
(DPPH radical-scavenging activity [RSA] and lipid peroxidation
inhibitory activity [LIA]), and it was found that humulone and
lupulone had IC50 values of 3.2 × 10−5 M and 2.5 × 10−5 M
(DPPH-RSA) and 7.9 × 10−5 M and 3.9 × 10−5 M (LIA), re-
spectively. Humulone and lupulone had comparable antioxidant
activities, as measured by the DPPH–RSA assay, to the natural an-
tioxidants α-tocopherol (IC50 = 2.8 × 10−5 M) and ascorbic acid
(IC50 = 3.3 × 10−5 M; Tagashira and others 1995). Humulone
inhibited hydrogen peroxide-induced hemolysis (IC50 = 2.8 μM;
Tobe and others 1997a).
RSA was different for different hop bitter compounds. From
the strongest to the weakest values of RSA, the order was: α-
acids, β-acids, dihydro-iso-α-acids, hexahydro-iso-α-acids, and
tetrahydro-iso-α-acids (IC50 ; 0.21, 0.96, 1.36, 1.40, 1.78 mg/mL,
respectively). For LIA activity, the order was different: α-acids,
β-acids, iso-α-acids, tetrahydro-iso-α-acids, dihydro-iso-α-acids,
hexahydro-iso-α-acids (Liu and others 2007; Van Cleemput and
others 2009a).
Antimicrobial Activities
Bitter acids
Beer is often considered to be a “functional beverage” for several
reasons including its prolonged shelf-life and absence of microbial
contamination through the use of hops, which provides a char-
acteristic mechanism of microbial inhibition (Zanoli and Zavatti
2008; Van Cleemput and others 2009a). The mechanism of inhi-
bition of beer spoilage bacteria is known. Gram-positive bacterial
species such as Lactobacillus, Streptococcus, Staphylococcus, Micrococus,
Bacillus, and Pediococcus (Shimwell 1937; Chin and others 1949b;
Schmalreck and Teuber 1975; Sakamoto and Konings 2003) can
spoil beer, increase turbidity, and produce unpleasant aromatic
compounds such as diacetyl or hydrogen sulfide (Sakamoto and
Konings 2003). The mechanism of inhibition of sensitive cells
Biologically active compounds from hops . . .
Figure 5–Mechanism of hop antimicrobial effects and hop resistance of cells: (A) multidrug resistance pump HorA; (B) pmf-dependent transporter;
and (C) H+ ATPase (adapted from Sakamoto and Konings 2003).
by hop resins was 1st explained by Simpson (Simpson 1993a).
β-Acids, α-acids, and also iso-α-acids are incorporated into cell
membranes (Gerhauser 2005b) where they act as mobile-carrier
ionophores, catalyzing processes including the electroneutral in-
flux of undissociated molecules, exchange of protons for divalent
cations such as Mn2+ , and efflux of the resulting complex. This
leads to the intracellular accumulation of protons, dissipation of
the transmembrane proton gradient, decrease in proton motive
force (pmf)-driven uptake of nutrients, starvation, and cell death
(Fernandez and Simpson 1993; Simpson 1993a,b,c; Sakamoto and
Konings 2003; Figure 5).
Unfortunately some microorganisms have developed mecha-
nisms to increase their resistance to this effect. Cell membranes
of Gram-negative bacteria such as Pectinatus cerevisiiphilus, Pecti-
natus frisingensis, and Megasphera cerevisiae (Sakamoto and Konings
2003) reduce permeation of nonpolar substances, so these anaero-
bic microorganisms are almost totally resistant to hop compounds
(Chihib and others 1998, 1999). Other hop-resistant bacteria are
capable of excluding hop compounds by a multidrug resistance
pump (HorA) or a pmf-dependent transporter (Sakamoto and oth-
ers 2001; Suzuki and others 2002), as well as by pumping protons
back outside the cell by H+ ATPase that was overexpressed after
exposure to hop resins (Sakamoto and others 2002). Modification
of the lipid composition of the cytoplasmic membrane in beer
spoilage-causing lactic acid bacteria can also result in increased
resistance to hop substances (Yasui and others 1997).
Individual hop resin compounds are differentially effective. The
antibacterial activities of β-acids and α-acids are higher than that
of iso-α-acids, although, in practice, because of their lower solu-
bility in beer, their efficiency is lower than iso-α-acids (Sakamoto
and Konings 2003). As hop acids are weak acids and only the
548 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
undissociated forms are active, antibacterial effects decrease with
decreasing pH. Potential antimicrobial activity is also increased by
the higher hydrophobicity of hop compounds (number and length
of acyl and prenyl groups in side chains; Schmalreck and Teuber
1975). It is also notable that the major antimicrobial effects of hop
polyphenols are similar—inhibition of ion flux (Einhellig 2004).
Yeast species such as Saccharomyces cerevisiae and Saccharomyces
pastorianus are not inhibited by normal concentrations of bitter
acids, and only very high concentrations have inhibitory effects
(Schmalreck and Teuber 1975). This is an advantage for beer
production where hop bitter acids keep beer safe from bacterial
contamination without affecting cultured yeast strains. Very lim-
ited inhibition was detected for Penicillium and Aspergillus species
(Engelson and others 1980; Mizobuchi and Sato 1985). Com-
paring antimicrobial activities of hop compounds, the following
order was observed: lupulone > humulone > isohumulone
(Larson and others 1996). However, despite their effectiveness in
beer production, hop acids impart an undesirable bitterness that
makes their application as a microbial inhibitor in other foods
less attractive. Schur and others (2015) studied the antimicrobial
effects of humulinic acid, which is derived from iso-α-acids. The
minimum inhibitory concentration (MIC) of humulinic acid was
1.4 μM for Lactobacillus brevis, which is the lowest MIC from all
hop substances studied (iso-α-acids, methyl-iso-α-acids, cis-iso-
cohumulone, methyl-cis-iso-cohumulone, humulinic acids, and
imino-iso-α-acids). We suggest that humulinic acids may be used
in food preservation because of the fact that they do not impart
any bitter taste; they may have future potential as taste-neutral food
preservatives.
Because of their antibacterial effects, hop compounds can also
be used in human or veterinary medicine. Researchers have also

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Biologically active compounds from hops . . .

reported on the combined use of hop compounds and antibiotics protozoan parasites. A similar mechanism of action was also ob-
(Natarajan and others 2008). Lupulin and xanthohumol, together served against certain virulence factors that induce various DNA
with antibiotics such as polymyxin B sulfate, tobramycin, and or RNA viruses. The antimicrobial mechanism involves the ability
ciprofloxacin were tested. MICs were determined to elucidate pos- to accumulate inside cells or to penetrate phospholipid cell mem-
sible common mechanisms of action of antibiotics and hop com- branes and cause inhibition (Alvesalo and others 2006). Antimicro-
pounds. Both Gram-positive and Gram-negative bacteria were bial activities are dependent particularly on the hydrophobic char-
used in this evaluation. All Gram-positive bacteria responded acter of compounds because of their interaction with the bacterial
to treatment and, surprisingly, there were also some positive ef- cell wall (Gerhauser 2005b). It is also assumed that polyphenols act
fects against certain Gram-negative bacteria (Natarajan and otherssynergistically with various antibiotics against multidrug-resistant
microorganisms (Daglia 2012).
2008). This fact was used for testing inhibitory effects of fresh hops
on the growth of Helicobacter pylori. Fresh hops (variety Saaz) that Polyphenols with a flavan structure, such as flavan-3-ols,
contain very high concentrations of lupulone were homogenized flavonols, and tannins are particularly active(Daglia 2012). These
after harvest and the homogenate was pascalized (high pressure polyphenols exert inhibitory activities against a wide range of
Gram-positive bacteria including Staphylococcus aureus, Lactobacillus
treatment for food preservation). This preparation was used to test
acidophilus, Actinomyces naeslundi, Streptococcus mutans (Sendaman-
for inhibitory effects on strains of H. pylori, a pathogenic microor-
ganism that was isolated from patients suffering from gastritis orgalam and others 2011), and C. perfringens and against Gram-
gastric ulcers. The tests demonstrated the potential of hops as a negative bacteria such as Prevotella oralis, Prevotella melaninogenica,
supplement to antibiotic treatment of H. pylori infections (CermakFusarium nucleatum, or Escherichia coli. Alvesalo and others (2006)
and others 2015). Lupulone may also have applications in veteri- also demonstrated inhibitory effects of phenolic compounds on
nary medicine against Clostridium perfringens, a pathogenic type Athe Gram-negative pathogenic bacterium Chlamydia pneumoniae
bacterium found in chicken intestinal tracts, particularly the je-that plays a crucial role in several respiratory infections, such as
junum and cecum (Siragusa and others 2008). This application pneumonia, which represent increased risk factors in diseases such
for chickens may avoid the development of antibiotic resistance as asthma or lung cancer. Quercetin and myricetin have especially
that commonly occurs after the prolonged use of antibiotics in strong anti-chlamydial activities in human cells.
animal feed. The effect of hop β-acids (lupulone) on growth of Phenolics such as gallic, caffeic, or ferulic acids exert weaker
antimicrobial activities than flavonoid polyphenols, but worthy of
clostridia in soil-contaminated pressed sugar beet pulp silages was
also investigated (Emerstorfer and others 2011). It was confirmed mention are antimicrobial activities against some Gram-positive
that hop β-acids improved the preservation effect of lactic acid bacteria such as S. aureus, L. monocytogenes, and Gram-negative
bacteria in suppressing clostridial growth in silages. Some appli-bacteria including Pseudomonas aeruginosa. Dı́az-Goméz and oth-
cations of β-acid derivatives (hexahydrolupulones) were patented ers (2014) investigated the antibacterial activities of gallic acid in
(Nutter and others 1997, 1998). A problematic issue in the food comparison with catechin, showing that gallic acid exerts even
higher growth inhibitory effects on E. coli.
industry is contamination by Listeria monocytogenes, particularly in
dairy and meat products (Larson and others 1996). β-acids were Among polyphenols with antimicrobial effects, prenyl-
shown to possess high antimicrobial activity against Gram-positiveflavonoids, because of their more hydrophobic character, have at-
tracted the most attention in recent years. Prenylflavonoids exhibit
bacteria in vitro and in a practical application for meat preservation
antibacterial activities, especially against certain Gram-positive
(Kramer and others 2015). Statistically significant antibacterial ac-
tivity of hop extract on L. monocytogenes was also demonstrated bacteria of the genera Staphylococcus and Streptococcus. However,
in the production of red smear-ripened cheese. The surface of growth inhibitory effects of xanthohumol on S. mutans were
the cheese was contaminated with 2 to 3 logs of L. monocyto- 6 times weaker in comparison with the β-bitter acids (Gerhauser
genes/g cheese and the cheeses were smeared daily with a solution 2005b). Antifungal activities of prenylflavonoids include the abil-
containing a hop extract (30 μg/g cheese); contamination after ity of xanthohumol and 6-prenylnaringenin to effectively inhibit
treatment was reduced by about one log (Kuehnast and Braun the growth of the dermatophytic fungi Trichophyton mentagrophytes
2013). Hop extract (β-acids) can also be used as an antimicro- and Trichophyton rubrum (Gerhauser 2005b).
bial agent in preparations for producing pickled vegetables (Ii and In addition, prenylflavonoids inhibit protozoan parasites such
Takata 2001). as Plasmodium falciparum, the causative agent of malaria. The an-
However, there is very limited information about antiviral ac- timalarial mechanism of prenylflavonoids includes the inhibition
tivities of hop compounds (Buckwold and others 2004). Pure iso- of cysteine protease, an enzyme responsible for the degradation of
α-acids displayed low to moderate antiviral activity against bovine
hemoglobin (Gerhauser 2005b).
viral diarrhea virus (BVDV, therapeutic index [TI] = 9.1), which Antiviral activities of polyphenols, especially prenylflavonoids,
was used as a model for hepatitis C virus, and cytomegalovirus have been demonstrated in numerous studies against a wide range
(CMV, TI = 4.2) with IC50 values in the low μg/mL range of virulence factors such as the RNA viruses, bovine viral diarrhea
(Buckwold and others 2004). Hop acids also have anti-protozoal virus (BVDV), which is a surrogate of hepatitis C virus (HCV;
activities (Srinivasan and others 2004), whereas ciliated protozoaZhang and others 2010) and cytomegalovirus (CMV), and against
were more sensitive to hop acids than amebae. Plasmodia were also the DNA viruses herpes simplex type 1 and 2 (HSV-1, HSV-
2; Buckwold and others 2004). Proanthocyanidins exert antiviral
sensitive, but at a lower level than to synthetic anti-malarial drugs.
β-Bitter acids, tetrahydro-iso-α-acid and xanthohumol were stud- activities against influenza A virus and also HSV by their ability
ied and were found to be particularly potent against protozoa to prevent entry of the virus into the host cell, which is the 1st
(Srinivasan and others 2004). critical step in HSV-1 infection. Phenolic compounds also have
potent inhibitory activities against human immunodeficiency virus
Polyphenols 1 (HIV-1) by inhibition of HIV-1 reverse transcriptase in vitro,
Antimicrobial activities of polyphenols are based on inhibiting suppressing several crucial steps in viral replication (Wang and
the replication of microorganisms, including bacteria, fungi, and others 2004).


C 2016 Institute of Food Technologists® Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 549
Biologically active compounds from hops . . .
Significant antimicrobial properties also include reduction of ad-
hesion of microorganisms to abiotic surfaces, and thus inhibition
of biofilm formation. Rozalski and others (2013) investigated the
inhibition of biofilm viability by a spent hop extract free of xan-
thohumol (42.8% reduction), a hop cone extract containing 51%
xanthohumol (78% reduction), and pure xanthohumol (86.5%
reduction).
Essential oils
Antimicrobial and antiviral effects were demonstrated using a
very broad spectrum of plant essential oils (Bassole and Juliani
2012) and their use in food technology (Burt 2004), cosmetics
(Singh and others 2011; Dreger and Wielgus 2013), and medicine,
for example to control bacterial infections resistant to conventional
antibiotics (Solórzano-Santos and Miranda-Novales 2012; Yap and
others 2014), has been discussed. Unfortunately, most attention
has been focused on examining these effects using plant extracts,
whose composition is complex and variable, and only a few studies
have examined properties of pure substances.
Generally speaking, extracts containing hop essential oils usu-
ally have weaker antimicrobial activity than extracts containing
hop resins. Hop oil products that showed moderate antibacterial
effects against the Gram-negative bacteria E. coli, Gram-positive
bacteria Bacillus subtilis and S. aureus, and antifungal activity against
the yeast Candida albicans and the fungus Trichophyton interdigitale,
were obtained by hydro-distillation of hop cones (Langezaal and
others 1992). This was confirmed by Jirovetz and others (2006)
who demonstrated antimicrobial effects of hop oils against Gram-
positive S. aureus and Enterococcus faecalis, Gram-negative Esherichia
coli and Salmonella sp., and the yeast C. albicans. Moreover, in this
study, the properties of selected pure terpenes were examined and
some of these compounds also inhibited growth of Gram-negative
Proteus vulgaris and P. aeruginosa.
Among the most studied topics are the antimicrobial effects
of terpenic oxidative derivatives, particularly alcohols. Linalool,
geraniol, terpineol, and limonene oxide were tested in a large study
(Kotan and others 2007) for antibacterial effects against 63 bac-
terial strains, confirming their activity against a number of them.
Antimicrobial properties of linalool were confirmed (minimal in-
hibitory concentration; MIC = 0.3 − 1.9 mg/mL) by testing
against the bacterial species S. aureus, E. coli, B. subtilis, Pasteurella
multocida, filamentous fungi Aspergillus niger, Mucor mucedo, Fusar-
ium solani, Botryodiplodia theobromae, and Rhizopus solani (Hussain
and others 2008), and the yeast C. albicans (MIC = 8 mM; Hsu and
others 2013a). Linalool and α-terpineol showed potent antibacte-
rial activity against bacteria that cause dental problems (Park and
others 2012) and linalool and geraniol have also shown abilities to
suppress the growth of many strains of bacteria that cause diseases
of agriculturally important plants (Lo Cantore and others 2009).
An interesting property of geraniol lies in its ability to synergisti-
cally increase the effect of the antibiotic chloramphenicol (Ilic and
others 2014). Farnesol, an alcohol derived from the sesquiterpene
farnesene, which is a characteristic constituent of Saaz hops, at a
concentration of 30 mM significantly reduced the formation of a
S. aureus biofilm that causes a wide range of orthopedic infections
(Unnanuntana and others 2009).
The monoterpenes and sesquiterpenes also have many inter-
esting antimicrobial properties. The major hop sesquiterpenes,
α-caryophyllene, and β-humulene showed moderate antimicro-
bial effects against the bacteria P. vulgaris, E. faecalis, E. coli, P.
aeruginosa, Salmonella sp., and the yeast C. albicans (Jirovetz and
others 2006; Yousefzadi and others 2008), and humulene was also
550 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
active against Sarcina lutea and Xanthomonas campestris (Rahman
and others in press). Essential oil fractions rich in caryophyllene
(42 rel.%), and humulene (28 rel.%), containing a wide range of
other compounds also present in hops, demonstrated significant
activity against B. subtilis and P. aeruginosa, as well as against
the yeasts Candida glabrata, C. albicans, and A. niger (Sabulal and
others 2006). The antifungal and antibacterial effects of other
monoterpenes commonly present in hops, such as myrcene
and limonene (Marei and others 2012), α-muurolene (Edrada
and others 2000), σ -cadinene (Perez-Lopez and others 2011),
β-pinene, and limonene (Tserennadmid and others 2011), were
also demonstrated.
In contrast to the flavonoid compounds, antiviral effects of es-
sential oil products obtained by steam distillation against any of
11 DNA and RNA viruses have not been demonstrated (Buck-
wold and others 2004). The pure sesquiterpene caryophyllene, and
2 oxygenated sesquiterpene derivatives, farnesol and caryophyl-
lene oxide, however, showed antiviral activity against herpes sim-
plex virus (HSV-1; Astani and others 2011). These compounds
reduced HSV-1 infection by 40% to 98% depending on the con-
centration, where the IC50 was 0.25 μg/mL (caryophyllene),
0.7 μg/mL (caryophyllene oxide), and 3.5 μg/mL (farnesol).
These concentrations were 10 to 140 times higher than the cyto-
toxic concentrations.
Sedative Effects
In addition to the obvious sedative effects of beer caused by
ethanol, the ability of hops to affect the central nervous system was
also demonstrated. Historically, studies on the sedative properties
of hops were based on experiences with symptoms of fatigue and
sleepiness, which were observed in workers during harvesting and
processing of hop cones (Tyler 1987). The use of hop extracts
for calming or improving the quality of sleep was described in
historical pharmacological manuals (Jackson 1871) and attention
has been drawn to them in a number of recent studies (Schiller
and others 2006; Zanoli and Zavatti 2008). Neuropharmacological
activities of hops have been studied in detail using techniques that
include receptor binding assays (Van Cleemput and others 2009a),
and researchers now try to identify bioactive compounds in hops
and explain their molecular mechanisms of action.
The principle of the sedative action of hops
The underlying principle of sedation or other neuropharma-
ceutical effects of hops and hop extracts is mostly allosteric mod-
ulation of specific neurotransmitter receptors by hop constituents
such as essential oils or hop resins. So far, most attention has been
focused on interactions with GABA (γ -aminobutyric acid) re-
ceptors, although some studies have also examined interactions
of hop essential oils with N-methyl-D-aspartate (NMDA) recep-
tors (Elisabetsky and others 1999; Batista and others 2008). The
structure of the GABAA receptor is shown in Figure 6. This is a
multi-subunit protein, consisting of 5 subunits surrounding a cen-
tral chloride ion-selective pore (Uusi-Oukari and Korpi 2010).
So far, 19 genes encoding human GABAA receptor subunits have
been identified (Sigel and Steinmann 2012), and these subunits can
be classified into 8 families: alpha (6 members), beta (3), gamma
(3), rho (3), and epsilon, delta, theta, and pi (1 member of each
family). Based on consensus, it is assumed that in the human cen-
tral nervous system, the predominant receptor structure is formed
from alpha1, beta2 and gamma2 subunits, although the existence
of many other structures and their classifications has been suggested
(Barnard and others 1998).

C 2016 Institute of Food Technologists®
Biologically active compounds from hops . . .
Figure 6–Structure of GABAa receptor (adapted from Uusi-Oukari and Korpi 2010).
Binding of GABA to specific binding sites between the al-
pha1 and beta2 subunits leads to allosteric changes in the protein
structure, opening the ion channel and increasing conductivity
caused by chloride ions. This prevents the development of new
action potentials and therefore attenuates neural activity (Sigel and
Steinmann 2012). So far, it has not been confirmed whether the
constituents of hops and/or hop-derived ingredients from beer
are capable of directly binding to receptors, as was found for
melatonin and serotonin receptors (Abourashed and others 2004),
or whether they only modulate the GABAA receptor response
through an unknown mechanism (Aoshima and others 2006).
Studies of the sedative effects of hops
Although not systematically investigated, the history of research
into sedative, anxiolytic, and relaxation effects of hop extracts and
constituents extends deep into the 1st half of the last century. Al-
though the crucial importance of any specific substance was not
proven, current findings suggest that hop resins, hop oils, and/or
their degradation products have decisive impacts. In the 1930s,

C 2016 Institute of Food Technologists® Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 551
the sedative effects of hop bitter acids were observed in small birds
fed hops (Steidle 1932). In contrast, rabbits exhibited virtually the
opposite effect with an increase in body temperature and dyspnea
(Steidle 1932). This inconsistency was documented in several later
studies. Hänsel and Wagener (1967) did not observe any effect
of hop extracts on hexobarbital-induced sleeping time, locomo-
tor abilities, and muscle relaxation in mice; and in another study
(Stocker 1967), no effects of administration of hop extracts to
human subjects were found. On the contrary, injection of the
hop organic extracts led to soothing (Bravo and others 1974),
hypothermic, anticonvulsant, and analgesic effects and also to a
dose-dependent sedative effect, as shown by an increased length
of pentobarbital-induced sleeping time and in reduced locomotor
activity (Lee and others 1993). The fact that these effects have
been demonstrated only in the case of application by injection
indicates that one of the issues may be bioavailability of the ac-
tive ingredients. One of the products of oxidative degradation
of hop resins, 2-methyl-3-buten-2-ol, was also studied (Hänsel
and others 1980, 1982,). This substance showed narcotic and
Biologically active compounds from hops . . .
mobility-reducing properties, but in amounts that are not available
in hops (hundreds of mg/kg b.w.), so it is unlikely that this com-
pound is responsible for the sedative properties of hops (Wohlfart
and others 1982; Wohlfart and others 1983).
In the last 20 y, interest in studying various biological activi-
ties of plant secondary metabolites has dramatically increased and
the question “how do hop constituents affect the central nervous
system?” again came into focus. Considering recent progress in re-
search on the binding of various substances to neuroreceptors and
in the development of new analytical methods, it is now possible
to obtain a wide range of valuable information about the neu-
ropharmacological effects of individual hop components. Zanoli
(2005) studied the properties of hop resins, in particular α- and
β-bitter acids. He showed that commercial CO2 extracts com-
monly used for beer production, as well as pure α-bitter acids,
affected the CNS of rats. This effect was manifested by dose-
dependent extension of pentobarbital-induced sleep time, at doses
from 10 mg/kg b.w. However, no effects of hop extracts or pure
α-bitter acids on anxiety and locomotor abilities of test animals
were demonstrated when using common tests (open field test and
elevated plus maze test). A similar study was performed by the
same author using β-bitter acids. This group of substances also
affected pentobarbital-induced sleeping time of rats in amounts
of 5 to 10 mg/kg. In addition, β-bitter acids have an impact
on exploratory activity measured using an open field test, may
worsen seizures induced by picrotoxin, and they may also act as an
antidepressant. Measuring GABA-evoked currents in cerebellum
granule cells showed the dose-dependent capability of β-bitter
acids to decrease these currents, but this effect was probably not
caused by direct binding to the benzodiazepine binding site of the
GABAA receptors (Zanoli and others 2007). The sedative effects
of ethanol and CO2 hop extracts were also tested by Schiller and
others (2006). In this work, higher doses (up to 500 mg/kg b.w.)
were used to test the impact of resins and essential oil components
on locomotor activity, sleeping time induced by ketamine, and
the body temperature of mice. The main sedative components of
hops were shown to be α-bitter acids, but the contribution of
other tested fractions (β-bitter acids and essential oils) was also
significant.
Very often, hops are combined in medicinal products with an-
other herb having anxiolytic and hypnotic properties, such as va-
lerian (Valeriana officinalis L.; Bone and Mills 2012), and various
combinations of valerian and hops are readily available as commer-
cial soothing preparations in the form of drops or baths (Weeks
2009). A double-blind placebo-controlled study demonstrated
that the use of a combination of hops (400 mg/d) and valerian
(240 mg/d) extracts can improve the quality of sleep, and this may
help to reduce the required high doses of pharmaceuticals used
in the treatment of insomnia (Müller-Limmroth and Ehrenstein
1977). More recent studies confirmed that a combined methanol
extract of hops and valerian was capable of significantly shortening
sleep latency in the monitored groups of subjects (Koetter and oth-
ers 2007). Extension of the deep sleep phase after administration of
a hop-valerian preparation, compared to the placebo, has also been
shown by measuring electrohypnograms of 2 groups of volunteers
(Dimpfel and Suter 2008). The results of 6 clinical trials have been
summarized in the assessment report of the European Medicines
Agency, which is a decentralized agency of the European Union
responsible for the scientific evaluation of medicines developed by
pharmaceutical companies for use in the European Union (Bone
and Mills 2012). The authors of most studies mentioned in the pre-
vious cited text agree that the key neuropharmacologically active
552 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
hop compounds are hop resins; however, Shishegar and Monadi
(2013) used intraperitoneal injection of hop extracts with differ-
ent polarities in rats (100 mg/kg b.w.) and showed that the highest
sedative effects were from a polar fraction that would not contain
hop resins. In contrast, this fraction would be relatively rich in
flavonoid and prenylflavonoid compounds, and, for example, xan-
thohumol has been proven to actively bind to GABAA receptors
(Meissner and Haberlein 2006).
Also, one of the terpenic alcohols, linalool, which is present in
relatively large amounts in hops and beer (Takoi and others 2010;
Vazquez-Araujo and others 2013) has, in recent years, been the
subject of considerable interest for its sedative and anti-anxiolytic
properties. This is probably because of the capability of linalool and
other terpenic alcohols such as geraniol and myrcenol to poten-
tiate the GABAA receptor response induced by GABA (Aoshima
and others 2006). These properties have been confirmed by studies
performed with animal and human subjects (Aprotosoaie and oth-
ers 2014). In nature, linalool occurs in the form of 2 enantiomers,
(3S)-(+)-linalool and (3R)-(–)-linalool. Several studies on humans
indicate that the effects of the enantiomers or a racemic mixture
may differ considerably, in some cases being completely opposite
(Hoferl and others 2006). In mice, demonstrated effects included
a reduction in body temperature, a decrease in locomotor activ-
ity (Linck and others 2009), intensification of social activities, a
decrease in aggressiveness (Linck and others 2010), and an exten-
sion of barbiturate-induced sleeping time (Linck and others 2009).
Furthermore, these effects were proven by directly monitoring a
decrease in the activity of sympathetic nerves and an increase in
the activity of parasympathetic nerves in olfactory-stimulated rats
(Tanida and others 2006).
Inhalation of (R)-(–)-linalool by human subjects reduces
aggression and hostility and causes relaxation and sedation
(Aprotosoaie and others 2014). From electroencephalographs of
healthy subjects, these effects were manifested by a decrease in the
intensity of the β rhythm during inhalation, but the results differed
significantly, depending on the type of activity that preceded
inhalation (Sugawara and others 2000). In terms of modifications
of blood pressure and heart rate, linalool enantiomers differ
significantly. Although (R)-(–)-linalool acts as a stress-relieving
agent, (S)-(+)-linalool has the opposite effect (Kuroda and others
2005; Hoferl and others 2006). The anxiolytic effect of pure
linalool (Umezu and others 2006) and its derivative linalool oxide
(Souto-Maior and others 2011) was verified in a small number
of studies in rats. Greater attention was paid to these properties in
lavender essential oils, where linalool and other terpene alcohols
are major components (Bradley and others 2007, 2009; Chioca
and others 2013) than in a commercial lavender preparation,
Silexan (Woelk and Schlafke 2010; Kasper and others 2014).
Although the most important natural source of hop compounds
in the human diet is beer, it is interesting that these sedative ef-
fects have been demonstrated for nonalcoholic beer. The study
of Franco and others (2012) concluded that moderate consump-
tion of nonalcoholic beer can significantly improve the quality of
rest, for example, in subjects who are involved in stressful profes-
sional activities causing significant fluctuations in the natural sleep
rhythm (for example nurses).
Neurobiological-Related Activities
Epidemiological studies suggest that high dietary intake
of polyphenols is associated with a decreased risk of various
neurodegenerative diseases such as dementia (50% reduction),

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Biologically active compounds from hops . . .
Alzheimer’s disease, or Parkinson’s disease (Vauzour and others
2010).
Neurodegenerative disorders and brain aging are very closely
linked to oxidative stress and involve a decrease in the sensitivity of
several neurochemical systems such as the adrenergic, dopaminer-
gic, cholinergic, and opioid systems (Giacalone and others 2011).
The leading cause of morbidity in industrialized countries to-
day is ischemic stroke, which damages neurological activity of
the brain because of a disturbance in the cranial blood supply.
Raza and others (2013) demonstrated the neuroprotective effect
of naringenin, inhibiting nuclear transcription factor kappa beta
(NF-κB)-induced inflammatory brain damage, and they suggested
that this flavonoid could be a potential neuroprotectant for patients
at high risk of ischemic stroke. Prenylflavonoids such as xantho-
humol also exhibit neuroprotective activity against ischemic stroke
in rats (Bartmanska and others 2013).
Effects Against Specific Health Threats
Cancer-related activities
Cancer is one of the leading causes of death in industrialized
countries (Torre and others 2015). Treatment of cancer is demand-
ing in terms of time and financial requirements, instrumentation,
and psychological treatment of patients. Prevention of cancer is
therefore of major importance and substances with anticarcino-
genic potential are the focus of a number of scientific studies.
In recent years, numerous studies have demonstrated the anti-
carcinogenic potential of polyphenols and other hop secondary
metabolites and their ability to stop or reverse the process of tu-
mor formation. These compounds exhibit different protective ef-
fects against the formation and development of cancer, as has been
demonstrated on various models in vitro and in vivo (Gerhauser
2009a; Araujo and others 2011).
Polyphenols
To investigate the possible relationship between intake of
polyphenol-rich foods and the risk of cancer, many population-
based case–control studies were performed. Le Marchand and oth-
ers (2000) found statistically significant inverse relationships be-
tween lung cancer risk and the intake of the flavonoid quercetin.
Garcia and others (1999) investigated the relationship between a
lower risk of gastric cancer and the intake of specific flavonoids
that are present in hops (quercetin, kaempferol, and myricetin).
In recent years, great importance has been placed on
prenylflavonoids, which could theoretically find potential appli-
cations in the prevention of cancer. For example, xanthohumol is
able to inhibit the activation of procarcinogens, to induce enzymes
involved in the destruction of carcinogens, or even to prevent tu-
mor growth, both in early and advanced stages of proliferation
(Gerhauser and others 2002).
Modulation of biotransformation of carcinogens. Activation of
potentially harmful substances from procarcinogens into carcino-
gens in the body is performed by enzymatic conversion using
endogenous oxidase systems, primarily via the cytochrome P450
family (CYP). Enzymes such as CYP1A, CYP1A1, and CYP1B1
are particularly associated with certain types of cancer, such as
lung and colorectal. The anticarcinogenic effects of phenolic com-
pounds such as kaempferol and xanthohumol lie in their ability to
inhibit CYP450 and thus to inhibit the initiation stage of carcino-
genesis (Hodek and others 2002; Nowak and others 2014).
Henderson and others (2000) investigated structural determi-
nants of phenolic compounds for their abilities to inhibit CYP1A1
and CYP1B1 at a concentration of 10 μM (compared with the

C 2016 Institute of Food Technologists®
inhibitory effects of 8-prenylnaringenin and naringenin), and they
showed that the presence of a prenyl group in the molecule and
a methoxy group in the 6’ position, as represented by chalcone
xanthohumol, were significant. Isoxanthohumol showed an even
greater inhibitory effect on CYP1A2 than xanthohumol.
Miranda and others (2000a) demonstrated the ability of
prenylflavonoids to inhibit CYP1A2, an enzyme responsible for
mutagenic activation of some potential human procarcinogens
such as the heterocyclic amine 2-amino-3-methylimidazo[4,5-
f]quinoline (IQ), or for the metabolic activation of aflatoxin B1.
Xanthohumol, isoxanthohumol, and 8-prenylnaringenin inhib-
ited the metabolic activation of IQ mediated by cDNA-expressed
human CYP1A2, and thus prevented the development of cancer
induced by heterocyclic amines; 8-prenylnaringen was the most
effective.
Anticarcinogenic effects of polyphenols also involve the detox-
ification of carcinogens through phase II enzymes such as
UDP-glucuronosyl transferase, quinone reductase, or glutathione
S-transferase (Moon and others 2006). Polyphenols such as
quercetin, myricetin, kaempferol or xanthohumol possess the abil-
ity to activate these enzymes and, thus, are considered to be po-
tential chemo-preventative agents (Nowak and others 2014).
Inhibition of angiogenesis. Angiogenesis is a very complicated
process consisting of a sequence of complex steps involved in many
diseases such as diabetic retinopathy, chronic inflammation, and
cancer (Cao and others 2002). Angiogenesis plays a crucial role in
tumor growth in progressive stages of carcinogenesis and is linked
with the production and release of angiogenic factors by endothe-
lial cells and includes the formation of blood vessels from a preex-
isting microvascular network. These angiogenic factors include the
matrix metalloproteinase (MMP) and vascular endothelial growth
factor (VEGF). MMP is a family of zinc-containing endopepti-
dases that are involved in degradation of the basement membrane
of existing blood vessels. For instance, myricetin is able to inhibit
expression of matrix metalloproteinase 2 (MMP-2) in colorectal
carcinoma cell lines (Nowak and others 2014). Polyphenols were
found to inhibit several crucial steps of angiogenesis by suppressing
enzymes involved in proliferation, endothelial cell migration, and
blood vessel formation of human microvascular endothelial cells
in a dose-dependent manner (Tan and others 2003; Mojzis and
others 2008).
In a number of experimental models, quercetin showed signif-
icant antiangiogenesis potential in vitro and in vivo. Quercetin has
been found to inhibit the expression and activity of MMP-2 (Tan
and others 2003) and MMP-9 in the prostate cancer cell line PC-3
(Vijayababu and others 2006). Quercetin also inhibited the activity
of protein kinase C, another key enzyme with inhibitory effects
on angiogenesis (Igura and others 2001). Moreover, quercetin, at
concentrations of 25, 50, and 100 μM, reduced blood vessel for-
mation by 47.1%, 58.8%, and 76.5%, respectively, in comparison
with the control group. A similar trend was also reflected in the
inhibition of human microvascular dermal endothelial cell migra-
tion (100 μM resulted in 92.2% inhibition; Tan and others 2003).
Ellagic acid and flavonoids such as kaempferol also demonstrated
the ability to inhibit pro-angiogenesis factors such as vascular en-
dothelial growth factor (VEGF; Nowak and others 2014).
Prenylflavonoids such as isoxanthohumol reduced the growth of
newly formed capillaries with an IC50 value of 4.8 μM (Bertl and
others 2004). Furthermore, xanthohumol and the prenylflavanone
isoxanthohumol inhibited the migration of immortalized human
dermal microvascular endothelial cells HMEC-1 (Ades and oth-
ers 1992). Microcapillary tube formation of HMEC-1 cells was
Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 553
Biologically active compounds from hops . . .
inhibited by xanthohumol at micromolar concentrations (Mojzis
and others 2008).
Effect on cell cycle and apoptosis. Effects on tumor growth in
advanced stages of carcinogenesis can be reflected by changes in
the cell cycle and the induction of apoptosis. Apoptotic processes
are also suggested to be linked with blood thrombogenicity and
thus alterations in these processes might play a crucial role in risk
reduction for cardiovascular diseases (Tedgui and Mallat 2003).
Polyphenolic compounds are able to induce cell-cycle arrest
and to stop mitosis. It was demonstrated that quercetin was able to
arrest the cell cycle at G1 /S or G2 /M, depending on the type of
cell line (Yang and others 2006), gallic acid at G0 /G1 (Reddy and
others 2012), or kaempferol at G2 /M (Nowak and others 2014).
The effect of polyphenols on apoptosis consists of modulating
the expression of different pro-apoptotic factors. Polyphenols are
able to induce apoptosis in malignant cells and especially significant
is their ability to activate pro-apoptotic factors such as caspases
(caspases-3, -7, -8, and -9), and to downregulate expression of the
apoptosis regulator gene, Bcl-2 (B-cell lymphoma 2).
Xanthohumol can decrease human recombinant DNA poly-
merase activity α in the MDA MB 435 human breast cancer
cell line (Gerhauser 2009a). Moreover, xanthohumol can inhibit
growth or induce apoptosis in vitro in numerous types of cancers:
ovarian, breast (Monteiro and others 2008), colonic (Miranda and
others 1999; Pan and others 2005), prostate (Delmulle and others
2006; Deeb and others 2010), hepatic (Dorn and others 2010),
pulmonary, leukemia (Benelli and others 2012). Larrosa and others
(2006) investigated the inhibitory effect of ellagic acid on Caco-2
cell lines and demonstrated cell-cycle arrest in S phase, and in-
duction of apoptosis via the intrinsic pathway. Quercetin pro-
moted induction of apoptosis in various cancer cell lines such as
leukemia (Chen and others 2005), breast (Oh and others 2010),
ovarian (Scambia and others 1992), pulmonary (Nguyen and oth-
ers 2004), hepatoma (Hultberg and others 2006), oral (Huang
and others 2013), and colonic (van Erk and others 2005), even at
micromolar concentrations (29 to 150 μM; Ramos 2007). Fur-
thermore, gallic acid can induce apoptosis in numerous types of
cancers, for instance in human leukemia cell lines K562 (Reddy
and others 2012).
Anti-inflammatory. Inflammation is part of the complex bio-
logical response of vascular tissues to injury and infection. How-
ever, excessive inflammation can be dangerous and may lead to
pathological changes in cells. Inflammatory abnormalities are a
large group of disorders that are associated with numerous dis-
eases such as cancer, atherosclerosis, erectile dysfunction, arthritis,
obesity, or ischemic heart disease (Nemzer and others 2011; Raza
and others 2013). In a significant number of studies, in vitro and in
vivo, the effect of polyphenols on expression and activity of pro-
inflammatory factors have been demonstrated. Anti-inflammatory
effects of phenolic compounds are because of their various chem-
ical structures, where significant antiinflammatory activity is espe-
cially associated with the presence of OH groups on C7 and C4
together with a double bond between C2 and C3 groups on the
C ring of the molecule (Nowak and others 2014). Several stud-
ies in vitro, in vivo, or in animal models have described quercetin
as a compound able to affect inflammation by acting mainly on
leukocytes and targeting many intracellular signaling kinases and
phosphatases, enzymes, and membrane proteins that often play
crucial roles in specific cellular functions (Chirumbolo and others
2010).
The main molecular target for anti-inflammatory effects of
polyphenols is NF-κB, a protein that can regulate inflammation
554 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
by promoting expression of proinflammatory genes (Quinones
and others 2013), such as inducible nitric oxide synthase (iNOS),
cyclooxygenases-1 and -2 (COX-1 and COX-2), tumor necro-
sis factor alpha (TNF-α) in vascular endothelial cells (Quinones
and others 2013), interleukin-1β (IL-1β), and interleukin-6 (IL-
6; Raza and others 2013). Xanthohumol and 8-prenylnaringenin,
in particular, strongly inhibit activation of NF-κc in microglial cell
lines (Bartmanska and others 2013).
Anti-inflammatory effects of polyphenols are also reflected in
the activation of Sirtulin 1 (SIRT1) natural killer T-lymphocytes
(NK-T-Ly, T8 ). According to several epidemiological studies, the
flavonoids kaempferol, quercetin, naringenin, and anthocyanin can
suppress the activation of NF-κB. The activation of NF-κB is very
closely linked with oxidative stress (Chun and others 2008).
Phenolic compounds have been demonstrated to modulate
arachidonic acid metabolism by inhibiting specific enzymes such
as cyclooxygenases (COXs), lipoxygenases (LOXs), and phospho-
lipase A2 (PLA2 ). Phospholipase A2 is responsible for releasing
arachidonic acid from phospholipids. Phenolic compounds, espe-
cially quercetin, demonstrated inhibitory activity toward PLA2 in
human leukocytes (Kim and others 2014c). COXs are key enzymes
that catalyze the conversion of arachidonic acid to prostaglandins,
which are also thought to be involved in the development of in-
flammation. COXs are also involved in the generation of the major
inflammatory mediator, nitric oxide (NO). Suppression of COX
expression by polyphenols has been demonstrated in vitro in several
studies. The IC50 value for inhibition of COX-1 activity was 5.2
and 7.5 μM for (+)-catechin and (−)-epicatechin, respectively
(Gerhauser 2009a). The IC50 value of xanthohumol for inhibi-
tion of COX-1 and COX-2 was determined as 17 and 42 μM,
respectively (Gerhauser and others 2002). Quercetin has the abil-
ity to inhibit COX-2 in mouse macrophages, breast cancer, and
neuronal HT22 and microglial BV2 cell lines (Igura and others
2001; Kang and others 2013). Oxidative stress plays a crucial role
in the production of some specific enzymes involved in inflam-
mation; LOXs, especially 5-LOX and 12-LOX, are involved in
inflammatory disorders. Phenolic compounds such as kaempferol,
quercetin, morin, and myricetin can inhibit LOX (Kim and others
2014c).
Nitric oxide is a ubiquitous compound involved in inflamma-
tion and plays a crucial role in vasodilation via the relaxation of
vascular smooth muscles (Nemzer and others 2011). Excessive
production of NO is catalyzed by iNOS (González-Gallego and
others 2014). Inhibition of iNOS is mediated by NF-κB, or by ac-
tivator transcription 1 (STAT-1), and compounds with the ability
to inhibit iNOS are considered to be antiinflammatory. Flavonoids
such as quercetin, kaempferol, naringenin, or catechin can sup-
press the activity of iNOS (Liang and others 1999). Gerhäuser
(2009a) demonstrated that gallic acid, xanthohumol, isoxanthohu-
mol, kaempferol, quercetin, and quercitrin inhibit iNos induction
in murine macrophages, with IC50 values ranging from 18.7 to
40.6 μM.
Another biomarker for a chronic inflammatory condition is in-
creased levels of C-reactive protein (CRP). This protein is secreted
in response to enhanced concentrations of inflammation factors
such as IL-6 and IL-1β. Chun and others (2008) demonstrated
that consumption of flavonoids such as quercetin and kaempferol
was inversely correlated with levels of CRP in the serum.
Antiproliferative activity. Inflammation has been closely
associated with uncontrolled proliferation of cancer cells at later
stages of cancer (Stevens and Page 2004). Polyphenols have been
shown to inhibit cellular transformation and proliferation in

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Biologically active compounds from hops . . .
several studies in vitro (Kuntz and others 1999; Miranda and others
1999; Tan and others 2003; Hudcova and others 2014).
Antiproliferative activity is determined by position, number,
and substitution of the hydroxyl groups on aromatic rings. Yánez
and others (2004) proposed structural determinants for antipro-
liferative activity of 13 selected polyphenols against 3 melanocyte
cell lines (B16F10, SK-MEL-1, and Melan-a). For instance, the
presence of at least 3 adjacent hydroxyl groups increased antipro-
liferative effects. However, methylation of these hydroxyl groups
did not reduce these effects. From those 13 phenolic compounds,
quercetin, myricetin, gallic acid, and sinapinic acid, which oc-
cur in hops, showed antiproliferative effects. In the case of cell
line B16F10, gallic acid had the greatest effect, and in the case
of cell line Melan-a, myricetin was the most significant inhibitor
(Yanez and others 2004). Kuntz and others (1999) tested different
polyphenol classes, including flavonols and flavanones, on cell pro-
liferation in 2 human colon cancer cell lines, Caco-2, and HT-29.
Growth inhibition by the polyphenols occurred in the absence of
cytotoxicity.
It has been well documented that quercetin has antiproliferative
potential and exerts antiproliferative activity on human fibrob-
lasts and endothelial and tumor cells such as breast, ovarian, and
stomach cancer cell lines in vitro (Igura and others 2001; Tan and
others 2003). Igura and others (2001) tested quercetin for an-
tiproliferative activities on bovine aorta endothelial cells (BAE). It
was confirmed that quercetin inhibited cell proliferation, even at
micromolar concentrations (IC50 = 19.5 μM).
Bitter acids
Hop bitter acids have been identified as promising molecules for
use in cancer chemotherapy or cancer chemo-prevention. Plant-
derived substances could decrease the risk of developing cancer
by preventing metabolic activation of pro-carcinogens or, alter-
natively, they may inhibit cancer development by arresting or re-
versing processes of tumor initiation, promotion, and progression
(Hong and Sporn 1997; Gerhauser 2005b, 2009b).
Modulation or biotransformation of carcinogens. Hop bit-
ter acids can induce the biosynthesis of cytochrome P-450
detoxification enzymes (Van Cleemput and others 2009a). The
induction of P-450 and several P-450-dependent enzyme ac-
tivities (ethylmorphine N-demethylation, aniline hydroxylation,
and benzo[a]pyrene hydroxylation) by colupulone, in a dose- and
time-dependent manner, was demonstrated in rats. These results
were confirmed using a hop hexane extract and crude hops
(Mannering and others 1992).
Inhibition of angiogenesis. Humulone inhibited angiogenesis
(chick embryo chorioallantoic membrane model), with an ED50
(effective dose, for 50% of subjects receiving the compounds) of
1.5 μg/chorioallantoic membrane. Ten μM of humulone inhib-
ited tube formation of vascular endothelial cells in vitro. Humulone
also inhibited the production of vascular endothelial growth factor
(VEGF). Based on these findings, humulone is an angiogenic in-
hibitor with future prospects, and it may be a novel compound for
the therapy of various angiogenic diseases (Shimamura and oth-
ers 2001). Lupulone (2.5 to 50 μg/mL) caused a concentration-
dependent inhibition of proliferation of human umbilical vein
endothelial cells and reduced the number of closed capillary-like
structures, indicating a strong inhibitory effect on neovascular-
ization. These facts demonstrate that lupulone is able to inhibit
angiogenesis in vitro and in vivo (Siegel and others 2008).
Nitric oxide is a gas that is involved in the regulation of pro-
duction of vascular endothelial growth factor, which, when over-

C 2016 Institute of Food Technologists®
expressed, can induce angiogenesis and accelerate tumor devel-
opment (Van Cleemput and others 2009a). Hop resin extract can
inhibit both NO production and the formation of iNOS. Pure
lupulone inhibited NO production, but without reducing iNOS
synthesis (Nozawa and others 2005b).
Effect on apoptosis. Hop bitter acids have an effect on can-
cer cells by the induction of programmed cell death (apopto-
sis). The 1st work was carried out in 1997 (Tobe and others
1997a), when induction of apoptosis by humulone was examined
in promyeloid leukemia HL-60 cells. The effect of humulone
(1 to 100 μg/mL) was dependent on time and dose, although
iso-α-acids (100 μg/mL) did not induce cell death, even after
long-term incubation (Tobe and others 1997a). Chen (2004) used
a hop extract to demonstrate dose-dependent induction of cell
death in human leukemia HL-60 cells (IC50 = 8.7 μg/mL) and
in human histolytic lymphoma cells (IC50 = 58.9 μg/mL). This
fact was confirmed by DNA fragmentation and the appearance of
a sub-G1 DNA peak, which was preceded by disruption of the
mitochondrial membrane potential. This was followed by release
of cytochrome C and subsequent induction of the caspase cascade
(Chen and Lin 2004; Chen and others 2014c).
Pure lupulone (40 μg/mL) was also recognized as a trigger of
cell death of TNF-related apoptosis-inducing ligand (TRAIL)-
sensitive human colonic cancer cells (SW480) and TRAIL-
resistant metastatic cells (SW620). Lupulone was able to activate
TRAIL-death signaling pathways even in TRAIL-resistant cancer
cells (Lamy and others 2008).
Anti-inflammatory activity. Anti-inflammatory effects of hops
have been known for a long time and hop was used as a tradi-
tional medicine to suppress tooth and ear pain (Van Cleemput
and others 2009a; Akazawa and others 2012). Bitter acids and
polyphenolic substances from hops have comparable antiinflam-
matory mechanisms. Humulone, as the active compound of hop
extract, was found to inhibit ear edema (inflammation) induced
by 12-O-tetradecanoylphorbol-13-acetate. Humulone (50% inhi-
bition dose; ID50 0.2 mg/ear) had the same effect as indomethacin
(ID50 0.3 mg/ear) but a weaker effect than hydrocortisone (ID50
0.03 mg/ear; Yasukawa and others 1993). A similar effect was ob-
served with hexahydro-β-acids, which are reduced derivatives of
β-acids (Hsu and others 2013b). Humulone was also found to in-
hibit arachidonic acid-induced ear edema in mice (Yasukawa and
others 1995). Individual hop acids were confirmed as selective in-
hibitors of COX-2 (Van Cleemput and others 2009b). Humulone
can suppress TNF-α-mediated induction of cyclooxygenase-2 in
an osteoblastic cell model by inhibition of prostaglandin E2 (PGE2 )
synthesis (IC50 = 30 nM). These results indicated that humulone
has a glucocorticoid-like suppression activity in TNF-α-induced
cyclooxygenase-2 transcription and may act independently of the
glucocorticoid receptor (Yamamoto and others 2000). Rho-iso-α-
acids RIAA inhibited lipopolysaccharide (LPS)-stimulated PGE2
synthesis with 200-fold greater selectivity than COX-2 (IC50 =
1.3 μg/mL) in comparison with COX-1 (IC50 > 289 μg/mL;
Hall and others 2008). Iso-α-acids in isomerized hop extracts
have very similar effects. Prostaglandin E2 (PGE2 ) concentrations
in colonic mucosa of rats treated with azoxymethane were signif-
icantly reduced by feeding with these iso-α-acids (Nozawa and
others 2005a). Similar results were achieved using a standardized
CO2 hop extract for testing its effectiveness as COX-1 and COX-
2 inhibitors by using a whole blood assay. Hop extract exhibited
a decrease in PGE2 production in the COX-2 whole blood assay
(IC50 = 20.4 μg/mL), but for COX-1 there was no inhibition of
PGE2 production (Hougee and others 2006).
Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 555
Biologically active compounds from hops . . .
Topical application of humulone (10 μmol in 200 μL of ace-
tone) to shaved mouse dorsal skin significantly inhibited TPA-
induced epidermal COX-2 expression. Humulone suppressed
TPA-induced activation of NF-κB and AP-1, and subsequent
expression of COX-2, by blocking kinases, and this may be re-
sponsible for the antitumor effects on mouse skin carcinogenesis
(Lee and others 2007). There are also several works that are fo-
cused on hop bitter acid effects in vivo (Hougee and others 2006;
Lee and others 2007; Van Cleemput and others 2009a).
Acute inflammation was induced in mice by subcutaneous in-
jection of zymosan in the paw. A dose of 250 μg of iso-α-acids
or α-acids effectively inhibited paw edema, a characteristic symp-
tom of inflammation (Van Cleemput and others 2009b). This was
in contrast to Hougee and others (2006), who used a CO2 hop
extract in a mouse diet and zymosan was applied by injection into
the knee to induce arthritis. This experiment did not confirm a
reduction in the symptoms of inflammation. These findings can
be explained by the low bioavailability of hop bitter acids after
oral administration (Hougee and others 2006). Based on knowl-
edge from basic research, some food supplements and preparations
containing hop acids have been developed and applied in practice
for the treatment of inflammatory diseases such as arthritis. These
preparations contain reduced iso-α-acids and rosemary extracts,
and decreased the pain felt by patients suffering from arthritis (Lee
and others 2007; Minich and others 2007).
Antiproliferative activity. Hop bitter acids also have antiprolif-
erative activity (Stephan and others 1998; Lamy and others 2007).
β-Acids (lupulone, colupulone), and the derivative hexahydro-
colupulone, dramatically decreased cell growth of some human
cancer cell lines. Hexahydrocolupulone had the greatest effect of
all β-acids on a human breast cancer cell line. The mechanism
was based on its action on macromolecules such as RNA and,
consequently, inhibition of protein synthesis (Stephan and oth-
ers 1998). Antiproliferative mechanisms of β-acids on a human
colonic carcinoma cell line (SW620) were also confirmed. Lupu-
lones inhibited SW620 cell growth by 70% at concentrations of 10
to 60 μg/mL and human leukemia U937 cells (IC50 = 3.4 μM;
Lamy and others 2007). The active form of vitamin D, 1α,25-
dihydroxyvitamin D3, can inhibit proliferation of leukemia cells.
However, this application is limited by its effect on hypercalcemia.
Humulone can be used as inhibitor of bone resorption and so
allow above-mentioned clinical application of active vitamine D
(Honma and others 1998).
Essential oils
Hop essential oils, in terms of anticancer effects, have been sig-
nificantly less investigated than hop polyphenols or bitter acids.
Nevertheless, efforts to develop new, effective, and easily available
anticancer drugs have led to studies on the cytotoxic properties of a
wide range of herbal extracts, including monoterpenes, sesquiter-
penes, and their oxidized derivatives that also occur in hops and,
at lower levels, in beer (Briggs and others 2004; Kishimoto and
others 2005).
Silva and others (2008) showed that a solution of 2 major
constituents of hop oils, α-humulene and β-caryophyllene, ex-
hibited cytotoxic activity against 3 human tumor cell lines, A-
549 (lung adenocarcinoma), HeLa (cervical cancer), and HT-29
(colorectal adenocarcinoma). The cytotoxic dose, the concen-
tration of the substance inhibiting cell growth by 50% (CD50 ),
for these compounds ranged from 20 to 40 μg/mL, although
concentrations causing the same level of growth inhibition in
healthy mammalian cells (Vero and macrophages cells) were 3 to
556 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
6 times higher. Extracts of sage, extremely rich in humulene (80%
rel.) and caryophyllene (65% rel.) at concentrations from 100 to
200 μg/mL, and pure substances at concentrations from 30 to
80 μg/mL also showed cytotoxic activity against human breast
cancer (MCF-7), colon cancer (HCT-116), and mouse leukemia
(RAW 264.7) cell lines (el Hadri and others 2010). β-
Caryophyllene and derived caryophyllene oxide are able to reg-
ulate expression of several pro-apoptotic (Caspase-8, Caspase-9,
Bax, bak1, and ATM) as well as antiapoptotic (cmyb, COX2,
mdm2, and bcl-2) genes, and it has been demonstrated that they
can induce apoptosis in lymphoma and neuroblastoma cells (Sain
and others 2014). However, caryophyllene oxide may contribute
to suppression of cancer in many other ways, including inhibi-
tion of the constitutive activation of the PI3K / AKT / mTOR
/ S6K1 cascade and modulation of the mitogen-activated protein
kinase signaling pathway that leads to induction of apoptosis in
human breast cancer and prostate cancer cells (Park and others
2011). It is also capable of modulating the NF-κB pathway, thus
significantly amplifying TNF-induced apoptosis, leading to a sup-
pression of tumor growth (Kim and others 2014b). Caryophyllene
oxide has also been tested for its ability to inhibit the activity of
transcription factor STAT3 (Kim and others 2014a) whose activa-
tion occurs during the growth of many different types of cancer
(Steensma and others 2006; Siveen and others 2014). However,
there is also a suggestion that caryophyllene and its derivatives may
only amplify anticarcinogenic effects of other natural cytostatics
(Legault and Pichette 2007).
Another component of hop oils with significant anticarcino-
genic effects is the terpenic alcohol linalool. Cherng and others
(2007) demonstrated its relatively strong antiproliferative activ-
ity against cervical (HeLa; IC50 = 0.37 μg/mL), skin (BCC-1 /
CMC; IC50 = 9.14 μg/mL), lung (H520; IC50 = 5.21 μg/mL),
stomach (AGS; IC50 = 14.1 μg/mL), and bone (U2 OS; IC50 =
7.21 μg/mL) cancer cell lines. Slightly better IC50 values were
obtained in a further study performed on lines of breast, gas-
trointestinal tract, and liver cancer cells (Chang and Shen 2014).
Recently identified mechanisms of action include activation of the
cellular tumor antigen p53 and cyclin-dependent kinase antigens
in leukemia cells (Gu and others 2010), induction of apoptosis,
stimulation of the production of a broad spectrum of cytokines
involved in the regulation of tumor formation (Chang and Shen
2014) and disruption of the respiratory chain in HepG2 liver can-
cer cells (Usta and others 2009). Linalool can also enhance the
effect of the chemotherapeutic agent doxorubicin (Ravizza and
others 2008; Miyashita and Sadzuka 2013).
Estrogenic and Osteoporosis-Related Activities
The 1st mention of the estrogenic properties of hops dates back
to 1953, by Koch and Heim (1953). Hops have been considered
to be an important source of substances having estrogenic effects,
including the ability to bind to estrogen receptors (subtypes ERα
and ERβ) and to mimic estrogenic actions, or the ability to inhibit
specific enzymes.
Polyphenols
Among these substances are assorted flavonoids. It has been
demonstrated that estrogenic potential is associated with the pres-
ence of a prenylated group, especially in the C8 position. Helle
and others (2014) compared the relative binding affinities (RBA)
of naringenin and 8-prenylnaringenin to ERα and ERβ, and they
showed that 8-prenylnaringenin has stronger binding affinity for
both ERs with a preference for ERα (19.5% RBA with respect to

C 2016 Institute of Food Technologists®
Biologically active compounds from hops . . .
the positive control 17-β-estradiol). 8-Prenylnaringenin has been
shown to be one of the most potent phytoestrogens identified so
far (Stevens and Page 2004), with an EC50 value (concentration re-
quired to achieve 50% of its maximum effect) of 4.4 nM, although
the EC50 value for 17-β-estradiol was 0.82 nM. The estrogenic
activities of other hop prenylflavonoids were much lower and de-
creased in the order: 8-prenylnaringenin > 6-prenylnaringenin
> 8-geranylnaringenin > 6,8-diprenylnaringenin (Milligan and
others 2000).
Osteoporosis is the imbalance between bone formation and
bone resorption, caused by progressive reduction in bone mass
and bone density, especially affecting postmenopausal women.
The intake of prenylflavonoids is positively associated with the
prevention of osteoporosis and protection of bone health, whereas
prenylflavonoids can modulate bone cell expression, enhancing
the expression of osteoblasts (cells responsible for bone formation)
and suppressing the expression of osteoclasts (bone cells that re-
sorb bone tissue). Jeong and others (2011) demonstrated the effect
of xanthohumol on inhibition of expression and transcription of
RUNX2, a major gene of osteoblast differentiation. Suh and others
(2013) investigated the ability of xanthohumol to suppress recep-
tor activator of NF-κB ligand (RANKL) signaling in RAW264.7
cells, a crucial aspect in osteoclastogenesis. Tobe and others (1997b)
demonstrated that a hop extract consisting of humulone and xan-
thohumol strongly inhibited bone resorption, whereas humulone
alone was reported to be a stronger inhibitor of bone resorption
with an LD50 value of 5.9 nM. Moreover, in an adult ovariec-
tomized rat model, in vivo 8-prenylnaringenin protected against
ovariectomy-induced bone loss through the compensatory loss of
bone mineral density (Humpel and others 2005).
The estrogenic potential of hop flavonoids can be utilized as
a possible alternative to hormone replacement therapy (HRT)
for treatment of menopausal symptoms such as osteoporosis, hot
flushes, night sweats, and insomnia. Treating these disorders with
HRT is connected with an increased risk of endometrial or breast
cancer (Helle and others 2014). The potential to use the estro-
genicity of prenylflavonoids as an alternative to HRT is promising,
mainly because of the natural character of these compounds.
Estrogenic hormones such as 17-β-estradiol may participate in
the initiation of cancer growth (Gerhauser and others 2002). It
was demonstrated that xanthohumol and isoxanthohumol antag-
onized the effect of 17-β-estradiol, therefore they have an anti-
cancer effect (Guerreiro and others 2007; Monteiro and others
2007).In addition, estrogenic properties of prenylflavonoids have
been demonstrated with their ability to act on specific enzymes
such as aromatase, an enzyme that transforms androgens into estro-
gens. In the breast cell line SK-Br-3, 8-prenylnaringenin has been
shown to be the most potent inhibitor of aromatase, with an IC50
= 0.08 μM. Xanthohumol and isoxanthohumol also modulated
aromatase activity, with IC50’s = 3.2 and 25.4 μM, respectively
(Monteiro and others 2007).
Bitter acids
There are several studies that confirm α-acids, iso-α-acids, and
also β-acids as suppressors of osteoporosis. Especially, n-humulone
was found to be a strong inhibitor of bone resorption and inhibits
the formation of osteoporotic lesions (pit formation assay, IC50
value of 5.9 nM). Adhumulone is similarly active, although co-
humulone had no inhibitory activity. Lupulone was also demon-
strated to be a strong inhibitor of bone resorption (Tobe and
Kitamura 1995 Apr 6; Tobe and others 1997b; Kondo 2004). The
question is whether this function can be confirmed in vivo. Some

C 2016 Institute of Food Technologists®
experiments with long-term administration of hop-enriched di-
ets to rats did not confirm the improvement in bone param-
eters. However, the authors concluded that the body weights
were significantly lower in those rats fed the hop diet than in
the control group (Van Cleemput and others 2009a). Therefore,
it might have been difficult to detect positive effects of hops on
bone, because lower body mass is associated with lower bone mass
(Figard and others 2007). It should also be noted that recent studies
have established an unequivocal relationship between osteoporosis
and inflammation (elevated serum levels of systemic inflammation
markers—IL-6, TNF-α, and C-reactive protein), which is cor-
related significantly with a lower bone mineral density (Koh and
others 2005; Ding and others 2008), so the anti-inflammatory ef-
fect of hop acids probably can also contribute to the prevention
and treatment of osteoporosis (Van Cleemput and others 2009a).
Obesity and Diabetes-Related Activities
In affluent western countries, the prevalence of metabolic dis-
ease has attained epidemic proportions because of cardiovascu-
lar complications and mortality. A metabolic syndrome is associ-
ated with risk from 5 factors: abdominal (central) obesity, elevated
blood pressure, elevated plasma glucose, high serum triglycerides,
and low high-density lipoprotein levels (Miranda and others 2005;
Legette and others 2013). Treatment is focused on reduction of
the risk of heart disease by lowering LDL cholesterol and reduc-
ing high blood pressure, and then on treatment of diabetes. Very
important is a reduction in weight by proper diet and exercise
(Dillard and German 2000; Miranda and others 2005).
Polyphenols
Beneficial effects of phenolic compounds for diabetic patients
consist of improving blood glucose and lipid profiles, and reducing
insulin resistance and adiposity (Marquardt and Watson 2014). Kar
and others (2009) reported a significant improvement in markers
for insulin resistance and concentrations of CRP in plasma after
the administration of a polyphenol-rich grape seed extract to 32
type-2 diabetes mellitus patients for 4 wk.
Phenolic compounds exert antiobesity effects that are closely
linked with antioxidant effects, through their ability to modu-
late lipid and energy metabolism and thus enable weight loss and
reduce obesity (Marquardt and Watson 2014). For instance, cate-
chins can also stimulate AMP-activated protein kinase, an enzyme
that plays a crucial role in the regulation of glucose and lipid
metabolism (Habauzit and others 2014).
Regulation of cholesterol metabolism by phenolic compounds
may reduce certain factors linked with hypercholesterolemia and
dyslipidemia (Legette and others 2013). Prenylflavonoids such as
xanthohumol have been demonstrated to have strong antiobesity
activities including the ability to inhibit diacylglycerol acyltrans-
ferase in rat liver, to inhibit triglyceride transport using a HepG2
cell line, and to inhibit the secretion of apolipoprotein B, the
main constituent of the cholesterol LDL fraction (Bartmanska and
others 2013).
Therapeutic potential of polyphenols as treatment for obesity
is also associated with the ability to inhibit α-glucosidase, an en-
zyme that controls blood glucose levels. Liu and others (2014)
investigated the ability of xanthohumol to bind to α-glucosidase,
to reduce the hydrophobicity of α-glucosidase, and to induce
changes in conformation of these enzymes. Legette and others
(2013) demonstrated a positive effect of oral administration of
xanthohumol (16.9 μM/kg b.w.) on glucose metabolism in male
obese rats.
Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 557
Biologically active compounds from hops . . .
Bitter acids
Iso-α-acids are able to improve health by influencing lipid
metabolism, glucose tolerance, and body weight. Iso-α-acids
were identified as substances that activate peroxisome proliferator-
activated receptors (PPAR) α and γ . PPAR-α is a transcription
factor and a major regulator of lipid metabolism in the liver,
and iso- α-acids effectively lower serum triglycerides and raise
serum HDL-cholesterol levels. PPAR-γ regulates fatty acid stor-
age and glucose metabolism. Diabetic mice treated with iso-α-
acids showed reduced plasma glucose, triglyceride, and free fatty
acid levels by 65.3%, 62.6%, and 73.1%, respectively (Yajima and
others 2004; Gerhauser 2005a). Iso-α-acids reduced insulin resis-
tance in C57BL/6N female mice fed a high-fat diet (mice were
fed this diet for 12 wk), upregulated the expression of genes in-
volved in fatty acid oxidation in the liver, and reduced adipocyte
hypertrophy in white adipose tissue (Yajima and others 2004).
When mice were fed hop iso-α-acids in their diet, with high
levels of cholesterol, an increase in plasma HDL-cholesterol and
a reduction in cholesterol and triacylglycerol content in the liver
were observed (Yajima and others 2005). Quantitative analysis of
hepatic mRNA levels demonstrated that iso-α-acids were respon-
sible for upregulation of mRNA for acyl-CoA oxidase, acyl-CoA
synthetase, hydroxymethylglutaryl-CoA synthetase, and lipopro-
tein lipase and fatty acid transport protein, and downregulation of
mRNA for Apo CIII and Apo AI. When a specific agonist for
PPAR-α was used with a cholesterol diet, marked hepatomegaly
occurred, plasma HDL-cholesterol increased, hepatic cholesterol
content decreased, and alterations in hepatic mRNA levels oc-
curred, similar to that for iso-α-acids (Miura and others 2005;
Shimura and others 2005; Yajima and others 2005). The inhibi-
tion of intestinal dietary fat absorption may also be the mechanism
by which iso-α-acids affect weight loss in high-fat diet-fed mice.
The modulatory effect of iso-α-acids on lipid metabolism may also
be responsible for lost body weight. These results are promising for
application of iso-α-acids in humans for the prevention of diet-
induced obesity and perhaps even metabolic syndrome (Yajima
and others 2004, 2005).
Cardiovascular-Related Activities
According to data published by the World Health Organiza-
tion, cardiovascular diseases are the leading cause of mortality in
industrialized countries today (Quinones and others 2013). In a
significant number of population studies, the intake of polyphenols
through the human diet was shown to be inversely correlated with
the presence and progression of risk factors associated with cardio-
vascular diseases, including hypertension or atherosclerosis (Hertog
and others 1993; Knekt and others 1996; González-Gallego and
others 2014).
Beneficial effects of polyphenols on cardiovascular diseases par-
ticularly relate to their antioxidant activities and the stimulation of
antioxidant enzymes that were mentioned in the corresponding
chapter. Polyphenols, through their antioxidant potential, improve
lipid profiles, and prevent the oxidation of LDL induced by metal
ions (copper and iron) or by tert-butyl hydroperoxide. However,
polyphenolic substances are able to enhance the concentration of
HDL cholesterol in plasma (Chen and Blumberg 2009).
In the control of vascular homeostasis and regulation of vascu-
lar function, some specific endothelium-derived relaxing factors
such as NO, prostacyclin, or endothelium-derived hyperpolarizing
factor are involved. Polyphenolic substances have been demon-
strated to enhance NO levels by expression of endothelial NO
synthase, an enzyme responsible for the endothelial production of
558 Comprehensive Reviews in Food Science and Food Safety r Vol. 15, 2016
nitric oxide (Stoclet and others 2004) by an extracellular calcium-
dependent mechanism (Li and others 2000). Flavan-3-ols are ca-
pable of inducing endothelium-dependent relaxation in isolated
human internal mammary artery in a dose-dependent manner,
with a maximum vasorelaxant effect at 50 μM (Stoclet and others
2004).
Not only polyphenols but also phenolic acids are known to
be strong antioxidants with protective effects on cardiovascular
health. Cardio-protective effects of gallic acid have been reported
in numerous studies in vitro and in vivo, including various anti-
hyperglycemic, anti-lipid peroxidative, or antioxidant mechanisms
(Zanwar and others 2014).
One of the most important factors for cardiovascular diseases is
the negative effect of a high salt content in the diet. If rats received a
high salt diet with iso-α-acids, a high mean blood pressure did not
develop. Probably iso-α-acids reduced oxidative stress and level of
bioavailable NO present because of the high-salt diet (Namikoshi
and others 2007).
Toxicology of Hop Components
Toxicity and toxicological effects of hops must always be con-
sidered with respect to the manner of application, and also with
respect to concentrations of individual hop compounds. Although
hops have been used for a long time, both in beer production and
folk medicine, no cases of serious toxicity, and no general aller-
gic reactions when hop constituents were in contact with human
skin (applications in cosmetics) have been observed (Cookson and
Lawton 1953; Newmark 1978; Spiewak and others 2001; Spiewak
and Dutkiewicz 2002). Nevertheless, much work has been done
to test hop substances for toxicity in vitro and in vivo, but usually
with negative results.
Bitter acids
Intravenous application of small doses of lupulone stimulated
respiration in rabbits and cats (Chin and others 1949a). On the
contrary, oral doses of lupulone to mice, from 10 to 100 mg/kg
b.w., did not cause any detrimental effects (Hänsel and Wagener
1967). If humulone was applied intravenously and repeatedly
(1 to 10 mg/kg), hyperventilation and hyperthermia in cats oc-
curred. Lethal dose (LD50 ) values of iso-α-acids and dihydro-
iso-α-acids were approximately 1 g/kg b.w. for rats. Long-term
application of iso-α-acids, dihydro-iso-α-acids, tetrahydroiso-α-
acids, or hexahydro-iso-α-acids in rat diets (1% [w/w] for 90 d)
led to a reduction in body weight without side effects. No muta-
genic or genotoxic effects were detected during oral application of
tetrahydro-iso-α-acids, hexahydro-iso-α-acids, and dihydro-iso-
α-acids. Tetrahydro-iso-α-acids and hexahydro-iso-α-acids were
well tolerated after oral administration to dogs in amounts of 50
and 100 mg/kg b.w., respectively. Toxic effects of high doses of
isomerized hop acids were limited to the gastrointestinal tract,
most probably because of irritation by these compounds (Chappel
and others 1998). There is only limited information about the
safety of hop bitter acids for humans. Lupulone (5 g) administered
daily for a long period was not toxic to internal organs. However,
each patient had some manifestation of gastrointestinal irritation
(Farber and others 1950). During clinical trials of preparations
containing dihydro-iso-α-acids (440 mg daily for 8 weeks), no
changes in blood pressure, complete blood counts, or liver and
kidney functions were recorded. There were no negative effects
on gastrointestinal markers normally affected by selective COX-2
enzyme inhibitors (Lukaczer and others 2005; Minich and others

C 2016 Institute of Food Technologists®
Biologically active compounds from hops . . .

2007). The same data were found after application of dihydro-iso- tude lower than for normal cells. Xanthohumol (0.5%) in the diet,
α-acids (Lukaczer and others 2005; Minich and others 2007). and 1000 mg/kg b.w, using gavage was given to rats (Sprague–
Dawley) for 28 d (Hussong and others 2005). Only very weak
Polyphenols hepatotoxic effects and poor development of mammary glands in
Toxicity in vivo of a hop extract containing polyphenols (pro- female rats were detected, with no other negative effects. When
cyanidins, flavan-3-ols, flavonols), originating from hop bracts, has the dose of xanthohumol was 100 mg/kg b.w. no negative ef-
been studied relatively thoroughly (Nagasako-Akazome and oth- fects on fertility of rats were recorded (Hussong and others 2005).
ers 2007). Rats were subjected to an acute toxicity test and 14, 28, 8-Prenylnaringenin is the strongest phytoestrogen from plants
and 90-d toxicity tests with a 28-d test recovery. Doses of 2000 (hop). In recent times, clinical studies were carried out in
mg/kg (Sprague–Dawley rats) and 5000 mg/kg (male Wistar rats) menopausal women to evaluate the safety of a hop extract rich in
in the form of single oral administration by gavage were used in rats xanthohumol and with a standardized level of 8-prenylnaringenin
(male and female, 1:1). During this test, there were no symptoms (van Breemen and others 2014). Toxicity results were very promis-
or significant changes caused by these high doses of the extract. ing; no acute toxicity was found and no effects on sex hormones
During tests based on regular feeding of the extract orally for or blood clotting were detected (van Breemen and others 2014).
14 d, at doses of 0, 500, 1000, 2000, and 3000 mg/kg, problems
with a decreased level of albumin were observed in the group with Essential oils
the highest dose. Because changes in the organism caused by these Acute and long-term toxicity of terpenes and terpenic alcohols
doses were not harmful, a 28-d test was carried out, the doses is currently a subject of interest, particularly with regard to their
being 500, 1000, and 2000 mg/kg b.w. per day. During the 28-d use in the cosmetic (Belsito and others 2008) and food industries
test, none of the rats died. The same results were obtained in 90-d (Adams and others 2011; Llana-Ruiz-Cabello and others 2015).
toxicity tests with a follow-up 28-d recovery test. It is therefore Generally, the toxicity of the main hop terpenic constituents is
likely that doses of 2000 mg/kg b.w. or even higher do not cause very low (acute oral LD50 ˃ 5 g/kg b.w.; Buchbauer and others
mortality and do not represent risk to any group of rats (Nagasako- 1991; Adams and others 2011). Doses above 100 mg/kg b.w., reg-
Akazome and others 2007). A human clinical study showed that ularly administered to rats and/or mice, had certain adverse effects,
there were no clinical changes after daily intake of 2500 mg of hop such as changes in body, liver, and kidney weights, lethargy, and
extract containing polyphenols for 28 d (Tagashira 2007). ataxia (Belsito and others 2008; Adams and others 2011). How-
Quercetin is a polyphenol that is found in hops and has a ever, these amounts are at least an order of magnitude higher than
very controversial history of toxicity. From the older literature we those for which health benefits have been confirmed. Low or no
can track information about possible carcinogenic properties of genotoxicity has been repeatedly confirmed in vitro for myrcene
quercetin (Pamukcu and others 1980; Dunnick and Hailey 1992). (Roscheisen and others 1991; Gomes-Carneiro and others 2005),
In 1998, quercetin was even classified in the group of carcinogenic limonene (Myhr and others 1990), caryophyllene (Di Sotto and
compounds by the Intl. Agency for Research on Cancer. How- others 2008; Di Sotto and others 2010), geraniol (Sinha and oth-
ever, the carcinogenic properties of quercetin have been repeatedly ers 2014), and linalool (Beric and others 2008; Mitic-Culafic and
investigated and carcinogenicity has not been confirmed by other others 2009). Certain negative effects on mitochondrial respiration
researchers (Harwood and others 2007). There were also repeated were shown for caryophyllene oxide (Monzote and others 2009),
safety studies of quercetin in mutagenicity tests, and short- and and some hop terpenes have also been identified as compounds
long-term studies in vivo, in animals and humans. Numerous tox- with moderate toxicity in a study by Indian authors (Balaji and
icological studies (Nakamura and others 2000; Garcia-Saura and Chempakam 2010), which unfortunately does not contain infor-
others 2005) concluded that dietary exposure to quercetin did mation about concentrations used, thus making risk assessment
not represent any safety risk to the health of humans or animals difficult. Dermatological problems after the application of some
(Harwood and others 2007). In recent studies (Ruiz and others terpenes to mammalian and human skin were also reported (Skold
2006, 2009), the potential effects of high doses of quercetin were and others 2006; Belsito and others 2008).
evaluated in Swiss mice. The animals were fed quercetin in a
28-d test at doses of 0, 30, 300, and 3000 mg/kg of body weight. Prospects for Use Hops Biologically Active Compounds
There were no animal mortalities at high doses of quercetin and no Although hops have been used for beer production since an-
changes or abnormalities (Ruiz and others 2009). In 2014, stud- cient times, we are still finding in novel substances in hops. Even
ies were carried out on the effects of quercetin on cytotoxicity our knowledge about sensory active compounds which are trans-
in cells, especially on expression levels of a mitochondria-specific ferring from hop to beer is not sufficient yet (Dresel and others
polymerase (Chen and others 2014b). 2015). Only a minor part of hops is currently used for nonbrew-
The same catechins (flavan-3-ols) present in hops are also present ing applications, but they are which still expanding. A very recent
in green tea and therefore many useful toxicological studies have application utilizes hop for suppression of pests in stored products
been carried out on green tea extracts. Green tea extracts of 0, (Jackowski and others 2015). Hop contains also the compounds
120, 400, and 1200 mg/kg were administered orally (by gavage) that are not so important in brewing and their content in regular
to rats for 6 mo. None of these doses had any negative effects on hops and consequently in beers are very low. Examples of such
biochemical and clinical indicators (Morita and others 2009). compounds are prenylated flavonoids. Because of this reason there
Xanthohumol is a very interesting substance with anticancer are recently efforts for breeding and also genetic manipulation of
effects, so it is very important that, in addition to these effects, it hop plant with aimed at reaching the increased levels of these
has very low toxicity against normal cells (Dorn and others 2010; types of biologically active compounds (Gatica-Arias and others
Hudcova and others 2014). It was found that concentrations of up 2013; Kavalier and others 2014). These compounds can be also
to 100 μM had no negative effects on human hepatocytes in vitro. used for pharmaceutical purposes. The 1st variety which filled
The advantage for cancer therapy is the fact that the inhibitory these requirements was variety VITAL bred by Hop Research In-
concentration (IC50 ) of cancer cells is about 1 to 2 orders of magni- stitute in Saaz. VITAL was bred in 2008 and is unique in high


C 2016 Institute of Food Technologists® Vol. 15, 2016 r Comprehensive Reviews in Food Science and Food Safety 559
Biologically active compounds from hops . . .
content of desmethylxanthohumol which is a direct precursor of
8-prenylnaringenin.
Hop plants have been used in folk medicine from ancient times
and hop cones from the parent plant have also been used in brewing
for a long time. No toxic effects on human health have been de-
tected. Because of the fact that hops and hop substances exhibited
very interesting activities, they have been subjected to system-
atic research over the last 20 y. The longest studied is probably the
sedative effect of hops. Compounds mainly responsible for sedative
effects are bitter resins and essential oils. It is already clear that hops Astani A, Reichling J, Schnitzler P. 2011. Screening for antiviral activities of
also have very interesting antibacterial properties. β-Bitter acids
have the strongest antibacterial effects. There are very promis-
ing therapies using lupulone in cases where antibiotic therapy has
failed (Cermak and others 2015). The application of hop extracts
with a standardized content of 8-prenylnaringenin for nonhor-
monal treatment of menopausal symptoms of women is also very
promising and we assume a success of these preparations with stan-
dardized content of 8-prenylnaringenins and minimal content of
isoxanthohumol. Other quite promising substances are prenylated
chalcones, in particular xanthohumol, which has been identified as
a substance with a great potential in cancer treatments. This com-
pound works as an antioxiodant. Moreover, it induces apoptosis of
cancer cells, has antiproliferative effects, modulates biotransforma-
tion of carcinogens, and inhibits angiogenesis. Antiinflammatory
effects of α-acids and iso-α-acids are also of considerable interest.
These compounds can be particularly effective in treatments for
arthritis. Wide publicity was given to the iso-α-acids that influ-
ence lipid metabolism and glucose tolerance, and thus have an
effect on weight loss.
Over the last decade, several dietary supplements based on hops
have been introduced on the market. The effects of some food
supplements were confirmed in fundamental clinical trials (van
Breemen and others 2014). Because of the effects of hop sub-
stances, as well as their low toxicity, the 1st drugs containing hop
substances as active ingredients may be expected in the near future.
Acknowledgment
The authors thank the Technological Agency of the Czech C. 2004. Inhibition of endothelial cell functions by novel potential cancer
Republic (project TE02000177) for its financial support.
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