6 Prenylnaringenin

• Hormonal balance
• Antioxidant protection
• Metabolic regulation
• Cellular detoxification

• Menopausal symptom relief
• Bone density support
• Cardiovascular health
• Anti-inflammatory
• Cancer chemopreventive potential
• Liver protection

6-Prenylnaringenin (6-PN) exerts its biological effects through multiple mechanisms, with its most notable activity being its interaction with estrogen signaling pathways. While less potent than its isomer 8-prenylnaringenin (8-PN), 6-PN still demonstrates significant phytoestrogenic activity by binding to estrogen receptors (ERs), with a preference for ER-α over ER-β. This selective estrogen receptor modulation contributes to its effects on hormonal balance, particularly in menopausal women. A key distinguishing mechanism of 6-PN is its potent activation of the aryl hydrocarbon receptor (AhR), which plays a crucial role in xenobiotic metabolism and cellular detoxification.

Through AhR activation, 6-PN upregulates cytochrome P450 enzymes, particularly CYP1A1 and CYP1A2, enhancing the 2-hydroxylation pathway of estrogen metabolism. This preferential enhancement of 2-hydroxylation over 16α-hydroxylation is significant, as it favors the production of 2-hydroxyestrone, a less genotoxic metabolite, over 16α-hydroxyestrone, which has been associated with increased cancer risk. This metabolic modulation may contribute to 6-PN’s potential chemopreventive properties. The antioxidant activity of 6-PN stems from its flavonoid structure, allowing it to directly scavenge free radicals and reactive oxygen species.

Additionally, it may enhance endogenous antioxidant defenses by activating nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of antioxidant enzymes. This antioxidant protection extends to various tissues, including the cardiovascular system, where 6-PN may help prevent oxidative damage to blood vessels and reduce lipid peroxidation. In the context of inflammation, 6-PN exhibits inhibitory effects on pro-inflammatory enzymes such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), reducing the production of inflammatory mediators. It may also suppress nuclear factor-kappa B (NF-κB) signaling, a master regulator of inflammatory responses.

For bone health, 6-PN’s estrogenic activity may help maintain bone density by modulating osteoblast and osteoclast activity, though this effect is likely less pronounced than with 8-PN. In metabolic regulation, 6-PN may influence glucose and lipid metabolism through multiple pathways, including peroxisome proliferator-activated receptor (PPAR) modulation and AMP-activated protein kinase (AMPK) activation. Emerging research suggests 6-PN may also exhibit neuroprotective effects through reduction of oxidative stress in neural tissues and potential modulation of neurotransmitter systems. In the liver, 6-PN’s activation of detoxification enzymes through AhR and Nrf2 pathways may contribute to hepatoprotective effects, enhancing the clearance of potentially harmful compounds.

The prenyl group attached to the flavonoid structure increases the lipophilicity of 6-PN, enhancing its ability to interact with cellular membranes and potentially improving its bioavailability compared to non-prenylated flavonoids. This structural feature also contributes to its unique receptor binding properties and biological activities.

No established standard dosage exists for isolated 6-Prenylnaringenin. Most supplements contain hop extracts standardized to total prenylated flavonoids (including 6-PN, 8-PN, and xanthohumol), typically providing 100-500 μg of total prenylated flavonoids daily.

Low to moderate; research indicates that 6-Prenylnaringenin has lower oral bioavailability compared to its isomer 8-Prenylnaringenin. Studies suggest approximately 5-15% absolute bioavailability, though this varies significantly between individuals. The prenyl group increases lipophilicity compared to non-prenylated flavonoids, which may enhance membrane permeability but can also increase binding to plasma proteins.

Consumption with dietary fats significantly improves absorption due to the lipophilic nature of the prenyl group, Micronized formulations can increase surface area and improve dissolution rate, Liposomal delivery systems may enhance bioavailability by improving solubility and cellular uptake, Phytosome complexes (binding to phospholipids) can enhance absorption through the intestinal epithelium, Combining with black pepper extract (piperine) may inhibit glucuronidation and increase bioavailability, Cyclodextrin complexation can improve solubility in aqueous environments, Emulsified formulations may enhance absorption by increasing dispersion in the gastrointestinal tract, Consumption with grapefruit juice may inhibit intestinal CYP3A4 metabolism, though this approach requires caution due to potential drug interactions

For optimal absorption, take with a meal containing moderate fat content (15-25g fat). Morning or evening administration appears equally effective for general health benefits. For menopausal symptom relief, consistent timing throughout the day is more important than specific timing. Avoid taking simultaneously with high-fiber supplements or meals, as fiber may bind to prenylated flavonoids and reduce absorption.

The half-life of 6-PN is estimated to be 7-9 hours, suggesting once-daily dosing is sufficient for maintaining steady-state levels. Consistent daily administration is crucial for hormonal benefits, as effects are cumulative and typically require 6-12 weeks to become fully apparent. Some research suggests that the gut microbiota may play a role in the metabolism and activation of prenylated flavonoids, so maintaining healthy gut flora through probiotic supplementation or fermented foods may potentially enhance the biological activity of 6-PN, though this requires further research.

• Mild gastrointestinal discomfort (occasional)
• Headache (uncommon)
• Menstrual cycle changes in premenopausal women (possible with higher doses)
• Breast tenderness (rare)
• Nausea (uncommon)
• Dizziness (rare)
• Skin rash or allergic reactions (rare, more common in individuals with hop allergies)
• Temporary changes in liver enzyme levels (very rare, typically normalizes with continued use)

• Estrogen-sensitive conditions such as estrogen receptor-positive breast cancer, endometriosis, or uterine fibroids (due to phytoestrogenic activity)
• History of thromboembolic disorders (theoretical concern based on estrogen effects)
• Pregnancy and breastfeeding (insufficient safety data)
• Known allergy to hops or related plants in the Cannabaceae family
• Scheduled surgery (discontinue 2 weeks before due to theoretical concerns about effects on blood clotting)
• Severe liver disease (may affect metabolism)
• Children and adolescents (insufficient safety data and concerns about effects on hormonal development)

• Hormone replacement therapy (potential additive estrogenic effects)
• Oral contraceptives (potential interaction with hormonal components)
• Tamoxifen and other selective estrogen receptor modulators (potential interference with therapeutic effects)
• Aromatase inhibitors (potential opposition to therapeutic effects)
• Anticoagulants/antiplatelet drugs (theoretical interaction due to potential effects on clotting factors)
• Medications metabolized by CYP1A1 and CYP1A2 enzymes (potential alteration of drug metabolism due to AhR activation)
• Sedatives (mild potential to enhance sedative effects due to hop components)
• Medications for insomnia (potential additive effects with other hop components)

No established upper limit; most clinical studies use hop extracts providing up to 500 μg of total prenylated flavonoids daily without significant adverse effects. Higher doses may increase the risk of hormonal side effects, particularly in premenopausal women. Long-term safety data beyond 12 months of continuous use is limited. Due to its phytoestrogenic activity, cycling usage (e.g., 3 weeks on, 1 week off) may be prudent for premenopausal women to avoid potential disruption of natural hormonal cycles.

6-Prenylnaringenin as an isolated compound is not specifically approved or regulated by the FDA. Hop extracts containing 6-PN are regulated as dietary supplements in the United States under the Dietary Supplement Health and Education Act (DSHEA) of 1994. As with other dietary supplements, the FDA does not review hop extracts for safety or efficacy before they are marketed. Manufacturers are responsible for ensuring their products are safe before marketing and that product labels are truthful and not misleading.

Hop extracts are generally recognized as safe (GRAS) for use as flavoring agents in food and beverages, primarily in the context of beer production, though this designation does not specifically address concentrated extracts used for supplementation.

Eu: In the European Union, 6-Prenylnaringenin is not specifically regulated as an isolated compound. Hop extracts are permitted as food ingredients and flavoring agents, primarily in the context of beer production. For use in food supplements, hop extracts fall under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has not issued specific opinions on the safety of concentrated hop extracts for supplementation. In Germany, the Commission E has approved hops for mood disturbances, anxiety, and sleep disorders, though not specifically for hormonal or menopausal applications.

Canada: Health Canada has listed hop extracts in the Natural Health Products Ingredients Database. Products containing hop extracts must meet specific quality and labeling requirements. Health Canada has not issued specific guidance on 6-Prenylnaringenin or standardized hop extracts for hormonal applications.

Australia: The Therapeutic Goods Administration (TGA) permits hop extracts in listed complementary medicines (AUST L). Specific therapeutic claims must be supported by evidence of traditional use or scientific research. The TGA has not issued specific guidance on 6-Prenylnaringenin or standardized hop extracts for hormonal applications.

Japan: In Japan, hop extracts are primarily regulated in the context of food and beverage production. The Ministry of Health, Labour and Welfare has not issued specific guidance on hop extracts for supplementation or medicinal purposes.

China: The China Food and Drug Administration regulates hop extracts primarily as food ingredients and flavoring agents. Traditional uses of hops in Chinese medicine are recognized, though not specifically for hormonal applications.

Medium to high

Standardized hop extracts containing prenylated flavonoids: $0.80-2.50 per day; Research-grade isolated 6-PN: Significantly higher, typically only available for laboratory use

6-Prenylnaringenin is primarily available as a component of standardized hop extracts rather than as an isolated compound for supplementation. These standardized extracts typically contain a mixture of prenylated flavonoids including 6-PN, 8-PN, xanthohumol, and isoxanthohumol. The cost of these extracts is moderate to high compared to many botanical supplements, reflecting the specialized extraction and standardization processes required. For menopausal symptom relief, standardized hop extracts represent a moderately cost-effective alternative to hormone replacement therapy, with fewer potential side effects, though possibly less rapid or comprehensive symptom relief.

When compared to other phytoestrogen sources like soy isoflavones or red clover, hop extracts are typically more expensive but may offer a different spectrum of benefits due to the unique properties of prenylated flavonoids, particularly 6-PN’s ability to activate the aryl hydrocarbon receptor and favorably modulate estrogen metabolism. The cost-effectiveness for bone health support is less clear, as longer-term studies are needed to fully establish efficacy in this area. For general antioxidant support, hop extracts would not be the most cost-effective option, as many less expensive antioxidants are available. The value proposition of hop extracts containing 6-PN is strongest for women seeking natural support for menopausal symptoms, particularly those who have not responded well to other botanical approaches.

Products standardized to specific levels of prenylated flavonoids typically command premium prices but offer better consistency in results. The emerging research on 6-PN’s potential chemopreventive properties through favorable modulation of estrogen metabolism may eventually provide additional value beyond symptom relief, though more clinical research is needed in this area. Overall, while not inexpensive, standardized hop extracts containing 6-PN represent a reasonable value for their specific applications, particularly when the quality of extraction and standardization is high.

Pure isolated compound: 1-2 years when properly stored; Standardized hop extracts: 2-3 years; Capsules and tablets: 2-3 years when properly stored; Liquid extracts: 1-2 years after opening

Store in airtight, opaque containers protected from light, heat, and moisture. For pure compound or research-grade material, refrigeration (2-8°C) is recommended, preferably under inert gas (nitrogen or argon) to prevent oxidation. Commercial supplements containing hop extracts should be kept in their original containers with desiccant packets if provided. Avoid exposure to direct sunlight or UV light, which can accelerate degradation of prenylated flavonoids.

For long-term storage of research-grade material, freezing at -20°C under inert gas is recommended. Once opened, products should ideally be used within 6 months for optimal potency.

Oxidation is the primary degradation pathway, with the prenyl group being particularly susceptible to oxidative damage, Exposure to light, especially UV light, causes photodegradation and isomerization, High temperatures accelerate all degradation processes, particularly oxidation, Moisture can promote hydrolysis of the flavonoid structure, pH extremes affect stability, with greater stability observed in slightly acidic conditions (pH 5-6), Metal ions, particularly iron and copper, can catalyze oxidation reactions, Enzymatic degradation can occur in plant extracts if not properly processed, Microbial contamination may lead to biotransformation of the compound, Repeated freeze-thaw cycles can accelerate degradation, Exposure to air (oxygen) progressively reduces potency through oxidation of the prenyl group and flavonoid structure

Synthesis Methods

Natural Sources

Quality Considerations

6-Prenylnaringenin (6-PN) itself has no significant historical usage as an isolated compound, as it was only identified and characterized in the late 20th century. However, it exists naturally in hops (Humulus lupulus), which have a rich history of traditional use spanning over a millennium. Hops have been used in beer brewing since at least the 9th century in Europe, primarily for their preservative properties and bitter flavor. Beyond brewing, hops have a long history of medicinal use in European traditional medicine.

By the 16th century, hops were recognized for their sedative properties and were used to treat insomnia and anxiety. Herbal pillows stuffed with hop cones were used to promote sleep, a practice that continued into the early 20th century. Traditional herbalists also employed hops for digestive complaints, particularly as a bitter tonic to stimulate appetite and digestion. Interestingly, historical accounts from hop-growing regions noted that female hop pickers often experienced menstrual disturbances during the harvest season, an observation now understood to be related to the estrogenic compounds (including prenylated flavonoids like 6-PN) absorbed through the skin during handling of the hop cones.

This phenomenon, sometimes called ‘hop picker’s menstrual disorder,’ represents perhaps the earliest unintentional human exposure to the hormonal effects of these compounds. In traditional Chinese medicine, hops were occasionally used for restlessness, insomnia, and digestive disorders, though they were not as prominent as in European herbal traditions. Native American tribes in regions where hops grew naturally used them for pain relief, sedation, and as a digestive aid. The specific prenylated flavonoids in hops, including 6-PN, were unknown to traditional healers, who worked with whole plant preparations.

The scientific discovery and isolation of 6-PN occurred in the late 20th century as part of research into the chemical constituents of hops. Its identification as a compound with significant biological activity, particularly its ability to activate the aryl hydrocarbon receptor (AhR) and influence estrogen metabolism, is entirely modern. The current interest in 6-PN and related prenylated flavonoids for menopausal symptom relief, hormonal balance, and potential chemopreventive properties represents a contemporary application based on modern scientific understanding rather than traditional usage.

Abdi F, Roozbeh N, Mortazavian AM. Effects of date palm pollen on fertility: research proposal for a systematic review. BMC Research Notes. 2017;10(1):363., Possemiers S, Bolca S, Grootaert C, Heyerick A, Decroos K, Dhooge W, De Keukeleire D, Rabot S, Verstraete W, Van de Wiele T. The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine. Journal of Nutrition. 2006;136(7):1862-1867.

Evaluation of hop extract containing prenylated flavonoids for bone health in postmenopausal women (Clinical Trials Registry: NCT03822546), Effects of standardized hop extract on metabolic parameters in overweight adults (Clinical Trials Registry: NCT04123366), Hop flavonoids for management of menopausal symptoms: a randomized controlled trial (Clinical Trials Registry: NCT02421549)