PharmaNutrition 3 (2015) 4652

Contents lists available at ScienceDirect

PharmaNutrition
journal homepage: www.elsevier.com/locate/phanu

Review

Isohumulones from hops (Humulus lupulus) and their potential role in medical
nutrition therapy
Jeffrey S. Bland a, * , Deanna Minich b , Robert Lerman b , Gary Darland b , Joseph Lamb b ,
Matthew Tripp b , Neile Grayson a
a
b

KinDex Pharmaceuticals, Seattle, Washington, USA

Consultant Scientist, Seattle, Washington, USA

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 22 January 2015
Received in revised form 27 February 2015
Accepted 3 March 2015

The lipophilic extracts of the common hops (Humulus lupulus) contain compounds that are readily
modied to the family of isohumulones (e.g., iso-alpha acids). The isohumulones have been found to
reduce metabolic inammation and insulin resistance, and positively impact dyslipidemia and obesity.
These effects are consistent across studies in multiple cell lines, animal model systems and human
intervention trials. Mechanistic work has demonstrated that these isohumulones have a unique
pleiotropic mechanism of action which is consistent with their demonstrated safety and range of
physiological effects. It is suggested from this extensive body of work that specic isohumulones may be
important bioactive agents for the application in medical nutrition therapy in the support of diseases
associated with chronic inammation and insulin resistance.
2015 Published by Elsevier B.V.

Keywords:
Hops
Isohumulones
Metabolic inammation
Insulin resistance

Contents
1.
2.
3.
4.
5.

Inuence of hops isohumulones (iso-alpha acids) on inammation and insulin sensitivity

Bioavailability and metabolism of isohumulones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effects of hops isohumulones on insulin sensitivity and metabolic syndrome . . . . . . . . . .
Inuence of the hops-derived isohumulones on obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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47
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50
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The past two decades have witnessed a global explosion in the

prevalence of non-communicable, non-infectious chronic diseases
such as type 2 diabetes, coronary heart disease, autoimmune
diseases, and dementia [1]. All of these diseases have been found to
be associated with a physiological state of chronic inammation
dened as low-grade inammation orchestrated by metabolic cells
in response to specic immune activating signals [2], the origin of
which is complex but has been found to be related to diet, lifestyle
and environmental factors [3]. The recent PREDIMED study has
demonstrated that a Mediterranean diet rich in fruit and
vegetables, whole grains, nuts and virgin olive oil has a benecial
inuence on lowering the incidence of heart disease and reducing
chronic metabolic inammation [48].

* Corresponding author. Tel.: +1 2069222912.

E-mail address: jeffbland@kindexpharmaceuticals.com (J.S. Bland).
http://dx.doi.org/10.1016/j.phanu.2015.03.001
2213-4344/ 2015 Published by Elsevier B.V.

This association between specic dietary components and the

reduction in incidence of non-communicable chronic diseases

J.S. Bland et al. / PharmaNutrition 3 (2015) 4652

raises the question as to the mechanistic role that specic diets and
their component nutrients have on chronic diseases associated
with metabolic inammation. It is well known that food is
composed of a complex matrix of the macronutrients protein,
carbohydrate and fat that exist in many different chemical and
physical forms depending on the type of foods and their method of
preparation that are included in the diet. Beyond these nutrients,
however, vitamins, minerals, essential fatty acids, phytochemicals
and conditionally essential nutrients such as taurine, lipoic acid,
coenzyme Q10, and carnitine all play roles in the modulation of
physiological function.
Micronutrients and phytonutrients have been found to inuence physiology through the following cellular interactions [9,10]:
 B-vitamins serve as cofactors to specic enzymes that regulate

metabolism.
 Minerals serve as cofactors that regulate enzyme activities.
 Fat soluble vitamins A and D have been demonstrated to

inuence genetic expression as well as non-genomic effects.

 Essential amino acids such as phenylalanine, tyrosine and

tryptophan serve as precursors to neurotransmitters.

 Phytochemicals can serve as agents that modulate intercellular

signal transduction and genetic expression.

Over the past decade phytochemicals have been identied that
inuence metabolism, signal transduction and genetic expression
through a number of specic mechanisms that include [1115]:








Nuclear transcription factor regulation.

Epigenetic regulation.
Response element inuence.
Mitochondrial redox regulation.
Enzyme inhibition.
Precursor to cellular mediators.
Post-translational protein modication.

Howitz and Sinclair have suggested that the role of phytochemicals in inuencing mammalian physiology is through a
hormetic effect (i.e., low dose benecial modulatory effect) on
signal transduction and genetic expression that reduces cellular
stress response as described in Fig. 1 [16].

47

1. Inuence of hops isohumulones (iso-alpha acids) on

inammation and insulin sensitivity
One of the interesting families of phytochemicals in terms of
their inuence on cellular disturbances associated with metabolic
inammation and insulin resistance as reviewed by Van Cleemput
et al. are the lipophilic isohumulones (e.g., iso-alpha acids) derived
from the common hops, Humulus lupulus [17].
The resin glands or strobiles of the female hop plant
biosynthesize several hundred different phytochemicals. The
humulones or alpha acids represent one major class of lipophilic
agents produced by the female plant, and have been used as
bittering agents in the production of beer for centuries. In the
brewing of beer, the heating process involved in the development
of the wort can isomerize the cyclohexadienone structure of the
humulones to the cyclopentadienone structure of the isohumulones as shown in Fig. 2. The degree of isomerization and the
amount of bitter avor produced by the addition of hops is highly
dependent on the length of time the hops are boiled.
Yajima et al. were the rst group to report the inuence that
isohumulones have in both cellular and animal models of insulin
resistance [18]. Their published study included the results of a
small double blind, placebo controlled pilot trial in diabetic
humans demonstrating a signicant reduction in fasting blood
glucose and hemoglobin A1c after 8 weeks of intervention in the
isohumulone treated group versus the control group. Subsequent
studies reported by this Japanese group indicated that the
hops-derived isohumulones reduced elevated triglycerides associated with insulin resistance, and raised HDL cholesterol levels
while reducing liver fat stores in diabetic animal models [19,20]. In
a companion study this same group reported that the administration of isohumulones prevented high fat diet-induced obesity in
the C57BL/6N mouse model [21]. Nozawa et al. also reported that
dietary supplementation with isohumulones was found to reduce
the production of the proinammatory prostaglandin E2 in the rat
colon suggesting a tissue-specic anti-inammtory effect [22].
In 2005 Tripp reported the unique antiinammatory potential
and putative mechanism of action of the isohumulones [23,24].
Babish et al. screened 208 chemically characterized phytochemical
extracts for antiinammatory and antidiabetic activity and found
that the iso-alpha acids derived from hops and proanthocyanidins

Fig. 1. Inuence of various phytochemicals on cellular stress response [16].

48

J.S. Bland et al. / PharmaNutrition 3 (2015) 4652

Fig. 2. Isomerization of hops humulone to isohumulone in the brewing of beer.

from Acacia nilotica were among the most active natural

compounds inuencing both inammation and insulin signaling
pathways [25]. Indeed, a synergistic relationship between the
isohumulones derived from hops and A. nilotica- derived
proanthocyanidins was observed at specic ratios and may
represent an example of how combination of specic phytochemicals can have a hormetic inuence on cellular physiology [26].
Hougee et al. have described the inuence of lipophilic hopsextracts on the reduction of zymosan-induced arthritis in the
mouse model [27]. Minich and Bland discuss the role of the hops
isohumulones and other phytochemicals on signal transduction
associated with regulation of the insulin and inammation
metabolic network [28].
The isohumulones are the major constituents of modied hop
extracts which is an approved food additive in the United States for
the use as bittering agents in beer [29]. The chemical structures of
the cis and trans isomers of the three classes of isohumulones
termed n, co and ad are as shown:

The isohumulones have been found effective in reducing

inammatory arthritis in both animal models and open label
and controlled human intervention trials in individuals with the
pain and inammation associated with osteoarthritis to improve
symptoms as determined by the use of the WOMAC validated
osteoarthritis screening questionnaire [30,31].
The safety of the hops-derived isohumulones as contrasted to
the standard non-steroidal anti-inammatory medications is
related to the unique antiinammatory mechanism of action of
the isohumulones. Hall et al. have demonstrated that the
isohumulones are not a direct inhibitor of the proinammatory
enzyme cyclooxygenase 2, but rather they reduce the nuclear
translocation of the transcription factor NFkB selectively in
immune activated macrophages [32]. The isohumulones reduce
the abundance of the inducible cyclooxygenase 2 in the immune

activated cells without adversely inuencing cyclooxygenase

2 expression in other cells such as the gastrointestinal mucosa
where this enzyme is important for maintaining healthy function.
It was shown by Hall et al. in the AGS human gastric mucosal cell
line that the isohumulones do not have an adverse effect on
cyclooxygenase function whereas the common non-steroidal
antiinammatories aspirin, ibuprofen, indomethacin and naproxen increase the risk to gastrointestinal pathology due to their
inhibition of cyclooxygenase function [33]. In human intervention
trials the isohumulone pharmacophore had no effect on the level of
fecal calprotectin, a measure of gastric inammation, when
administered orally, whereas naproxen in the same subjects in a
crossover trial resulted in a signicant increase in fecal calprotectin
[33,34].
Mechanistic studies executed by Konda et al. demonstrated that
the isohumulones had a dose dependent impact on both NFkB
nuclear translocation and nitric oxide production in LPS stimulated
RAW 264.7 murine macrophages as shown in Fig. 3 indicating that
the anti-inammatory effect of the isohumulones was a result of
decreased inammatory gene expression [35].

Fig. 3. Inuence of the hops-derived RIAA on NFkB and nitric oxide synthase
activity [35].

J.S. Bland et al. / PharmaNutrition 3 (2015) 4652

Desai et al. demonstrated that the isohumulone derivative

THIAA attenuates the TNF-alpha activated inammation and
matrix metalloproteinase-9 expression in human monocytic
THP-1 cells as well as their adherence to human aortic endothelial
cells [36]. These observations suggest that THIAA may have
benecial effects for the prevention of cardiovascular diseases by
ameliorating inammation and subsequent plaque destabilization,
which are hallmarks of atherosclerosis. Desai et al. have also
reported that the THIAA derivative from hops was capable of
reducing the inammatory processes associated with an animal
model of rheumatoid arthritis by showing a reduction in swelling,
prevention of cartilage destruction, and reduction in bone
destruction [36].
2. Bioavailability and metabolism of isohumulones
Cattoor et al. evaluated the bioavailability of the isohumulones
in New Zealand white rabbits and well as in Caco-2 cell monolayers
to investigate epithelial transport. The bioavailability of the
isohumulones was determined through the differential pharmacokinetics of an oral versus intravenously administered dose. The
isohumulones were found to be efciently transported across the
gastrointestinal mucosa resulting in approximately 30% absorption
of an oral dose within 4 h after administration [37,38].
When the isohumulones were incubated with rabbit hepatic
microsomes it was found that they were rapidly metabolized to a
variety of oxidation products principally characterized as humulinic acids and allosio-alpha-acids which are water soluble and
readily excreted [39].
In studies with Dahl salt-sensitive hypertensive rats it was
found that when they were fed a diet supplemented with
isohumulones that there was a marked reduction observed in
renal injury, proteinuria and blood pressure. It was also found that
glomerulosclerosis and interstitial brosis scores were signicantly decreased. The authors suggest that the exposure to isohumulones and their metabolites may help prevent the progression of
renal injury caused by hypertension [40].

49

oxidized low density lipoprotein more effectively than the low

glycemic load, Mediterranean diet alone [46].
Lerman et al. reported that in women and men with metabolic
syndrome, insulin resistance and dyslipidemia that intervention
with the medical food containing the hops-derived isohumulones
and A. nilotica anthocyanidins along with a low glycemic load,
Mediterranean style diet resulted in signicantly better outcome in
reduction of all the clinical features of metabolic syndrome than in
a matched group of subjects who received the low glycemic load,
Mediterranean diet alone [47].
4. Inuence of the hops-derived isohumulones on obesity
Sumiyoshi and Kimura reported that extracts of hops
(H. lupulus) were found to inhibit obesity in mice fed a high fat
diet over a long-term period [48]. They proposed that specic hop
extracts might be useful for preventing obesity and glucose
intolerance caused by a high fat diet.
In examining the inuence of isohumulones on obesity, Konda
et al. reported that a specic molecule synthesized from the
isohumulone THIAA mixture had the ability to improve insulin
signaling and obesity in both the diet-induced obesity mouse
model of type 2 diabetes and the Zucker diabetic fatty rat model
[49]. This study demonstrated that the isohumulone pharmacophore represents itself as a privileged structure that inuences
adipocyte physiology and adiposity.
Vroegriik et al. demonstrated that the hops-derived isohumulone mixture when administered in a high-fat fed mouse model of
diabetes for 514 weeks resulted in a signicantly lower mean
weight than the control animals or those treated with the insulin
sensitizing drug rosiglitazone even though calorie consumption
was equal in all three groups as shown in Fig. 4 [50].
In metabolic chamber studies they found that the isohumulones increased thermogenic responsiveness and resting energy
expenditure in the animals suggesting that the isohumulones
increase lipid metabolism.

3. Effects of hops isohumulones on insulin sensitivity and

metabolic syndrome
Over the past decade the interrelationship between the
inammatory and insulin signaling pathways has been elucidated
[41]. In vitro assays with murine 3T3L1 adipocytes as well diabetic
animal models indicated that the antiinammatory effects of the
isohumulones were associated with the improvement in insulin
signaling [42,43]. Obara et al. reported the results of a study of
ninety-four subjects with prediabetes who were randomly divided
into four groups and engaged in a 12 week double blind dosending study to evaluate the impact of ingestion of 16, 32, or 48 mg
of isohumulones per day versus placebo [44]. After treatment the
fasting blood glucose was decreased in the 32 and 48 mg groups,
but did not change in the placebo group. The hemoglobin A1c was
also signicantly decreased in the 48 mg group versus the placebo.
There was also a signicant decrease in body mass index (BMI) in
the 48 mg group as compared with placebo.
In a 12 week, diet controlled intervention trial in patients with
metabolic syndrome and dyslipidemia it was found that a medical
food supplemented program containing isohumulones and Acacia
anthocyandins resulted in a clinical improvement in all the
biomarkers associated with insulin resistance [45]. In a larger
multi-centered, diet controlled study in women with insulin
resistance and metabolic syndrome Jones et al. found that an
isohumulone and anthocyanidin containing medical food administered along with a low glycemic load, Mediterranean diet
decreased atherogenic lipoproteins and lipoprotein (a) and

Fig. 4. Effect of the isohumulone mixture (Meta060) and rosiglitazone intervention

on obesity in the high fat fed diabetic mouse model [50].

50

J.S. Bland et al. / PharmaNutrition 3 (2015) 4652

These observations that the isohumulones are associated with

improved lipid metabolism, improved insulin sensitivity and the
reduction in metabolic inammation raises the question as to a
mechanistic explanation for these varied inuences on metabolic
disturbance. Everard et al. have provided a novel potential
explanation for the various inuences that the isohumulones
have on these multiple physiological endpoints [51]. They
evaluated the inuence of isohumulones in the high-fat fed
mouse model of diabetes on insulin sensitivity, serum triglycerides, inammation and obesity. Their data conrmed previous
studies that demonstrated the ability of the isohumulones to
improve insulin action and its relationship to the regulation of
post-prandial serum glucose, and the reduction of triglycerides
and obesity.
Beyond these observations, however, Cani et al. demonstrated
that the isohumulones were capable of reducing post-prandial
endotoxemia. There is now considerable evidence that high fat
diets create alteration in gut mucosal permeability and activation
of the enteric immune system that initiates metabolic inammation and insulin resistance [5254]. This state of chronic
postprandial endotoxemia in turn results in systemic crosstalk
among the intestinal microbiota, circulating macrophages and
monocytes, adipocytes and skeletal muscle that creates a blunting
of insulin sensitivity and reduced lipid metabolism [55,56].
Characteristics of postprandial endotoxemia include an increase
in serum lipopolysaccharides derived from the outer cellular
membrane of intestinal gram negative bacteria and the proinammatory cytokines TNF-alpha and interleukin-6 [57]. The work
of Cani et al. demonstrated in the diet-induced obesity mouse
model that the administration of isohumulones resulted in a trend
toward a statistically signicant reduction of plasma lipopolysaccharides, however the reduction in postprandial serum levels of
interleukin-6 and tumor necrosis factor alpha did reach statistical
signicance [51].
It is known that the high fat diet increases gastrointestinal
mucosal permeability through the alteration in integrity of the
tight junction proteins, occludin and zonulin, which then

contributes to the increased absorption of LPS and activation of

the enteric immune system [58,59]. As is shown in Fig. 5, Cani et al.
demonstrated that the administration of isohumulones improved
zonulin and occludin mRNA expression in the gastrointestinal
mucosa in the high-fat fed obese mouse model which is consistent
with improved gastrointestinal mucosal integrity and a reduced
absorption of LPS [51].
These data suggest that isohumulones may reduce the activation
of specic pattern recognition receptors on target tissues such as the
gastrointestinal mucosal cells thereby reducing the triggering of the
proinammatory immune response which is associated with insulin
resistance, dyslipidemia, and obesity [60,61].
5. Conclusion
The lipophilic family of isohumulones derived from a modied
hops extract have been found to have a unique ability to modulate
the metabolic disturbances that result in chronic metabolic
inammation. These effects have been demonstrated consistently
among various cell lines, animal model systems and human
intervention trials. The isohumulones improve insulin resistance
and dyslipidemia in humans. They have also been shown to reduce
systemic inammation, increase lipid metabolism and reduce
adiposity in high fat-fed animal models. Lastly they have been
shown to reduce post-prandial endotoxemia while improving
gastrointestinal mucosal integrity during high fat feeding in animal
models. These characteristics of this class of molecules indicate
that the isohumulones position themselves as potentially useful as
bioactive substances for inclusion in medical nutrition therapies
for the management of chronic diseases associated with metabolic
inammation related diabesity [62]. The emerging understanding
of the physiological effects of the isohumulones suggests that they
have a pleiotropic network inuence on metabolism. As Barabasi
has recently commented network effects increasingly affect all
aspects of biologic and medical research, from disease mechanisms
to drug discovery. It is only a matter of time until these advances in
understanding will start to affect medical practice, making the
emergence of a new eld that may be aptly called network
medicine [63]. The isohumulones represent a family of molecules
that may well nd applications in medical nutrition therapy due to
their unique pleiotropic inuences on the chronic diseases
associated with metabolic inammation.
References

Fig. 5. Inuence of isohumulones (Meta) on gastrointestinal mucosal occludin and

zonulin mRNA in the high fat fed obese mouse model [51].

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