What Is the Use of Hop Extract in Beer?

Hops, scientifically known as Humulus lupulus L., also called snake grass, toad lily, Tang grass flower, hu bu, and yeast flower, are plants belonging to the Cannabaceae family within the Urticales order. Hops are dioecious perennial climbing herbs with fibrous roots, capable of growing in many regions worldwide. Most cultivation areas are concentrated between latitudes 35° and 55° north and south. Currently, the primary production regions are the United States, Europe, Australia, South America, and China.

Hops extract imparts a distinctive bitterness and unique flavor to beer and possesses certain preservative properties, earning it the title of “the soul of beer.” Since its introduction into beer brewing in the 12th century, its primary use remains in beer production. As an important medicinal plant, hops also have a long history of application. Starting in the 13th century, hops, like other herbs such as rosemary, valerian, coriander, and marsh marigold, began to be used as herbal medicine. In the “Compendium of Materia Medica” by Li Shizhen of the Ming Dynasty, the term “Tuo De Hua” refers to hops.

Recent studies have shown that hop extracts not only have sedative, calming, hypnotic, antibacterial, anti-inflammatory, and diuretic effects, but also possess multiple functions such as antioxidant, antiviral, antitumor, and phytoestrogenic activities.

1 Active Ingredients of Hop Extracts

Hundreds of different organic compounds have been identified in hop extracts, and their flavor characteristics are produced by the independent yet synergistic interactions of these compounds. Humulone accounts for approximately one-fifth of the dry weight of hops, containing the most important bitter components, hop essential oils, and polyphenolic compounds. The bitter components are composed of α-acids and β-acids, which exist in a soft oil or resinous form and are soluble in hydrocarbon solvents, hence they are commonly referred to as hop soft resins. Due to oxidation by air, hop bitter acids are converted into a complex class of compounds. These compounds are no longer soft and are insoluble in hydrocarbon solvents, and are therefore commonly referred to as hop hard resins. Hops also contain other inorganic and organic compounds, the contents of which in hops are shown in Table 1.

α-Acids are an important component of hops, and they are a class of substances composed of five main isomers: humulone, cohumulone, adhumulone, trans-humulone, and trans-cohumulone. The ratio of humulone to cohumulone is highly correlated with the variety of hops and brewing quality. Traditionally, hop varieties are broadly classified into three types based on their α-acid content and flavor characteristics: aromatic hops, bitter hops, and bitter-aromatic hops. In recent years, with the continuous development and promotion of new hop varieties with high α-acid content, the beer industry has placed more stringent requirements on hop quality. Currently, internationally, hops are generally classified into four major categories: premium aromatic hops, aromatic hops, bitter hops, and high α-acid hops [11-12]. The classification characteristics and representative varieties of these hops are shown in Table 2.

The α-acids in hops undergo isomerization under certain conditions, forming isosorbic acids with extremely strong bitterness. This compound is the primary component responsible for beer bitterness; however, due to its instability, particularly under light exposure, it decomposes, the resulting fragments react with sulfur-containing compounds in beer to form 3-methyl-2-butenyl mercaptan, which is the primary substance responsible for beer flavor deterioration, commonly referred to as “light-induced off-flavor” [13]. The reaction process is illustrated in Figure 1.

The reason for the decomposition of iso-α-acids is due to the presence of three unsaturated bonds in their side chains. To further improve the light stability of beer and enhance its quality, a series of chemically modified α-acid derivatives with better light stability have been applied in beer brewing [14-15]. These compounds include dihydro, tetrahydro, and hexahydro isohydroxy-α-acids, among which dihydro isohydroxy-α-acid has the best solubility, featuring a mild bitterness and stability, but its photostability is slightly poorer, and its bitterness is only 0. 7 times that of is α-acid. Tetrahydro is α-acid has slightly poorer solubility but exhibits extremely strong and persistent bitterness, with a slight astringency, and its bitterness is 1.6 times that of is α-acid. Additionally, it has excellent photostability and aids in forming fine, stable foam in beer, though it occasionally imparts a lingering bitterness. Hexahydroiso-α-acid has the lowest solubility compared to the above two products but the best photostability. Its bitterness is mild and stable, and it also helps foam stability, though it is relatively expensive. During the isomerization process of α-acid, due to the presence of cis-trans isomers, its isomers and hydrogenated derivatives are composed of a larger group of substances. Figure 2 provides a simple schematic diagram of the structural conversion process of α-acid and its derivatives.

β-acid is another important component of hop soft resin. which is almost insoluble in cold water and beer. However, the oxidation product of β-acid, humulone, has a very strong bitterness, which is twice that of iso-α-acid, and it also has a relatively high solubility in water. This compound typically plays a good supplementary and balancing role in compensating for the decrease in bitterness caused by the loss of α-acid and the oxidative degradation of iso-α-acid in beer. Similar to α-acids, β-acids are a class of compounds composed of five main isomers: humulone, cohumulone, adhumulone, trans-humulone, and trans-cohumulone. Typically, the first three compounds account for 95% of the total content [16], but their content and composition ratios are not important indicators of hop quality or variety. β-acids generally do not undergo isomerization, except for their own tendency to oxidize. Under certain conditions, β-acids can undergo hydrogenation reactions to form more stable and active hexahydro-β-acids. The chemical structures and transformation processes of β-acids and their oxidative and hydrogenated derivatives are shown in Figure 3.

The essential oil components in hop extracts are primarily terpenes and sesquiterpenes, such as humulene, carvone, limonene, farnesene, pinene, thujene, and juniperene, which account for over 75% of the total essential oil content. Other components include some oxygen-containing compounds and sulfur-containing compounds, which are not only crucial for the flavor of beer, but also the primary components responsible for the calming and sedative effects of hops [17-18]. The structural formulas of some essential oil components in hops are shown in Figure 4.

The cones of hops also contain polyphenolic active components such as tannins, flavonoids, and flavonoid glycosides. The polyphenolic compounds in hops are classified into four categories: phenolic acid compounds, flavonoids, catechins, and proanthocyanidins. The most abundant are catechins, including small amounts of epicatechin, gallocatechin, and epigallocatechin. The proanthocyanidins in hops polyphenols are primarily proanthocyanidins formed by the condensation of two or more flavan-3-ols, along with some anthocyanins, cyanidins, and delphinidins [19]. These compounds exist either in free form or as glycosides. Among these substances, known active compounds include cyanidin, asparagine, tannins and resins, luteolin glucoside, grandiflorin, oleanolic acid, isohydroxycinnamic acid, and 8-isopentenylnaringenin, among others.

Hops polyphenols are of great importance to beer quality, playing a role in enhancing and improving the biological stability and flavor stability of beer during the brewing process [20-21]. During beer production, quercetin undergoes further reactions, with reaction products including isoquercetin and dehydrocycloquercetin. Humulone and isohumulone in hops can inhibit the growth of certain human cancer cells without affecting the growth of non-cancerous cells in animals. They may also have similar effects on the female sex hormone estrogen in mammals, and research into their functional activities is a current focus in the study of the pharmacological properties of hops. The main polyphenolic compounds in hops are structurally represented in Figure 5.

2 Pharmacological Effects

Like its history in beer brewing, the medicinal use of hops is also very ancient. In 13th-century Europe, hops, along with other herbs such as rosemary, valerian, coriander, and marshmallow, began to be used as medicinal herbs. The Compendium of Materia Medica records [22] that hops are bitter and slightly cool in nature, with functions including stomachic, sedative, expectorant, and anti-tuberculosis properties. The Book of Food Herbs and Remedies records [23] that hops have inhibitory effects on various bacteria and exhibit sedative and estrogen-like activities. In folk medicine, hops are commonly used to make tea, with functions including stomach-strengthening, vision-improving, thirst-quenching, blood pressure-lowering, cough-relieving, diuretic, and sedative effects. The medicinal part is the green inflorescence, which has been processed into hop extract tablets, hop extract emulsion, and hop extract extract tablets for use.

2.1 Antimicrobial and anti-inflammatory effects

Modern pharmacological analysis shows that the chemical components in hop extracts, such as humulone and lupulone, have inhibitory effects on Mycobacterium tuberculosis, Staphylococcus aureus, and Bacillus subtilis, among others. Among these, humulone is more potent than lupulone [24-26]. This is because humulone has strong lipophilicity, a high distribution coefficient, and easily penetrates the wax membrane of Mycobacterium tuberculosis, exerting a special affinity and inhibiting its growth. A study using agar overlay technology on 11 varieties of hops and one wild hop species showed that both hops essential oil and solvent extracts exhibit strong inhibitory effects against Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus), acid-fast bacteria, and fungi (dermatophytes), but showed little activity against Gram-negative bacteria (Escherichia coli) and yeast [27]. Polyphenolic compounds in hops can inhibit the growth of streptococci and delay the onset of dental caries. Tagashira et al. [28] found that the minimum inhibitory concentration of hop polyphenol extracts for inhibiting the growth of dental caries streptococci was significantly lower than that of extracts from oolong tea or green tea.

Other studies have shown that under weakly acidic conditions (pH = 4–7), the antibacterial effect of hops increases with increasing acidity. When considering the degree of ionization, trans-isohumulone exhibits antibacterial activity 20 times higher than humulone, 11 times higher than humulone, and 9 times higher than trans-humulone acid [29]. Additionally, patent reports indicate that α-acid, β-acid, isosorbide, or polyphenolic compounds in hops can be used as new selective cyclooxygenase-2 (COX-2) inhibitors, reducing inflammation and significantly lowering the incidence of adverse cardiovascular events and gastric side effects [30]. Furthermore, traditional Chinese medicine uses hops, plantain, and Chine (15g each) decocted in water to treat urinary tract inflammation, cystitis, nephritis, edema, and difficulty urinating. In vitro experiments with wild hops decoction showed inhibitory effects against Staphylococcus aureus, diphtheria bacillus, Shigella, group B hemolytic streptococcus, Escherichia coli, Bacillus anthracis, and Salmonella typhi [31]. The pain-relieving and analgesic effects of hops are primarily attributed to the antibacterial properties of α-acids and β-acids, which can alleviate inflammatory symptoms and reduce or eliminate pain.

2.2 Antitumor Effects

A series of animal experiments have shown that hops can prevent cancer and provide significant protection against plasma oxidation. The flavonoid compounds containing isoprenyl groups in hops extract, particularly quercetin and isoquercetin, exhibit significant physiological activity in vitro, exhibiting anti-proliferative and cytotoxic effects on breast cancer cells (MCF-7), colon cancer cells (HT-9), and ovarian cancer cells (A-2780). The inhibitory effect is concentration-dependent at concentrations ranging from 0.1 to 100 μmol/L, with the mechanism of action involving inhibition of DNA synthesis [32]. Huangfuquan also inhibits the activity of the procarcinogenic enzyme cytochrome P-450, preventing its activation of carcinogens [33], and induces the activity of enzymes that detoxify carcinogens and anthraquinone reductase [34].

In vitro experiments have shown that humulone in hop extracts inhibits the proliferation and invasion of breast cancer cells. When B-chronic lymphocytic leukemia cells from patients were cultured in vitro, humulone exhibited antitumor activity in B-chronic lymphocytic leukemia cells in vitro experiments. The mechanism of action is through a cell apoptosis mechanism [35]. Humulone in hops has a significant inhibitory effect on inflammation induced by tumor cells treated with phorbol (12-O-tetradecanoylphorbol-13-acetate, TPA), and can also inhibit inflammation caused by arachidonic acid-induced ear edema in mice [36]. Humulone and caryophyllene have significant inhibitory effects on various tumor cells (e.g., leukemia cells); hydroxyflavonoids can inhibit the synthesis of a protein that promotes the development of human colorectal cancer, and inhibit the spread of gastric cancer cells, and the spread of squamous cells in throat and brain cancer [37-39]. The combination of lonicerin and vitamin D3 is more effective than vitamin D3 alone in treating leukemia. This combination holds great promise for the development of natural drugs against leukemia [40].

2.3 Antioxidant effects

Studies have shown that polyphenolic compounds in hops exhibit significant antioxidant effects [41-43]. Hops polyphenols can inhibit the activity of lipoxygenase (LOX), whose function is associated with its accessory enzymes and plays a central role in reactive oxygen species (ROS) activity. Certain dihydroflavonol derivatives, such as catechin and procyanidin B3, can bind to the polar groups of enzymes, thereby protecting “oxidatively sensitive substances” like lipids from rapid enzymatic oxidation. Additionally, polyphenolic compounds can act as chelating agents, blocking the transfer reactions of heavy metal ions (such as copper and iron), thereby eliminating their catalytic effects and preventing the generation of excessive oxygen free radicals. Furthermore, the “free radical theory” underlying the formation of beer aging flavors suggests that polyphenols in hops can capture free radicals from inorganic and organic compounds, weakening their reactions. The outcomes of these reactions directly influence the formation of aging flavor compounds. Coniferic acid has lipid-oxidizing inhibitory effects in the body and inhibits enzymes involved in the conversion of glycerol diester to glycerol triester.

2.4  Blood sugar-lowering function

Research has found that some components in hops have blood sugar-lowering effects and can inhibit the onset of diabetes [44]. Keiji's research results confirm that the isohumulone in hops can prevent obesity and the onset of type II diabetes, improve lipid metabolism, and inhibit the occurrence of atherosclerosis [45]. Peroxisome proliferator-activated receptors (PPARs) are a class of ligand-activated transcription factors involved in regulating various physiological responses, such as lipid metabolism, glucose homeostasis, cell differentiation, and apoptosis. There are three types of PPARs: PPAR-α, PPAR-β/δ, PPAR-γ are all expressed in endothelial cells.

The isohumulone in hop extract has the ability to activate PPAR-α and PPAR-γ. In diabetic KK-Ay mice, after administration of isohumulone, the levels of glucose, triglycerides, and free fatty acids in plasma were significantly reduced, but no significant increase in body weight was observed. After feeding C57BL/6N mice a high-fat diet and then administering isopentenylic acid, it was found that their glucose tolerance improved and insulin resistance decreased. The size of fatty livers in these animals decreased, and the number of apoptotic adipocytes increased. The results of a randomized controlled trial investigating the effects of isosorbide on diabetes showed that after administering isosorbide to mice with insulin antibodies and type 2 diabetes for 8 weeks, isosorbide significantly reduced blood glucose levels and hemoglobin A1c levels, and improved insulin sensitivity in mice fed a high-fat diet [46]. Other studies have reported that hop extracts, particularly the isohumulone component, exhibit very strong aldose reductase inhibitory activity, with inhibition rates comparable to those of the potent aldose reductase inhibitor quercetin [47].

2.5 Promoting digestion

Modern medicine suggests [48] that hop extracts have relaxing effects on smooth muscles and promote digestion. Therefore, hops are often used in combination with other medications to treat gastrointestinal dysfunction, segmental ileitis, and gastric discomfort. According to clinical reports, hops have excellent stomach-strengthening, digestive, and diuretic effects, and can be used to treat loss of appetite, abdominal distension, edema, and cystitis. They also demonstrate significant therapeutic efficacy in alleviating infections of the digestive organs and treating gastric and duodenal ulcers [49-50]. The diuretic effect of hops is primarily due to the presence of asparagine in hops. Additionally, there are reports of hops being used as a veterinary medicine. Studies by Sudley et al. [51] indicate that hops have good therapeutic effects on rumen atony, rumen impaction, rumen bloating in cattle, and gastrointestinal diseases in horses and mules.

2.6 Antiviral effects

Studies on the effects of compounds in hops on DNA and RNA viruses have shown [52-53] that the isohumulone in hops has certain antiviral effects against bovine filterable diarrhea virus and cytomegalovirus, while humulone and isohumulone have antiviral effects against cytomegalovirus, herpes simplex virus HSV-1, and HSV-2. with xanthohumol exhibiting significantly stronger activity than isohumulone. Xanthohumol also has antiviral effects against bovine filterable dysentery viruses. Fro..lich et al. [54] found that the isoprenylated flavonoids in hops exhibit antimalarial activity, with xanthohumol demonstrating stronger efficacy.

2.7 Sedative, Anxiolytic, and Sleep-Promoting Effects

Hops have sedative, hypnotic, and antispasmodic effects, and have been widely used since ancient Roman times [55-58]. Traditionally, hops have been used to treat insomnia, nervous tension, and neuralgia with excellent efficacy. Experimental studies have shown that hops can increase sleep duration reduced by pentobarbital. Other studies have shown that combining hops with the roots of Valerian and passionflower can improve sleep quality and prevent sleep disorders. When used as a sedative, hops are typically combined with one or more other herbs. When experimental animals were administered high doses of hops, it was found that 2-methyl-3-buten-2-ol in hops possesses central nervous system sedative activity. Although the amount of this compound in hops is relatively small, it can be synthesized in the body through the metabolism of bitter acids and humulone in hops, which explains the sedative effect of hops.

2.8   Estrogen-like effects

Research indicates that, in addition to the aforementioned effects, hops possess numerous other benefits [59-64]. Hops contain substances with progesterone-like activity and gonadotropin-inhibiting activity, some of which have emmenagogue effects. 8-Isopentenylflavone, a highly promising progesterone-like substance, can reduce hot flashes during menstruation in women. Additionally, hop preparations have significant efficacy in treating leprosy. Hops are also used to treat coughs, and topically applied to alleviate skin itching and measles, among other conditions. They are also suitable for treating various infections. Furthermore, studies have shown that lupeol in hop extracts has a preventive effect against osteoporosis, and that feeding rodents a diet containing isomerized hop extract with isoharpyranone can prevent diet-induced obesity.

3  Prospects

Due to the unique and irreplaceable role of hops in beer brewing, researchers will continue to focus on its brewing characteristics, including the separation, chemical modification, and modification of its main components to synthesize, separate, identify, and apply derivative products with superior brewing quality. In recent years, with the deepening of research on the bioactive components of plant extracts worldwide, the various biological and pharmacological activities of hop extracts have gradually been elucidated. As one of the traditional Chinese medicinal ingredients, the application of hops in traditional Chinese medicine has a history of over a thousand years, but it has been largely limited to clinical use and reports on its definite therapeutic effects, with the active components, their mechanisms of action, and their relationships not yet fully understood.

Modern chemical and pharmacological studies have revealed that, in addition to the well-studied active compounds such as humulone and lupulone, the polyphenols and flavonoids in hop extracts have garnered increasing attention. In terms of application, foreign countries have already expanded its use beyond the beer industry into food, alcohol production, sugar manufacturing, and the pharmaceutical industry. In recent years, domestic researchers have also begun to engage in related studies. It is believed that with the continuous strengthening of research on its active components and effective constituents, as a natural plant-derived active ingredient with strong antibacterial and anti-inflammatory properties, hops, this traditional Chinese medicine, will play an increasingly important role.

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