Skullcapflavone

• Anti-inflammatory
• Antioxidant
• Anticancer
• Hepatoprotective

• Neuroprotective
• Antimicrobial
• Antifibrotic
• Immunomodulatory
• Skin protection

Skullcapflavone, particularly Skullcapflavone II (SFII), exerts its biological effects through multiple molecular pathways, though it is less extensively studied than other flavonoids from Scutellaria baicalensis such as baicalein, baicalin, and wogonin. As an anti-inflammatory agent, SFII inhibits the production of pro-inflammatory cytokines and chemokines, including thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and regulated upon activation normal T cell expressed and secreted (RANTES) in stimulated keratinocytes. This inhibitory effect is mediated through suppression of the nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription (STAT) signaling pathways. SFII also inhibits the mitogen-activated protein kinase (MAPK) pathway, including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties.

In liver cells, SFII demonstrates hepatoprotective and antifibrotic effects through multiple mechanisms. It inhibits the activation of hepatic stellate cells (HSCs), which are key mediators of liver fibrosis, by inducing G2/M phase cell cycle arrest. This effect is associated with decreased expression of cyclin B1 and cyclin-dependent kinase 1 (CDK1), and increased expression of p21. SFII also suppresses the transforming growth factor-beta (TGF-β) signaling pathway, reducing the expression of fibrotic markers such as alpha-smooth muscle actin (α-SMA) and collagen type I.

Additionally, SFII has been identified as a novel inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), which plays a role in aristolochic acid-induced nephropathy. By inhibiting NQO1, SFII reduces the bioactivation of aristolochic acid and subsequent DNA damage, offering potential protection against aristolochic acid-induced kidney injury. In cancer cells, SFII demonstrates anticancer potential through multiple mechanisms. It induces apoptosis by modulating the expression of Bcl-2 family proteins and activating caspase cascades.

SFII also inhibits cancer cell proliferation by arresting the cell cycle and suppressing oncogenic signaling pathways. Furthermore, it may inhibit cancer cell migration and invasion by modulating matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT). In skin cells, SFII has shown protective effects against atopic dermatitis by suppressing inflammatory responses and maintaining skin barrier function. It reduces the infiltration of inflammatory cells, including mast cells and eosinophils, and decreases the production of immunoglobulin E (IgE) and pro-inflammatory cytokines.

SFII’s antioxidant properties are attributed to its ability to scavenge reactive oxygen species (ROS) and enhance the activity of antioxidant enzymes, though these effects may be less potent than those of other Scutellaria flavonoids with more hydroxyl groups. The polymethoxylated structure of SFII, with multiple methoxy groups, contributes to its lipophilicity and potential ability to penetrate cell membranes, which may enhance its intracellular effects and bioavailability compared to more hydrophilic flavonoids.

Skullcapflavone, particularly Skullcapflavone II (SFII), is rarely available as an isolated supplement, and optimal dosage ranges have not been established through human clinical trials. It is typically consumed as a component of Scutellaria baicalensis (Chinese skullcap) extracts, which contain multiple flavonoids including skullcapflavone in very small amounts (typically less than 0.5%). Standard dosages for Scutellaria extracts range from 300-900 mg daily.

The bioavailability of skullcapflavone, particularly Skullcapflavone II (SFII), has not been extensively studied in humans. Based on limited animal studies and data from structurally similar polymethoxylated flavonoids, skullcapflavone may have moderate oral bioavailability compared to other flavonoids. The presence of multiple methoxy groups in its structure increases its lipophilicity, which may enhance membrane permeability and absorption compared to more hydroxylated flavonoids.

However ,

it is still subject to first-pass metabolism in the liver and potential efflux by intestinal transporters.

Combination with piperine (black pepper extract) to inhibit P-glycoprotein efflux and intestinal metabolism, Liposomal encapsulation to improve solubility and intestinal absorption, Nanoparticle formulations to enhance cellular uptake and tissue distribution, Phospholipid complexation to improve lipid solubility and membrane permeability, Co-administration with other flavonoids from Scutellaria that may compete for metabolic enzymes, Emulsion-based delivery systems to enhance dissolution rate, Topical application for skin conditions, bypassing oral bioavailability limitations

As skullcapflavone is typically consumed as part of Scutellaria extracts rather than as an isolated compound, timing recommendations follow those for Scutellaria supplementation. These extracts are best absorbed when taken with meals containing some fat, which can enhance solubility and absorption of lipophilic flavonoids like skullcapflavone. Taking divided doses throughout the day may maintain more consistent blood levels. For liver protective effects, consistent daily dosing is recommended.

For topical applications targeting skin conditions, regular application as directed (typically 1-2 times daily) is recommended. The polymethoxylated structure of skullcapflavone may result in different pharmacokinetics compared to other Scutellaria flavonoids, potentially with slower metabolism and longer half-life, though specific data on its pharmacokinetic profile in humans is limited.

• Limited data on isolated skullcapflavone; side effects are primarily based on Scutellaria extracts containing skullcapflavone
• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Potential sedative effects at higher doses
• Allergic reactions (rare)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects of flavonoids)
• Bleeding disorders (due to potential antiplatelet activity of flavonoids)
• Hormone-sensitive conditions (due to potential phytoestrogenic effects of some flavonoids)
• Autoimmune conditions (caution due to immunomodulatory effects)
• Hypotension (may enhance blood pressure-lowering effects)
• Liver disease (caution due to potential effects on liver enzymes, though generally hepatoprotective)

• Anticoagulant and antiplatelet medications (may enhance bleeding risk)
• Sedatives and CNS depressants (may enhance sedative effects)
• Cytochrome P450 substrates (flavonoids may affect metabolism of drugs metabolized by CYP1A2, CYP2C9, and CYP3A4)
• P-glycoprotein substrates (may alter drug transport and absorption)
• Immunosuppressants (may interfere with therapeutic effects)
• Antihypertensive medications (may enhance blood pressure-lowering effects)
• Hepatotoxic drugs (potential for interactions affecting liver function)
• NQO1 substrates (SFII has been identified as an NQO1 inhibitor, which may affect the metabolism of drugs activated by this enzyme)

Due to limited human clinical data on isolated skullcapflavone, a definitive upper limit has not been established. Safety considerations are based on Scutellaria extracts, which contain skullcapflavone as a minor component. For Scutellaria extracts, doses exceeding 1000 mg daily are not recommended without medical supervision. For topical applications containing skullcapflavone, follow product-specific guidelines and discontinue use if skin irritation occurs.

Skullcapflavone itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Scutellaria baicalensis extracts containing skullcapflavone are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. 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 skullcapflavone specifically.

For topical applications, products containing Scutellaria extracts are generally regulated as cosmetics unless specific therapeutic claims are made.

Eu: In the European Union, skullcapflavone is not approved as a medicinal product. Scutellaria baicalensis extracts containing skullcapflavone may be sold as food supplements, subject to the general food safety regulations. The European Food Safety Authority (EFSA) has not issued specific health claims for skullcapflavone or Scutellaria extracts. Some EU member states may have their own regulations regarding traditional herbal medicinal products containing Scutellaria. Topical products containing Scutellaria extracts are generally regulated as cosmetics.

Canada: Health Canada regulates Scutellaria baicalensis extracts containing skullcapflavone as Natural Health Products (NHPs). Several Scutellaria products have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims related to traditional use in Chinese medicine. Isolated skullcapflavone is not specifically approved as a standalone ingredient. Topical products may be regulated as either cosmetics or natural health products depending on their claims.

Australia: The Therapeutic Goods Administration (TGA) regulates Scutellaria baicalensis extracts as complementary medicines. Several products containing these extracts are listed on the Australian Register of Therapeutic Goods (ARTG). Traditional use claims are permitted with appropriate evidence of traditional use in Chinese medicine. Skullcapflavone as an isolated compound is not specifically regulated. Topical products may be regulated as either cosmetics or therapeutic goods depending on their claims.

China: Scutellaria baicalensis (Huang Qin) is officially listed in the Chinese Pharmacopoeia as a traditional Chinese medicine. Various formulations containing this herb are approved for specific indications based on traditional use and modern research. Skullcapflavone as an isolated compound is primarily used in research rather than as an approved therapeutic agent. In recent years, there has been increasing interest in developing topical formulations containing Scutellaria extracts for skin conditions.

Japan: Scutellaria baicalensis is included in the Japanese Pharmacopoeia and is a component of several Kampo medicine formulations approved by the Ministry of Health, Labour and Welfare for specific indications. Skullcapflavone as an isolated compound is not specifically regulated for therapeutic use.

High (as isolated compound) / Medium (as part of Scutellaria extracts)

Isolated skullcapflavone is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $500-$1000 per 5-10 mg, making

it prohibitively expensive for regular supplementation. Standardized Scutellaria baicalensis extracts containing small amounts of skullcapflavone along with other flavonoids typically cost $0.50-$2.00 per day for basic extracts and $2.00-$5.00 per day for premium, highly standardized formulations. Topical products containing Scutellaria extracts range from $15-$50 per container, depending on the formulation and brand.

The cost-effectiveness of skullcapflavone must be evaluated in the context of Scutellaria extracts, as isolated skullcapflavone is not practically available for regular supplementation due to its high cost and limited commercial availability. Scutellaria extracts offer reasonable value for their anti-inflammatory, antioxidant, and hepatoprotective benefits, with the therapeutic effects resulting from the combined action of multiple flavonoids including baicalin, baicalein, wogonin, and skullcapflavone. The contribution of skullcapflavone specifically to the overall value of these extracts is difficult to quantify but may be significant for certain applications such as liver protection and inflammatory skin conditions. For research purposes, the high cost of pure skullcapflavone is justified for controlled studies investigating its specific mechanisms and effects.

For consumers seeking health benefits, standardized Scutellaria extracts represent a more practical and cost-effective approach to obtaining skullcapflavone along with complementary flavonoids. For topical applications targeting skin conditions, products containing Scutellaria extracts may offer good value compared to conventional treatments, particularly for conditions like atopic dermatitis where they may provide relief with fewer side effects than corticosteroids. Premium extracts with enhanced bioavailability or specialized delivery systems may offer better value despite their higher price point due to improved absorption and utilization of the active compounds. When comparing the cost-effectiveness of Scutellaria extracts to other botanical supplements with similar indications, they generally offer competitive value, particularly when the broad spectrum of biological activities is considered.

Pure skullcapflavone is relatively stable compared to more hydroxylated flavonoids due to its polymethoxylated structure, which reduces its susceptibility to oxidation.

When properly stored, isolated skullcapflavone may maintain stability for 2-3 years. Standardized Scutellaria extracts containing skullcapflavone typically have a shelf life of 2 years from the date of manufacture. Topical formulations containing skullcapflavone generally have a shelf life of 1-2 years, depending on the formulation and preservative system.

Store in a cool, dry place away from direct sunlight in airtight, opaque containers. Refrigeration is recommended for liquid formulations and can extend shelf life of extracts containing skullcapflavone. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure skullcapflavone, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

Topical formulations should be stored according to product-specific guidelines, typically at room temperature or refrigerated.

Exposure to UV light and sunlight – causes photodegradation, though less rapidly than more hydroxylated flavonoids, High temperatures (above 30°C) – accelerates decomposition, Moisture – can promote hydrolysis and microbial growth, particularly in topical formulations, Oxygen exposure – leads to oxidation, though the methoxy groups provide some protection compared to hydroxyl groups, pH extremes – skullcapflavone is most stable at slightly acidic to neutral pH (5-7), Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – may occur in improperly processed plant extracts, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with skullcapflavone

Synthesis Methods

Natural Sources

Quality Considerations

Skullcapflavone itself was not identified or isolated until modern times, but it is a constituent of Scutellaria baicalensis (Huang Qin or Chinese skullcap), which has been used in traditional Chinese medicine (TCM) for over 2,000 years. While the specific contribution of skullcapflavone to the traditional uses of Scutellaria was unknown to ancient practitioners, it is now recognized as one of the bioactive compounds in this historically important medicinal plant. In TCM, Scutellaria baicalensis root is classified as a cooling herb that clears heat, dries dampness, and eliminates toxins. It was traditionally used to treat fevers, inflammation, respiratory infections, diarrhea, jaundice, and bleeding disorders.

The herb appears in numerous classical TCM formulations, including Huang-Lian-Jie-Du-Tang and Xiao-Chai-Hu-Tang, which are still used today. The first documented medicinal use of Scutellaria baicalensis appears in the Shennong Bencao Jing (Divine Farmer’s Materia Medica), compiled around 200-250 CE, where it was recommended for treating abscesses, sores, and inflammatory conditions. During the Ming Dynasty (1368-1644 CE), the famous physician Li Shizhen included detailed descriptions of Scutellaria baicalensis in his monumental work, the Compendium of Materia Medica (Bencao Gangmu), noting its effectiveness for ‘clearing heat from the upper burner’ and treating coughs with yellow phlegm, thirst, and irritability. In Japanese Kampo medicine, which evolved from TCM, Scutellaria baicalensis (called Ogon) is a component of important formulations such as Sho-saiko-to, used for liver disorders.

In Korean traditional medicine, the herb (known as Hwanggeumgol) was used similarly to its applications in China. Skullcapflavone I and II were first isolated and characterized in the late 20th century as part of the scientific investigation into the active components of Scutellaria species. They were identified as polymethoxylated flavones, a class of compounds that has attracted scientific interest due to their unique biological properties and potential therapeutic applications. Modern scientific interest in skullcapflavone began to grow in the early 21st century as research revealed its anti-inflammatory, hepatoprotective, and potential anticancer properties.

Recent studies have particularly focused on Skullcapflavone II’s potential applications in liver fibrosis, inflammatory skin conditions, and as an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), which may protect against aristolochic acid-induced kidney injury. While skullcapflavone is present in smaller amounts than other flavonoids in Scutellaria, its unique polymethoxylated structure and biological activities have made it an interesting subject for pharmacological research.

No meta-analyses specifically on skullcapflavone are currently available; most analyses focus on Scutellaria baicalensis extracts containing multiple flavonoids including skullcapflavone as a minor component.

Limited ongoing trials specifically investigating skullcapflavone; most research focuses on Scutellaria extracts or other major flavonoids, Some preclinical research exploring skullcapflavone’s potential in liver fibrosis, inflammatory skin conditions, and as an NQO1 inhibitor, Investigations into topical applications for skin conditions such as atopic dermatitis