Description

Beer is a fermented aqueous drink based on starch and flavored with hops. Hops provide the characteristic bitterness of the beer and contribute to its aroma and foam stability.

The hop plant (Humulus lupulus L.) is a dioecious plant, meaning that there are separate male and female hop plants. Only the female hop plant produces the flowers, or, more specifically, the strobiles that are used for brewing or possible medicinal purposes. Male plants have no commercial value but are used to pollinate the female plants. Pollination stimulates higher yields by increasing cone size and seed set, but because brewers prefer seedless hops, males are only grown with otherwise poor-yielding female varieties. Hop seed from a pollinated female is only planted when a cross between the male and female is desired to obtain a new variety.

The term "hop' in a strict sense refers to the hop plant, and the term "hops' refers to the flower cones (""hop cones'' or ""hops''). However, both terms are commonly used interchangeably. The flowers in a female hop plant are arranged in characteristic clusters on stems. The flower cluster is called an inflorescence. The female inflorescences are rich in polyphenolic compounds and acyl phloroglucides that are widely used to preserve beer and give beer its characteristic flavor and aroma.

The hop cones are green, built like pine cones and vary in size. At the base of the leaves (bracts, also called scales) of the cones, are collections of small, yellow spheres called the lupulin glands. The lupulin glands are little sacs of bitter and aromatic acids and oils. In the lupulin glands can be found the alpha-acids and their derivatives, including the iso-alpha-acids and the rho-iso-alpha acids, the beta acids and xanthohumol, among several other compounds. The iso-alpha-acids, including isohumulone, account for the bitter taste of beer. The oils in the hops are mainly responsible for the aroma of beer.

In addition to their role in beer, hops extracts have been used for medicinal reasons. The traditional use of hops as a mild sedative has its origin in the observation that the transfer of hop resin from the hands of hop-pickers to their mouths appeared to cause sleepiness and fatigue in the workers. In Germany, the use of hops is approved for the treatment of restlessness, anxiety and sleep disorders. However, high-quality clinical studies supporting the use of hops as a sedative are few and far between. Thus, the effectiveness of the use of hops for the treatment of sleep disorders is uncertain.

Recently, there has been great interest in studying certain phytochemicals found in hops for their possible anti-inflammatory, anticancer, chemopreventive and estrogenic activities. Two of the phytochemicals found in hops that have been receiving a great deal of attention are xanthohumol for its possible anticancer activity and 8-prenylnaringenin for its phytoestrogenic activity (see 8-Prenylnaringenin).

Xanthohumol is a prenylated chalcone derived from hops. In hops, the yellow compound is found in high amounts in the lupulin glands of the female inflorescence.

Xanthohumol is secreted as part of the hop resin (lupulin) by glandular trichomes found on the adaxial surfaces of cone bracts. It is also found in the trichomes on the underside of young leaves. The chalcone is found in small amounts in the Chinese traditional medicine plant, Sophora flavescens, extracts of which are used in the treatment a number of diseases, including certain cancers and viral diseases. A chalcone is an aromatic ketone that forms the central core for a variety of biological compounds. Chalcones are the immediate precursors in the biosynthesis of flavonoids, and their structures differ from that of other flavonoids by the inclusion of an open C-ring. (Chalcones are sometimes referred to as open C-ring flavonoids.) Xanthohumol is usually referred to as a prenylflavonoid. It is the precursor of the flavonoid, isoxanthohumol, which belongs to the flavanone subclass of flavonoids. Xanthohumol possesses a free 2′-hydroxy group and can therefore readily isomerize to isoxanthohumol.

Xanthohumol has been found to have broad-spectrum anticancer activity.

However, in contrast to some other phytochemicals in hops, especially 8-prenylnaringenin, xanthohumol per se does not possess phytoestrogenic activity.

Xanthohumol's empirical formula is C₂₁H₂₂O₅, its molecular weight is 354.396, and its CAS Registry Number is 6754-58-1. Xanthohumol is described chemically as (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)phenyl]-3-(4-hydroxyphenyl)prop-2-en-1-one. It is also known as (3′-[3,3-dimethylallyl]-2′,4′,4-trihydroxy-6′-methoxychalcone).

In addition to being classified as a prenylated chalcone or prenylchalcone and a prenylflavonoid, xanthohumol can be classified as a terpenophenol and a polyphenol.

Xanthohumol is represented by the following chemical formula:

Chemical Structure

Xanthohumol

Xanthohumol is a plant secondary metabolite and has broad-spectrum activity against bacteria, viruses and fungi, all of which can cause damage to the plant. The amount of xanthohumol in beer is low (about 0.1 milligram per liter). This is due to the thermal conversion of xanthohumol to isoxanthohumol during the brewing process. Xanthohumol does impart some bitter taste to beer and helps to stabilize the foam.

Actions & Pharmacology

Actions

Xanthohumol has antioxidant activity. It may also have anticancer/chemopreventive, anti-inflammatory, antimicrobial, antiobesity, antiosteoporosis, and triglyceride-lowering activities.

Mechanism of Action

Antioxidant activity: Xanthohumol has a number of antioxidant activities. It has been demonstrated to scavenge hydroxyl, peroxyl and superoxide anion radicals. Xanthohumol was also found to inhibit superoxide anion radical formation by 12-O-tetradecanoylphorbol-13-acetate stimulation of differentiated HL-60 human promyelocytic leukemia cells. It is reported to inhibit nitric oxide formation. Xanthohumol was demonstrated to inhibit the oxidation of LDL (low density lipoprotein) in vitro. Oxidized LDL is thought to be a major factor in the pathogenesis of atherosclerosis. It was also shown to decrease conjugated diene formation, a measure of lipid peroxidation, and to inhibit liver microsomal lipid peroxidation induced by ferrous ascorbate, ferric-ADP/NADPH or tert-butyl hydroperoxide.

Anticancer activity: Xanthohumol appears to be a broad-spectrum anticancer/chemopreventive agent, acting by multiple mechanisms in the initiation, promotion and progression phase.

Xanthohumol was demonstrated to induce apoptosis and inhibit NF-kappaB activation in two different prostate epithelial lines: human benign prostate hyperplasia epithelial cells (BPH-1) and malignant androgen-independent prostate cancer epithelial cells (PC-3), representing both non-tumorigenic hyperplasia and malignant prostate cancer. It was suggested by the authors of this study that xanthohumol may be potentially useful as a chemopreventive agent during prostate hyperplasia and prostate carcinogenesis.

Xanthohumol was reported to kill B-chronic lymphocytic leukemia (B-CLL) cells via an apoptotic mechanism. Cell death was associated with poly (ADP-ribose) polymerase cleavage and annexin V positivity, indicative of an apoptotic mechanism.

Xanthohumol was shown to inhibit the growth of the vascular tumor line KS-IMM, a spontaneously immortalized iatrogenic Kaposi's sarcoma cell line obtained from a biopsy. Histopathology and in vivo angiogenesis assays revealed that tumor angiogenesis was involved and that xanthohumol inhibited the growth of the cells via an antiangiogenic mechanism. Xanthohumol was demonstrated to repress both the NF-kappaB and Akt pathways in human umbilical vein endothelial cells (HUVEC), a commonly used endothelial cell line. This finding suggests that components of the two pathways are major targets in the molecular mechanism of xanthohumol. Further, using in vitro analysis, it was shown that xanthohumol interferes with several points in the angiogenic process, including inhibition of endothelial cell invasion and migration, growth, and formation of a network of tubular-like structures. The authors of this study suggest that xanthohumol may be useful as an antiangiogenic chemopreventive substance and that its potential in cancer prevention and treatment should be evaluated.

Another study reported that xanthohumol inhibited cell proliferation of both acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) cell lines. Inhibition of cell proliferation was associated with induction of apoptosis, reduced vascular endothelial growth factor (VEGF) secretion, decreased cell invasion, decreased metalloprotease production and decreased adhesion to endothelial cells. The authors of this study had previously shown that xanthohumol has antiangiogenic properties both in vitro and in vivo associated with inhibition of Akt/NF-kappaB activation. They concluded that as endothelial cells and hematopoietic cells are mutually correlated in their development and growth, targeting both tumor cells and endothelial cells with an agent such as xanthohumol, which possesses both cytotoxic and antiangiogenic activities, may lead to synergistic antitumor effects, interrupting a reciprocal stimulatory loop between leukemia and endothelial cells. In short, xanthohumol appears to show potential as a double-edge anticancer agent.

In a recent study, xanthohumol was reported to inhibit MCF7 cell proliferation dose-dependently. (MCF7 is a human breast cancer cell line.) Oral administration of xanthohumol to nude mice inoculated with MCF7 cells (breast cancer xenografts) resulted in central necrosis within tumors, reduced inflammatory cell number, increased percentage of apoptotic cells and decreased microvessel density. Antiangiogenic effects of xanthohumol were appropriately confirmed. A significant reduction in a number of inflammatory factors, including NF-kappaB, was demonstrated. The findings of this study again suggested the double-edge anticancer activity of xanthohumol. Xanthohumol targeted both breast cancer cells and host cells, namely inflammatory and endothelial cells.

The mechanism of action of the anticancer activities of xanthohumol are far from being completely understood. Continued research in this promising area is needed and warranted.

Anti-inflammatory activity: Xanthohumol has been shown to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). It was also found to downregulate the proinflammatory transcription factor NF-kappaB in human benign prostate hyperplasia epithelial cells (BPH-1). Xanthohumol was demonstrated to repress both the NF-kappaB and Akt (protein kinase B) inflammatory pathways.

Xanthohumol was reported to reduce the expression of the lipopolysaccharide (LPS) receptor components, such as the toll-like receptor 4 (TLR4) and MD2, resulting in the suppression of NF-kappaB activation in lipopolysaccharide (LPS)-activated RAW264.7 cells (a mouse monocytic cell line). In interferon gamma (IFN-gamma)-stimulated RAW264.7 cells, the binding activity of signal transducer and activator of transcription-1 alpha (STAT-1alpha) and that of interferon regulatory factor-1 (IRF-1) was inhibited by xanthohumol. These results suggest that depending on the stimuli, differential signaling pathways are used by xanthohumol for the inhibition of excess inflammatory mediators in macrophages. Further research is needed and warranted in order to fully understand the mechanism of action of the various anti-inflammatory activities of xanthohumol.

Antimicrobial/antiplasmodial activity: Xanthohumol is a plant secondary metabolite and has broad antibacterial, antiviral and antifungal activity against organisms that can do damage to the hop plant. Xanthohumol was also found to prevent the cytopathogenic effects of the human immunodeficiency virus (HIV) and was demonstrated to inhibit the proliferation of the malarial pathogen Plasmodium falciparum. The mechanism of action of these effects is unclear.

Antiobesity activity: The effects of xanthohumol and hinokiol, a lignan isolated from Magnolia officinalis, on apoptotic signaling in mouse 3T3-L1 adipocytes were studied alone and in combination.

It was found that although xanthohumol and hinokiol showed little or no effect as individual compounds, xanthohumol in combination with hinokiol demonstrated enhanced activity in inducing apoptosis in the 3T3L1 adipocytes via the cytochrome c/caspase-3/PARP and PTEN/Akt pathways. What these results have to do with an antiobesity effect in humans is entirely unclear. However, they do suggest that a clinical study may be worthwhile to see if this combination might have some effect in humans.

Antiosteoporosis activity: In one study, xanthohumol was reported to prevent bone resorption in a model system. The mechanism of this activity is not clear and further investigation is needed and warranted.

Triglyceride-lowering activity: Xanthohumol was demonstrated to inhibit the activity of diacylglycerol acyltransferase (DGAT), an enzyme that catalyzes the acyl residue transfer from acyl-CoA to diacylglycerol to form triglycerides (triacylglycerols, TAGs). Accumulation of TAGs is linked to a number of potentially serious conditions, including nonalcoholic steatohepatitis (NASH), obesity and elevated plasma triglyceride levels (hypertriglyceridemia) associated with diabetes, the metabolic syndrome and atherosclerosis. However, this experiment did not provide any insights into how xanthohumol and DGAT inhibition might regulate hepatic apolipoprotein B (apoB) secretion. Triglyceride availability is known to be a major factor in the regulation of apoB secretion.

A later study examined the role of xanthohumol on apolipoprotein B (apoB) and triglyceride synthesis and secretion, using HepG2 cells. (The HepG2 cell line is a human hepatoma cell line.) Apolipoprotein B is the primary lipoprotein of LDL-cholesterol. Xanthohumol was demonstrated to decrease apoB dose-dependently. The decrease in apoB was associated with increased cellular apoB degradation. Xanthohumol also inhibited the synthesis of triglycerides in the microsomal membrane and the transfer of the newly synthesized triglycerides to the microsomal lumen. This indicated that triglyceride availability is a determining factor in the regulation of apoB secretion under the experimental conditions. The inhibition of triglyceride synthesis was caused by a reduction in DGAT (see above study), which corresponded to a decrease in DGAT-1 messenger RNA expression, but not DGAT-2 expression. Xanthohumol also decreased microsomal triglyceride transfer protein (MTP) activity dose-dependently. MTP might also control the rate of triglyceride transfer from the microsomal membrane to the active luminal pool. In conclusion, xanthohumol appears to be a potent inhibitor of apoB secretion.

Pharmacokinetics

There is little data on the pharmacokinetics (PK) of xanthohumol in humans. Some animal and tissue culture studies are available. Absorption, metabolism and excretion of xanthohumol have been studied in rats. The efficiency of absorption of xanthohumol from the small intestine following oral administration was low. Xanthohumol was detected in the plasma mainly in the form of two mono-glucuronides whose maximum concentration was reached after four hours. The cumulative amounts of both xanthohumol glucuronides excreted in the urine reached a plateau at 12 hours after oral administration and accounted for 0.3% and 0.05% of the oral dose. The recovery of unchanged xanthohumol from the urine was 0.2%.

The metabolism of xanthohumol was investigated in vitro using human liver microsomes. Hydroxylation of a prenyl methyl group was the primary route of oxidative metabolism forming the trans isomer of xanthohumol. The double bond on the prenyl group formed an epoxide, which was opened by an intramolecular reaction with the neighboring hydroxyl group. Some xanthohumol can be converted to isoxanthohumol via acid-catalyzed cyclization in the stomach. And, isoxanthohumol can be converted by the microflora of the large intestine to the potent phytoestrogen prenylnaringenin.

Another metabolic study of xanthohumol examined in vitro metabolism of the prenylchalcone by human UDP-glucuronosyltransferases and sulfotransferases. Three monoglucuronides as well as three monosulfates were identified. It was concluded that the findings of the study suggested a prominent role for the glucuronidation and sulfation of xanthohumol in the liver as well as in the gastrointestinal tract.

Xanthohumol can be converted to isoxanthohumol via acid-catalyzed cyclization in the stomach. And, isoxanthohumol can be converted by the microflora of the large intestine to the potent phytoestrogen prenylnaringenin (see 8-prenylnaringenin)

PK studies on xanthohumol in humans are needed to in order to fill in all the details on its ADME (absorption, distribution, metabolism and excretion).

Indications & Usage

There is preliminary experimental evidence that xanthohumol, a prenylated chalcone of the hop plant that is an ingredient of beer, may have anti-inflammatory, anticancer, antiatherogenic and anti-infective/immunoprotective potential. Though hops show significant estrogenic activity, xanthohumol itself does not.

Overdosage

There are no reports of overdosage.

Dosage

The optimal dosage of xanthohumol is unknown.

A few xanthohumol-containing dietary supplements are available. Doses higher than those recommended on the label should generally not be exceeded.

The only dietary source of xanthohumol is beer. However, the concentration of xanthohumol in beer is very low, about 0.1 mg per liter.

Literature

Research & Summary

In a review of some of the relevant literature, one group of researchers concluded that xanthohumol appears to be a broad-spectrum cancer chemopreventive agent. They cite in vitro studies showing that it can inhibit metabolic activation of procarcinogens, induce carcinogen-detoxifying enzymes and inhibit tumor growth at early stages. In one study, the chalcone demonstrated both antioxidant and anti-inflammatory activity, modulated enzymes involved in carcinogen metabolism and detoxification and significantly prevented carcinogen-induced preneoplastic lesions in mouse mammary gland organ tissues. In a number of in vitro and some in vivo animal studies, xanthohumol has also demonstrated notable tumor antiangiogenic activity. Male nude mice were injected with a Kaposi sarcoma cell line that forms highly angiogenic tumors. Mice receiving xanthohumol enjoyed significantly reduced tumor growth, compared with controls. The research suggested that the flavonoid may exert this favorable effect through, among other actions, inhibition of nuclear factor-kappaB (NF-kB) activity involved in inflammation and angiogenesis. Xanthohumol was found to again inhibit NF-kB activation and to impede prostate hyperplasia and prostate carcinogenesis in vitro in a dose-dependent manner in another study. Still other in vitro studies with this prenylchalcone have demonstrated some efficacy against hematologic malignancies, melanoma and other cancers.

While finding these results provocative and promising, most researchers have been careful to point out that levels of this chalcone sufficient to replicate the results seen in their studies cannot be achieved through consumption of beer alone. The concentration of xanthohumol in beer is low and it would take huge amounts of beer to achieve any of the above possible anticancer effects. Some have begun developing xanthohumol-enriched beers. Others believe xanthohumol supplements are the better option. In any case, further research into the anticancer properties of this chalcone, extending the inquiry into the clinical domain, is indicated.

There is in vitro evidence that xanthohumol, through its antioxidant activity, may be able to prevent lipid peroxidation and thus have cardioprotective effects. In a series of in vitro assays, xanthohumol proved more potent than a number of other recognized antioxidants in its ability to scavenge hydroxyl and peroxyl radicals, as well as superoxide anion radicals. Xanthohumol has shown some preliminary ability to inhibit LDL-cholesterol oxidation. In another in vitro study, xanthohumol decreased apolipoprotein B secretion as well as triglyceride synthesis and secretion. In combination with honokiol, a lignan isolated from Magnolia officinalis, xanthohumol induced apoptosis in mature adipocytes in vitro. Neither agent, when tested alone, was similarly effective. Whether xanthohumol might play a role in the prevention or treatment of obesity is unknown, and far more research will be required to determine whether it can be effective in cardiovascular health generally.

Through some demonstrated immunoprotective effects modulated through its anti-inflammatory activity, xanthohumol may be able to protect against some infections. In one study it helped preserve macrophage function in an inflammatory environment. In a review of the literature, it demonstrated broad-spectrum anti-infective effects, showing some activity against various bacteria, viruses, fungi and malarial protozoa. Among the viruses affected were cytomegalovirus, herpes simplex viruses type 1 and 2 and human immunodeficiency virus 1. Its reported activity against the malaria agent Plasmodium falciparum was associated with its inhibition of glutathione-mediated degradation and detoxification of hemin, a by-product of the parasitic digestion of hemoglobin. Animal and clinical investigation of this anti-infective potential is clearly warranted.

Finally, estrogenic effects of hops have been documented for some time. Xanthohumol itself, however, has shown either no or very weak estrogenic activity, and there is no likely role for this substance in the prevention or treatment of perimenopausal symptoms.

Contraindications, Precautions & Adverse Reactions

Contraindications

Xanthohumol-containing dietary supplements are contraindicated in those hypersensitive to any component of a xanthohumol-containing product. Hypersensitivity to xanthohumol is probably very rare.

Precautions

Those who wish to use xanthohumol supplements for a health condition should first discuss this with his or her physician.

Because of the lack of long-term studies on the safety of xanthohumol-containing dietary supplements, pregnant females and nursing mothers should avoid their use.

Adverse Reactions

No reports.

Interactions

Drugs

Xanthohumol inhibits cytochrome p450, and although there are no known reports of any interactions with drugs and xanthohumol, those using drugs that are metabolized via the cytochrome p450 system, for example, the statin atorvastatin, should be cautious in the use of xanthohumol supplements.

Nutritional Supplements

None known.

Herbs

None known.

Food

None known.