8 Prenylnaringenin

• Menopausal symptom relief
• Bone health support
• Hormonal balance
• Antioxidant properties

• Neuroprotection
• Cardiovascular support
• Metabolic regulation
• Anti-inflammatory effects
• Antimicrobial activity

8-Prenylnaringenin (8-PN) is a prenylated flavanone found in hops (Humulus lupulus L.) and is widely recognized as one of the most potent phytoestrogens discovered to date. Its chemical structure features a flavanone backbone with a prenyl group (3,3-dimethylallyl) at position 8 and hydroxyl groups at positions 5, 7, and 4′. This unique structure, particularly the prenyl group at position 8, contributes significantly to its potent estrogenic activity and other biological effects. The most well-established and significant mechanism of 8-prenylnaringenin is its interaction with estrogen receptors (ERs).

8-PN binds to both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) with high affinity, though it demonstrates a slight preference for ERα. The binding affinity of 8-PN for ERs is comparable to that of 17β-estradiol, the primary endogenous estrogen, making it one of the most potent phytoestrogens known. In competitive binding assays, 8-PN has been shown to have a relative binding affinity of approximately 0.1-0.01 compared to 17β-estradiol, which is significantly higher than most other phytoestrogens such as genistein or daidzein. Upon binding to ERs, 8-PN can activate both genomic and non-genomic estrogen signaling pathways.

In the genomic pathway, the 8-PN-ER complex translocates to the nucleus, binds to estrogen response elements (EREs) in the promoter regions of target genes, and regulates gene transcription. This leads to the expression of estrogen-responsive genes involved in various physiological processes, including cell proliferation, differentiation, and metabolism. In the non-genomic pathway, 8-PN can rapidly activate signaling cascades through membrane-associated estrogen receptors, leading to effects such as calcium mobilization, activation of protein kinases, and modulation of ion channels. The estrogenic effects of 8-PN are tissue-specific and dose-dependent, exhibiting selective estrogen receptor modulator (SERM)-like activity.

In some tissues, such as bone and brain, 8-PN acts as an estrogen agonist, mimicking the beneficial effects of estrogen. In other tissues, particularly in certain contexts in breast and uterine tissue, it may act as a partial agonist or even an antagonist, potentially offering a more favorable safety profile compared to conventional hormone replacement therapy. In bone metabolism, 8-PN demonstrates significant effects through its interaction with ERs in bone cells. It stimulates osteoblast activity (bone formation) by increasing the expression of bone formation markers such as alkaline phosphatase, osteocalcin, and type I collagen.

Simultaneously, it inhibits osteoclast activity (bone resorption) by decreasing the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and increasing osteoprotegerin (OPG) expression. This dual action on bone metabolism contributes to its potential benefits for bone health, particularly in postmenopausal women at risk of osteoporosis. In the context of menopausal symptoms, 8-PN’s interaction with ERs in the hypothalamus and pituitary gland plays a crucial role. It modulates the hypothalamic-pituitary-gonadal axis, affecting the release of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

Studies have shown that 8-PN can reduce serum LH and FSH levels in ovariectomized rats, similar to the effects of estradiol. This modulation of the neuroendocrine system may contribute to its ability to alleviate vasomotor symptoms (hot flashes and night sweats) associated with menopause. Additionally, 8-PN affects thermoregulation through its interaction with ERs in the hypothalamus, which contains the body’s thermoregulatory center. It helps stabilize the thermoregulatory set point, which becomes dysregulated during menopause due to estrogen deficiency, leading to hot flashes.

Beyond its estrogenic effects, 8-PN demonstrates antioxidant properties through multiple mechanisms. It can directly scavenge reactive oxygen species (ROS) and free radicals through its phenolic hydroxyl groups, which can donate hydrogen atoms to neutralize free radicals. Additionally, 8-PN may enhance endogenous antioxidant defenses by activating nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidant enzymes. This activation leads to increased expression of enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), and γ-glutamylcysteine synthetase (γ-GCS), enhancing the cell’s capacity to neutralize ROS and detoxify harmful compounds.

8-PN also exhibits anti-inflammatory effects through multiple pathways, with inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway being particularly important. It can inhibit this pathway at multiple points: preventing the activation of the IκB kinase (IKK) complex, inhibiting the phosphorylation and degradation of IκB, and directly interfering with the DNA-binding activity of NF-κB. Through these mechanisms, it suppresses the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (MCP-1, IL-8), adhesion molecules (ICAM-1, VCAM-1), and enzymes involved in inflammation (COX-2, iNOS). Additionally, 8-PN modulates other inflammatory signaling pathways, including the mitogen-activated protein kinase (MAPK) cascades (p38 MAPK, ERK, JNK) and the JAK-STAT pathway.

In cancer biology, 8-PN exhibits complex effects due to its estrogenic activity. In hormone-dependent cancers, its effects can be either beneficial or detrimental depending on the specific context. In breast cancer, for example, 8-PN may stimulate the growth of estrogen receptor-positive (ER+) cancer cells through its estrogenic activity, raising concerns about its use in women with a history of breast cancer or at high risk for the disease. However, in other contexts, 8-PN may exhibit anticancer properties through multiple mechanisms.

It can induce cell cycle arrest by modulating the expression and activity of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (p21, p27). It can trigger apoptosis (programmed cell death) in cancer cells through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways. Additionally, it may inhibit angiogenesis (formation of new blood vessels) by downregulating vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α), thereby limiting tumor growth and metastasis. In metabolic regulation, 8-PN demonstrates effects that are partly mediated through its estrogenic activity.

It can modulate adipokine production, increasing adiponectin and decreasing leptin levels, potentially improving insulin sensitivity. It may also activate adenosine monophosphate-activated protein kinase (AMPK), a master regulator of energy metabolism, leading to increased glucose uptake, enhanced fatty acid oxidation, and reduced lipogenesis. Additionally, it may improve insulin signaling pathways and reduce inflammation and oxidative stress in insulin-responsive tissues. In cardiovascular health, 8-PN may improve endothelial function by increasing nitric oxide (NO) production through activation of endothelial nitric oxide synthase (eNOS).

It also demonstrates vasodilatory effects and inhibits platelet aggregation and thrombus formation, potentially reducing the risk of thrombotic events. Additionally, it may improve lipid profiles by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides while increasing high-density lipoprotein (HDL) cholesterol. In neurological function, 8-PN demonstrates neuroprotective effects through multiple mechanisms. It protects neurons from oxidative stress and inflammation, which are key factors in neurodegenerative diseases.

It modulates neurotransmitter systems, potentially affecting mood, cognition, and stress responses. Additionally, it may enhance brain-derived neurotrophic factor (BDNF) expression, supporting neuronal survival and plasticity. 8-PN also possesses antimicrobial properties against a wide range of pathogens, including bacteria, fungi, and viruses. Its antimicrobial mechanisms include disruption of cell membranes, inhibition of cell wall synthesis, interference with nucleic acid synthesis, and inhibition of energy metabolism.

The prenyl group in 8-PN enhances its ability to interact with and disrupt microbial membranes. The pharmacokinetics of 8-PN are characterized by relatively low oral bioavailability, estimated at approximately 5-10% in humans. This limited bioavailability is due to several factors, including poor water solubility, extensive first-pass metabolism, and potential efflux by transporters like P-glycoprotein. In the liver, 8-PN undergoes phase I metabolism (primarily hydroxylation by cytochrome P450 enzymes) and phase II metabolism (glucuronidation, sulfation, and glutathione conjugation), forming metabolites that are more water-soluble and readily excreted in urine.

Interestingly, 8-PN can also be formed in vivo from isoxanthohumol, another hop compound, through O-demethylation by specific intestinal bacteria, particularly Eubacterium limosum and certain Bacteroides species. This conversion is highly variable between individuals, ranging from 0% to nearly 100%, depending on the composition of their gut microbiota. Individuals with gut microbiota capable of efficiently converting isoxanthohumol to 8-PN are referred to as ‘high converters’ and may experience more pronounced estrogenic effects from hop consumption. The plasma half-life of 8-PN is relatively short, estimated at approximately 10-20 hours in humans, necessitating multiple daily doses for sustained therapeutic effects.

The biological effects of 8-PN are thus a combination of its direct actions through multiple mechanisms, with its estrogenic activity being particularly significant for many of its potential health benefits.

Optimal dosage ranges for 8-prenylnaringenin (8-PN) are not well-established due to limited clinical studies specifically evaluating 8-PN as a supplement. Most research has been conducted in preclinical settings (cell culture and animal models) or with hop extracts containing 8-PN along with other bioactive compounds. Based on the available research and considering 8-PN’s potent estrogenic activity, the following dosage ranges can be considered: For standardized 8-PN extracts (rare as commercial supplements), the estimated dosage range is 100-500 μg (0.1-0.5 mg) daily, though this is primarily based on preclinical studies and limited human data. For hop extracts standardized to contain 8-PN, typical dosages range from 100-1000 mg daily, corresponding to approximately 50-500 μg of 8-PN depending on the standardization level.

In one of the few human studies, a standardized hop extract containing 100 μg of 8-PN daily was used for 12 weeks to alleviate menopausal symptoms, with positive results and no significant adverse effects. Another human study used a hop extract providing 85 μg of 8-PN daily for 8 weeks, also showing benefits for menopausal symptoms. It’s important to note that 8-PN is one of the most potent phytoestrogens known, with estrogenic activity comparable to that of 17β-estradiol in some assays. This potency necessitates caution with dosing, particularly for individuals with hormone-sensitive conditions.

Additionally, the formation of 8-PN from isoxanthohumol by intestinal microbiota adds complexity to dosage recommendations, as the effective dose may vary significantly between individuals depending on their gut microbiota composition. ‘High converters’ may experience more pronounced estrogenic effects from hop extracts containing isoxanthohumol, while ‘low converters’ may experience minimal estrogenic effects. For most health applications, starting with a lower dose (100-200 μg daily) and gradually increasing as needed and tolerated is recommended. Divided doses (2-3 times daily) may be preferred due to the relatively short half-life of 8-PN, though specific pharmacokinetic data in humans is limited.

8-Prenylnaringenin (8-PN) has relatively low oral bioavailability, estimated at approximately 5-10% in humans based on limited studies. Several factors contribute to this limited bioavailability. 8-PN has poor water solubility due to its prenylated flavanone structure and relatively high lipophilicity, which limits its dissolution in the gastrointestinal fluid. The compound undergoes extensive first-pass metabolism in the intestine and liver, primarily through phase I (hydroxylation) and phase II (glucuronidation, sulfation) reactions, which significantly reduce the amount of free 8-PN reaching the systemic circulation.

Additionally, 8-PN may be subject to efflux by intestinal transporters such as P-glycoprotein, further limiting its absorption. A unique aspect of 8-PN’s bioavailability is that it can be formed in vivo from isoxanthohumol, another hop compound, through O-demethylation by specific intestinal bacteria, particularly Eubacterium limosum and certain Bacteroides species. This conversion is highly variable between individuals, ranging from 0% to nearly 100%, depending on the composition of their gut microbiota. Individuals with gut microbiota capable of efficiently converting isoxanthohumol to 8-PN are referred to as ‘high converters’ and may experience more pronounced estrogenic effects from hop consumption, while ‘low converters’ may experience minimal estrogenic effects.

This variability in conversion adds complexity to 8-PN’s bioavailability and biological effects. The absorption of 8-PN occurs primarily in the small intestine through passive diffusion, facilitated by its moderate lipophilicity. The prenyl group enhances its membrane permeability compared to non-prenylated flavanones. Some evidence suggests that a small portion may be absorbed via active transport mechanisms, though the specific transporters involved have not been fully characterized.

After absorption, 8-PN undergoes extensive metabolism in the intestinal epithelium and liver. Phase I metabolism primarily involves hydroxylation by cytochrome P450 enzymes, particularly CYP1A2, CYP2C9, and CYP3A4. Phase II metabolism involves conjugation with glucuronic acid (glucuronidation) and sulfate (sulfation), forming conjugates that are more water-soluble and readily excreted in urine. These conjugates may be less biologically active than free 8-PN, though some evidence suggests they can be deconjugated in target tissues, releasing the active compound.

The plasma half-life of 8-PN is relatively short, estimated at approximately 10-20 hours in humans based on limited studies, necessitating multiple daily doses for sustained therapeutic effects. 8-PN demonstrates moderate distribution to various tissues, with some evidence suggesting it can cross the blood-brain barrier to some extent, which is particularly relevant for its potential neuroprotective effects. The prenyl group enhances its lipophilicity and may facilitate its accumulation in lipid-rich tissues. The bioavailability of 8-PN is influenced by various factors, including food matrix, processing methods, and individual factors such as gut microbiome composition, intestinal transit time, and genetic factors affecting metabolic enzymes.

Consumption with a high-fat meal may enhance the absorption of 8-PN by increasing bile secretion and improving its solubilization, though excessive fat may reduce absorption by slowing gastric emptying. The brewing process significantly affects 8-PN content in beer, with most 8-PN being formed from xanthohumol and isoxanthohumol during brewing and fermentation. However, the absolute amounts in beer are relatively small, typically in the range of 1-240 μg/L, with most commercial beers on the lower end of this range.

Liposomal formulations – can increase bioavailability by 3-5 fold by enhancing cellular uptake and protecting 8-PN from degradation, Nanoemulsion formulations – can increase bioavailability by 4-6 fold by improving solubility and enhancing intestinal permeability, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, potentially increasing bioavailability by 3-5 fold, Phospholipid complexes – enhance lipid solubility and membrane permeability, potentially increasing bioavailability by 2-4 fold, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, potentially increasing bioavailability by 2-3 fold, Solid dispersion techniques – enhance dissolution rate and solubility, potentially increasing bioavailability by 2-3 fold, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, potentially increasing bioavailability by 30-60%, Microemulsions – provide a stable delivery system with enhanced solubility, potentially increasing bioavailability by 3-5 fold, Co-administration with fatty meals – can increase absorption by stimulating bile secretion and enhancing lymphatic transport, potentially increasing bioavailability by 20-50%, Probiotic supplementation – can enhance conversion of isoxanthohumol to 8-PN by providing bacteria capable of O-demethylation, potentially increasing the effective dose of 8-PN in ‘low converters’

8-Prenylnaringenin is best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. However, extremely high-fat meals should be avoided as they may slow gastric emptying and potentially reduce absorption. Due to the relatively short half-life of 8-PN (estimated at 10-20 hours based on limited studies), divided doses (2-3 times daily) may be beneficial for maintaining consistent blood levels throughout the day, though specific human pharmacokinetic data is limited. For menopausal symptom relief, consistent daily dosing is recommended, with some women reporting better results when taking hop extracts containing 8-PN in the evening for night sweats or in the morning for hot flashes that occur during the day.

The estrogenic effects of 8-PN may take 4-8 weeks to become fully apparent, so patience and consistent dosing are important. For bone health support, consistent daily dosing is recommended, as the estrogenic effects of 8-PN on bone metabolism may take several months to become apparent. Some evidence suggests that evening dosing may be particularly beneficial for bone formation, as bone remodeling is more active during rest periods, though more research is needed. For cognitive support, consistent daily dosing is recommended, with some evidence suggesting that evening dosing may enhance neuroprotective effects during sleep, though more research is needed.

For cardiovascular support, consistent daily dosing is recommended, with some evidence suggesting that taking 8-PN with meals may help reduce postprandial oxidative stress and inflammation, which are risk factors for cardiovascular disease. For metabolic regulation, consistent daily dosing is recommended, with some evidence suggesting that morning dosing may be particularly beneficial for metabolic effects due to circadian rhythms in metabolic processes, though more research is needed. Enhanced delivery formulations like liposomes or nanoemulsions may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food for optimal absorption. The timing of 8-PN supplementation relative to other medications should be considered, as 8-PN may interact with certain drugs, particularly those with hormonal effects or those metabolized by the same enzymes.

In general, separating 8-PN supplementation from other medications by at least 2 hours is recommended to minimize potential interactions. For individuals interested in the estrogenic effects of 8-PN, combining supplementation with probiotics containing bacteria capable of O-demethylation (such as Eubacterium limosum) may enhance conversion of isoxanthohumol to 8-PN and increase biological activity, particularly in ‘low converters,’ though more research is needed in this area.

• Hormonal effects (common, due to potent estrogenic activity)
• Menstrual changes in women (common in premenopausal women)
• Breast tenderness (common, due to estrogenic effects)
• Gastrointestinal discomfort (mild to moderate, common)
• Nausea (uncommon)
• Headache (uncommon)
• Mood changes (uncommon, due to hormonal effects)
• Fluid retention (uncommon, due to estrogenic effects)
• Allergic reactions (rare, particularly in individuals with allergies to hops or related plants)
• Skin rash (rare)

• Hormone-sensitive cancers (breast, uterine, ovarian) due to potent estrogenic activity
• History of estrogen receptor-positive breast cancer
• Endometriosis or uterine fibroids (conditions that may be estrogen-sensitive)
• Pregnancy and breastfeeding (due to hormonal effects and insufficient safety data)
• Individuals scheduled for surgery (discontinue 2 weeks before due to potential effects on blood clotting)
• Children and adolescents (due to hormonal effects during development)
• Individuals with severe liver disease (due to potential effects on liver enzymes)
• Individuals with a history of blood clots or thromboembolic disorders (due to estrogenic effects)
• Individuals with known allergies to hops or related plants in the Cannabaceae family
• Individuals with known hypersensitivity to 8-prenylnaringenin or related compounds

• Hormone replacement therapy and hormonal contraceptives (may interfere with or enhance effects due to estrogenic activity)
• Tamoxifen and other selective estrogen receptor modulators (SERMs) (competitive binding to estrogen receptors)
• Aromatase inhibitors (may counteract the effects of these drugs used in breast cancer treatment)
• Anticoagulant and antiplatelet medications (may enhance antiplatelet effects, potentially increasing bleeding risk)
• Cytochrome P450 substrates (may affect the metabolism of drugs that are substrates for CYP1A2, CYP2C9, and CYP3A4)
• Thyroid medications (phytoestrogens may affect thyroid function in susceptible individuals)
• Antidiabetic medications (may enhance blood glucose-lowering effects, potentially requiring dose adjustment)
• Drugs metabolized by UDP-glucuronosyltransferases (UGTs) (potential competition for these enzymes)
• Drugs with narrow therapeutic indices (warfarin, digoxin, etc.) require careful monitoring due to potential interactions
• Sedatives and CNS depressants (potential additive effects, as hops have mild sedative properties)

Based on limited studies and considering 8-prenylnaringenin’s potent estrogenic activity, the upper limit for 8-PN supplementation is generally considered to be 500 μg (0.5 mg) daily for most adults. For hop extracts, upper limits should be calculated based on their 8-PN content to avoid exceeding 500 μg of 8-PN daily. Higher doses may significantly increase the risk of hormonal side effects and drug interactions, particularly in sensitive individuals. For general supplementation, doses exceeding these levels are not recommended without medical supervision.

The safety profile of 8-PN warrants particular attention due to its potent estrogenic activity, which is comparable to that of 17β-estradiol in some assays. This potency raises concerns about potential adverse effects similar to those associated with estrogen therapy, including increased risk of hormone-sensitive cancers, thromboembolic events, and other estrogen-related side effects. However, 8-PN’s tissue-specific effects and SERM-like activity may provide a more favorable safety profile compared to conventional hormone replacement therapy in some contexts. The long-term safety of 8-PN supplementation has not been fully established, with most safety data derived from preclinical studies and limited human trials of relatively short duration (typically 8-12 weeks).

Acute toxicity studies in animals have shown relatively low toxicity, with no significant adverse effects observed at doses equivalent to several times the recommended human doses. However, the potential for cumulative effects with long-term use remains a consideration. The diverse biological activities of 8-PN, including its effects on drug-metabolizing enzymes, add complexity to safety considerations. 8-PN may inhibit certain cytochrome P450 enzymes, potentially affecting the metabolism of drugs that are substrates for these enzymes.

Additionally, its potent estrogenic effects may interact with hormonal medications and affect hormone-sensitive conditions. The safety of 8-PN during pregnancy and breastfeeding has not been established, and its potent estrogenic effects raise concerns about potential developmental effects. Therefore, 8-PN supplementation is not recommended during these periods. For most individuals, obtaining 8-PN through moderate consumption of 8-PN-containing foods and beverages (such as hops and beer) as part of a balanced diet is likely safer than isolated 8-PN supplements, as food sources provide lower amounts and contain other compounds that may modulate its effects.

However, it should be noted that beer contains alcohol, which has its own health considerations, and the 8-PN content in most commercial beers is very low. For individuals with hormone-sensitive conditions or a history of hormone-sensitive cancers, 8-PN supplementation is generally not recommended due to its potent estrogenic activity. For other individuals, particularly postmenopausal women seeking relief from menopausal symptoms or support for bone health, 8-PN supplementation may be considered under medical supervision, starting with lower doses and monitoring for potential side effects.

8-Prenylnaringenin as an isolated compound is not specifically regulated by the FDA. It is not approved as a drug and is not generally available as a standalone dietary supplement. Hop extracts containing 8-prenylnaringenin are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this framework, manufacturers are responsible for ensuring the safety of their products before marketing, but pre-market approval is not required.

Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of 8-prenylnaringenin specifically. Given 8-PN’s potent estrogenic activity, there may be concerns about its long-term safety, particularly for individuals with hormone-sensitive conditions. However, the FDA has not issued specific guidance or warnings regarding 8-PN or hop extracts containing 8-PN.

Hops (Humulus lupulus) are generally recognized as safe (GRAS) for use in beer (21 CFR 182.20), but this designation does not specifically address 8-PN or hop extracts used as dietary supplements. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by the Alcohol and Tobacco Tax and Trade Bureau (TTB) and the FDA. The 8-PN content in beer is not specifically regulated, though it is indirectly affected by regulations on hop usage in brewing.

Eu: 8-Prenylnaringenin as an isolated compound is not specifically regulated in the European Union. Hop extracts containing 8-PN are primarily regulated as food supplements under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has not evaluated health claims related to 8-PN specifically. However, EFSA has evaluated and rejected health claims related to hops for menopausal symptom relief due to insufficient evidence. Hops are included in the European Medicines Agency (EMA) Community Herbal Monograph for medicinal use, primarily for sleep disorders and mild anxiety, though this does not specifically address 8-PN. The EMA has not issued specific guidance on 8-PN or hop extracts standardized for 8-PN content. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage, with regulations varying by country within the EU.

Uk: 8-Prenylnaringenin as an isolated compound is not specifically regulated in the United Kingdom. Hop extracts containing 8-PN are regulated as food supplements. They are not licensed as medicines and cannot be marketed with medicinal claims. The Medicines and Healthcare products Regulatory Agency (MHRA) has not issued specific guidance on 8-PN. Hops are included in the British Herbal Pharmacopoeia for medicinal use, primarily for sleep disorders and mild anxiety, though this does not specifically address 8-PN. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by the Food Standards Agency (FSA) and HM Revenue and Customs.

Canada: 8-Prenylnaringenin as an isolated compound is not specifically regulated in Canada. Hop extracts containing 8-PN are regulated as Natural Health Products (NHPs) under the Natural Health Products Regulations. Several products containing hop extracts have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims, primarily related to sleep and anxiety. Health Canada has not issued specific guidance on 8-PN. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by provincial liquor control boards and the Canadian Food Inspection Agency (CFIA).

Australia: 8-Prenylnaringenin as an isolated compound is not specifically regulated in Australia. Hop extracts containing 8-PN are regulated as complementary medicines by the Therapeutic Goods Administration (TGA). Several products containing hop extracts are listed on the Australian Register of Therapeutic Goods (ARTG), primarily for sleep and anxiety. The TGA has not issued specific guidance on 8-PN. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by Food Standards Australia New Zealand (FSANZ) and state/territory liquor licensing authorities.

Japan: 8-Prenylnaringenin as an isolated compound is not specifically regulated in Japan. Hop extracts containing 8-PN may be regulated as Foods for Specified Health Uses (FOSHU) if they meet specific criteria and have supporting evidence for their health claims. The Ministry of Health, Labour and Welfare has not issued specific guidance on 8-PN. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by the National Tax Agency and the Ministry of Health, Labour and Welfare.

China: 8-Prenylnaringenin as an isolated compound is not specifically regulated in China. Hop extracts containing 8-PN may be regulated as health foods and would require approval from the China Food and Drug Administration (CFDA) before marketing with health claims. The CFDA has not issued specific guidance on 8-PN. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by various government agencies, including the General Administration of Quality Supervision, Inspection and Quarantine (AQSIQ).

Korea: 8-Prenylnaringenin as an isolated compound is not specifically regulated in South Korea. Hop extracts containing 8-PN may be regulated as health functional foods and would require approval from the Ministry of Food and Drug Safety (MFDS) before marketing with health claims. The MFDS has not issued specific guidance on 8-PN. Beer, which contains small amounts of 8-PN, is regulated as an alcoholic beverage by the National Tax Service and the MFDS.

High

Isolated 8-prenylnaringenin is not typically available as a consumer supplement but is primarily used in research settings. Research-grade 8-PN (>95% purity) typically costs $500-$1000 per gram, making it prohibitively expensive for regular supplementation. Standardized hop extracts containing 8-PN typically cost $1.50-$4.00 per day for basic extracts (100-1000 mg daily, corresponding to approximately 50-500 μg of 8-PN depending on the standardization level) and $4.00-$8.00 per day for premium, standardized formulations or enhanced delivery systems. Specialized hop extracts specifically standardized for 8-PN content (such as those used in clinical trials for menopausal symptom relief) typically cost $3.00-$6.00 per day, providing approximately 100-500 μg of 8-PN daily.

Beer, which contains small amounts of 8-PN (typically 1-240 μg/L), is not a cost-effective source of 8-PN for therapeutic purposes due to the low concentrations and the presence of alcohol. Enhanced delivery formulations (such as liposomes, nanoemulsions, or phospholipid complexes) typically cost $6.00-$12.00 per day, though these may provide improved bioavailability that could justify the higher cost.

The value of 8-prenylnaringenin supplementation varies significantly depending on the specific health application, the form of supplementation, individual factors such as gut microbiota composition, and the desired biological effects. For menopausal symptom relief, 8-PN offers moderate to high value. Clinical studies have demonstrated significant reductions in hot flashes, night sweats, and other menopausal symptoms with standardized hop extracts containing 8-PN. When compared to hormone replacement therapy (HRT), 8-PN-containing supplements are generally less effective but may have a more favorable safety profile for some women, particularly those with contraindications to HRT.

When compared to other phytoestrogen sources (such as soy isoflavones), 8-PN-containing supplements are more expensive but may offer greater efficacy due to 8-PN’s potent estrogenic activity. For bone health support, 8-PN offers moderate to high value. Clinical studies have demonstrated improvements in bone mineral density and reductions in bone turnover markers with standardized hop extracts containing 8-PN. When compared to bisphosphonates and other osteoporosis medications, 8-PN-containing supplements are generally less effective but may have a more favorable safety profile for some individuals, particularly for prevention rather than treatment of established osteoporosis.

When compared to other natural approaches for bone health, 8-PN-containing supplements are more expensive but may offer greater efficacy due to 8-PN’s potent estrogenic activity. For cognitive support, 8-PN offers moderate value. Preclinical studies suggest potential benefits for cognitive function through estrogenic effects on the brain, but clinical evidence is limited. When compared to other cognitive support supplements, 8-PN-containing supplements are more expensive and may not offer significantly greater benefits for most individuals.

However, for postmenopausal women experiencing cognitive decline related to estrogen deficiency, 8-PN may offer unique benefits. For cardiovascular support, 8-PN offers moderate value. Preclinical studies suggest potential benefits for lipid profiles, vascular function, and inflammation through estrogenic effects, but clinical evidence is limited. When compared to other cardiovascular support supplements, 8-PN-containing supplements are more expensive and may not offer significantly greater benefits for most individuals.

However, for postmenopausal women with cardiovascular risk factors related to estrogen deficiency, 8-PN may offer unique benefits. When comparing the cost-effectiveness of different sources of 8-PN: Standardized hop extracts offer the best value for most health applications, providing consistent dosing of 8-PN along with other beneficial hop compounds that may have synergistic effects or moderate 8-PN’s potent estrogenic activity. Specialized hop extracts specifically standardized for 8-PN content offer more precise dosing but at a higher cost. These may be preferred for specific health applications where consistent, precise dosing is important, such as menopausal symptom relief.

Enhanced delivery formulations offer improved bioavailability, which may justify their higher cost for individuals with absorption issues or those seeking maximum therapeutic effects. However, the cost-benefit ratio should be carefully considered, as the improvement in bioavailability may not always justify the significantly higher cost. Beer is not a cost-effective or appropriate source of 8-PN for therapeutic purposes due to the low concentrations and the presence of alcohol. For most individuals, standardized hop extracts with verified 8-PN content offer the best balance of cost and efficacy for health applications.

These should be selected based on quality considerations, including standardization methods, extraction techniques, and third-party testing for purity and potency. For individuals specifically seeking the estrogenic effects of 8-PN, combining supplementation with probiotics containing bacteria capable of O-demethylation (such as Eubacterium limosum) may enhance the conversion of isoxanthohumol to 8-PN, potentially improving the cost-effectiveness of hop extracts containing isoxanthohumol rather than 8-PN directly.

Pure 8-prenylnaringenin has moderate stability, with a typical shelf life of 1-2 years when properly stored at -20°C under inert gas. At room temperature, its stability is significantly reduced, with a shelf life of approximately 3-6 months when protected from light, heat, and moisture. The prenyl group in 8-PN is particularly susceptible to oxidation, which can lead to degradation. Additionally, the hydroxyl groups can undergo oxidation and other reactions, further affecting stability.

Standardized hop extracts containing 8-PN typically have a shelf life of 1-2 years from the date of manufacture when properly stored in airtight, opaque containers at room temperature or below. The stability of 8-PN in these extracts may be enhanced by the presence of other hop compounds with antioxidant properties, such as xanthohumol. In beer, 8-PN content remains relatively stable during storage, with minimal degradation occurring over time compared to other hop compounds. However, exposure to light (particularly UV light) can cause photodegradation of 8-PN and other prenylated flavonoids, a phenomenon that contributes to the ‘skunky’ flavor of light-struck beer.

Hop pellets and whole hop cones, which contain small amounts of 8-PN along with its precursors xanthohumol and isoxanthohumol, have a shelf life of approximately 1-3 years when stored in vacuum-sealed packages at low temperatures (0-5°C). Proper storage is critical, as exposure to oxygen, heat, and moisture can significantly reduce the prenylated flavonoid content. In liquid formulations (such as tinctures or liquid extracts), 8-PN has reduced stability compared to solid forms, with a typical shelf life of 6-12 months when properly stored in airtight, opaque containers. The presence of alcohol in these formulations may help preserve 8-PN by inhibiting microbial growth and providing some protection against oxidation.

Enhanced delivery formulations (such as liposomes, nanoemulsions, or phospholipid complexes) may have different stability profiles depending on the specific formulation. These formulations often provide some protection against degradation, potentially extending the shelf life of 8-PN, but they may also introduce additional stability considerations related to the delivery system itself.

For pure 8-prenylnaringenin (primarily used in research), storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability. Protect from light, heat, oxygen, and moisture, which can accelerate degradation. For standardized hop extracts containing 8-PN, store in airtight, opaque containers at room temperature or below (preferably 15-25°C). Refrigeration (2-8°C) can extend shelf life but may not be necessary if other storage conditions are optimal.

Avoid exposure to direct sunlight, heat sources, and high humidity, which can accelerate degradation. For beer containing 8-PN, store in a cool, dark place (preferably 5-10°C) to preserve 8-PN content and overall beer quality. Avoid exposure to light, particularly sunlight, which can cause photodegradation of 8-PN and other prenylated flavonoids. For hop pellets and whole hop cones, store in vacuum-sealed packages at low temperatures (0-5°C) to preserve the prenylated flavonoid content.

Once opened, transfer to an airtight container and use within 1-2 months for maximum potency. For liquid formulations containing 8-PN, store in airtight, opaque containers at room temperature or below (preferably 15-25°C). Refrigeration (2-8°C) can extend shelf life but may not be necessary if other storage conditions are optimal. Avoid exposure to direct sunlight and heat sources.

For enhanced delivery formulations, follow specific storage recommendations for each formulation. These may include refrigeration, protection from light, or other special considerations depending on the delivery system. After opening, all 8-PN-containing products should be used within the recommended time frame specified by the manufacturer, typically 1-3 months for liquid formulations and 3-6 months for solid formulations. Proper sealing of containers after each use is important to minimize exposure to air and moisture.

For long-term storage of research-grade 8-PN, aliquoting into smaller portions before freezing is recommended to minimize freeze-thaw cycles, which can accelerate degradation.

Exposure to oxygen – leads to oxidation, particularly of the prenyl group and hydroxyl groups, forming epoxides and other oxidation products, Exposure to UV light and sunlight – causes photodegradation, particularly in beer and liquid formulations, High temperatures (above 30°C) – accelerates decomposition and oxidation, Strongly acidic or alkaline conditions – can lead to hydrolysis of the flavanone structure, Moisture – promotes hydrolysis and facilitates other degradation reactions, Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymes – certain enzymes, particularly oxidases, can degrade 8-PN, Microbial contamination – can lead to enzymatic degradation of 8-PN or its conversion to other compounds, Freeze-thaw cycles – can accelerate degradation, particularly in liquid formulations, Long-term storage at room temperature – leads to gradual degradation even when protected from other degradation factors

Synthesis Methods

Natural Sources

Quality Considerations

8-Prenylnaringenin (8-PN) itself was not identified or isolated as a specific compound until the late 20th century, so its direct historical usage as an isolated compound is limited to recent scientific and medical applications. However, 8-PN has been unknowingly consumed for centuries through beer and hop-containing preparations, where it is present in small amounts or formed during processing from precursors such as xanthohumol and isoxanthohumol. The earliest documented use of hops (Humulus lupulus), the plant source of 8-PN, dates back to ancient civilizations. Archaeological evidence suggests that hops were cultivated in ancient Babylon as early as 7000 BCE, though their specific uses during this period are not well-documented.

The first clear evidence of hops being used in beer brewing comes from the early medieval period in Europe. The earliest documented use of hops in beer brewing dates back to the 9th century in Europe, particularly in Germany and France. The Benedictine Abbot Adalhard of Corbie documented the use of hops in brewing in 822 CE in the statutes for the Abbey of Corbie. However, it is likely that hops were used in brewing even earlier, possibly by ancient Germanic tribes.

The German Beer Purity Law (Reinheitsgebot) of 1516 mandated the use of hops in beer, further establishing their role in brewing. This law, which restricted beer ingredients to water, barley, and hops (yeast was added later when its role was understood), ensured that hops would be a consistent component of beer, and consequently, that 8-PN would be present in the final product, albeit in very small amounts. While the presence of 8-PN in beer and hop preparations was not known at the time, the medicinal properties of hops were recognized in various traditional medicine systems. In medieval Europe, hops were used for their sedative and calming properties, often prescribed for insomnia, anxiety, and restlessness.

They were also used to stimulate appetite, improve digestion, and treat digestive disorders. Interestingly, some of these traditional uses, particularly those related to women’s health, may have been partly due to the estrogenic effects of 8-PN, though this connection was not understood at the time. In traditional European herbal medicine, hop preparations were sometimes used for female complaints, including menstrual disorders and menopausal symptoms. This traditional use aligns with the modern understanding of 8-PN’s estrogenic activity and its potential benefits for menopausal symptom relief.

The scientific discovery and characterization of 8-PN began in the late 20th century. 8-PN was first isolated and identified from hops in the 1990s, and its potent estrogenic activity was discovered shortly thereafter. In 1999, a landmark study by Milligan et al. identified 8-PN as one of the most potent phytoestrogens known, with activity comparable to that of 17β-estradiol in some assays.

This discovery sparked significant interest in 8-PN as a potential natural alternative to hormone replacement therapy for menopausal symptom relief. In the early 2000s, research on 8-PN expanded to include its effects on bone health, cognitive function, and metabolic regulation, all of which are affected by estrogen deficiency in postmenopausal women. Additionally, studies began to elucidate the formation of 8-PN from its precursors xanthohumol and isoxanthohumol during brewing and through intestinal metabolism. A significant breakthrough came in 2006 when Possemiers et al.

discovered that isoxanthohumol, another hop compound present in beer, could be converted to 8-PN by specific intestinal bacteria, particularly Eubacterium limosum. This conversion was found to be highly variable between individuals, depending on their gut microbiota composition, adding complexity to the understanding of 8-PN’s bioavailability and effects. In recent years, standardized hop extracts containing 8-PN have been developed for various health applications, particularly for menopausal symptom relief and bone health support. Clinical trials have demonstrated the efficacy of these extracts for reducing hot flashes, night sweats, and other menopausal symptoms, as well as for improving bone mineral density in postmenopausal women.

Today, while isolated 8-PN is primarily used in research settings, hop extracts standardized for 8-PN content are available as dietary supplements, marketed for various health benefits, particularly for women’s health. The modern understanding of 8-PN’s presence in traditional beverages and its potential health benefits represents a fascinating intersection of traditional brewing practices and contemporary scientific research.

Clinical trials evaluating standardized hop extracts containing 8-prenylnaringenin for menopausal symptom relief, particularly hot flashes and night sweats, Studies on the effects of 8-prenylnaringenin on bone health in postmenopausal women, including bone mineral density, bone turnover markers, and fracture risk, Investigations into the effects of 8-prenylnaringenin on cognitive function and mood in postmenopausal women, Research on the potential applications of 8-prenylnaringenin in metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes, Studies on the cardiovascular effects of 8-prenylnaringenin, including lipid profiles, vascular function, and inflammation, Investigations into the safety and efficacy of long-term 8-prenylnaringenin supplementation, Research on the development of enhanced delivery systems for 8-prenylnaringenin to improve its bioavailability and therapeutic efficacy, Studies on the potential synergistic effects of 8-prenylnaringenin with other natural compounds and conventional therapies, Investigations into the effects of probiotic supplementation on 8-prenylnaringenin metabolism and biological activity, Research on the tissue-specific effects of 8-prenylnaringenin and its potential SERM-like activity