Isovitexin

• Antioxidant
• Anti-inflammatory
• Neuroprotective
• Anxiolytic

• Cardioprotective
• Antidiabetic
• Hepatoprotective
• Anticancer
• Antimicrobial

Isovitexin (apigenin-6-C-glucoside) exerts its diverse biological effects through multiple molecular pathways. As a C-glycosylflavone, isovitexin possesses a unique structural feature where a glucose molecule is directly attached to the C-6 position of the apigenin backbone via a carbon-carbon bond, rather than through an oxygen atom as in O-glycosides. This C-glycosidic bond is resistant to hydrolysis by glycosidases, contributing to isovitexin’s distinct pharmacokinetic profile and biological activities. One of isovitexin’s most extensively studied mechanisms is its antioxidant activity.

Isovitexin scavenges reactive oxygen species (ROS) and free radicals through its hydroxyl groups, particularly those on the A and B rings of the flavone structure. It neutralizes superoxide anions, hydroxyl radicals, and peroxynitrite, preventing oxidative damage to cellular components including lipids, proteins, and DNA. Beyond direct scavenging, isovitexin enhances endogenous antioxidant defenses by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. By promoting Nrf2 nuclear translocation and binding to antioxidant response elements (AREs), isovitexin upregulates the expression of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1).

This dual approach to antioxidant protection—direct scavenging and enhancement of endogenous antioxidant systems—provides comprehensive defense against oxidative stress. As an anti-inflammatory agent, isovitexin inhibits the nuclear factor-kappa B (NF-κB) signaling pathway by preventing IκB kinase (IKK) activation and subsequent nuclear translocation of NF-κB, thereby reducing the expression of pro-inflammatory genes. It suppresses the production of inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Isovitexin also modulates the mitogen-activated protein kinase (MAPK) signaling pathways, including p38 MAPK, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties.

In the central nervous system, isovitexin exhibits neuroprotective effects through multiple mechanisms. It protects neurons from oxidative stress and excitotoxicity by reducing glutamate-induced calcium influx and maintaining mitochondrial function. Isovitexin also inhibits neuroinflammation by suppressing microglial activation and reducing the production of pro-inflammatory mediators in the brain. Furthermore, it has been shown to enhance brain-derived neurotrophic factor (BDNF) expression and activate the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, promoting neuronal survival and synaptic plasticity.

Isovitexin’s anxiolytic effects are mediated through modulation of the gamma-aminobutyric acid (GABA) system. It enhances GABAergic neurotransmission by binding to the benzodiazepine site of GABAA receptors, though with a different binding profile compared to classical benzodiazepines. This interaction increases chloride ion influx into neurons, resulting in hyperpolarization and reduced neuronal excitability, which contributes to its anxiolytic and mild sedative properties. Additionally, isovitexin has been shown to modulate serotonergic neurotransmission, potentially contributing to its anxiolytic and antidepressant-like effects.

In metabolic regulation, isovitexin improves insulin sensitivity and glucose metabolism through multiple mechanisms. It enhances glucose uptake in skeletal muscle and adipose tissue by activating AMP-activated protein kinase (AMPK) and increasing glucose transporter 4 (GLUT4) translocation to the cell membrane. Isovitexin also protects pancreatic β-cells from oxidative stress and inflammation, preserving insulin secretion capacity. Additionally, it inhibits α-glucosidase and α-amylase, enzymes involved in carbohydrate digestion, potentially reducing postprandial glucose levels.

In cancer cells, isovitexin demonstrates antiproliferative and pro-apoptotic effects. It induces cell cycle arrest primarily at the G0/G1 or G2/M phases by modulating the expression and activity of cell cycle regulators, including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Isovitexin also triggers apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways. It modulates the expression of Bcl-2 family proteins, decreasing anti-apoptotic proteins (Bcl-2, Bcl-xL) and increasing pro-apoptotic proteins (Bax, Bad), leading to mitochondrial membrane permeabilization, cytochrome c release, and activation of caspase cascades.

Furthermore, isovitexin has been shown to inhibit angiogenesis by reducing vascular endothelial growth factor (VEGF) expression and signaling, potentially limiting cancer progression and metastasis. In the cardiovascular system, isovitexin demonstrates protective effects by improving endothelial function, reducing inflammation, and preventing oxidative damage. It enhances nitric oxide (NO) production by endothelial cells through activation of endothelial nitric oxide synthase (eNOS), promoting vasodilation and improving blood flow. Isovitexin also inhibits platelet aggregation and thrombus formation, potentially reducing the risk of thrombotic events.

The C-glycosidic bond in isovitexin contributes to its unique pharmacological profile compared to its aglycone apigenin and its isomer vitexin (apigenin-8-C-glucoside). This structural feature affects its bioavailability, metabolism, and tissue distribution, potentially leading to different biological activities and therapeutic applications. The position of the glucose moiety at C-6 rather than C-8 (as in vitexin) results in subtle differences in receptor binding and molecular interactions, which may explain some of the distinct pharmacological effects observed between these isomers.

Optimal dosage ranges for isovitexin in humans have not been well established through clinical trials. Most research has focused on isovitexin as a component of herbal extracts, particularly from passion flower (Passiflora species) and bamboo leaves, rather than as an isolated compound. Based on preclinical studies and limited human research with herbal extracts containing isovitexin, estimated effective doses would range from 10-50 mg of isovitexin daily. For passion flower extracts, typical daily doses range from 300-800 mg of standardized extract containing 0.5-2% isovitexin and related C-glycosylflavones, corresponding to approximately 1.5-16 mg of isovitexin daily.

For bamboo leaf extracts, typical daily doses range from 200-600 mg of standardized extract containing 1-3% isovitexin, corresponding to approximately 2-18 mg of isovitexin daily. It’s important to note that isovitexin’s bioactivity may be influenced by other compounds present in herbal extracts, potentially leading to synergistic effects that allow for lower effective doses compared to isolated isovitexin.

Isovitexin has relatively low oral bioavailability, estimated at approximately 3-8% in animal studies. This limited bioavailability is primarily due to its C-glycosidic structure, which affects its absorption and metabolism. Unlike O-glycosides, the C-glycosidic bond in isovitexin (where the glucose is directly attached to the C-6 position of apigenin via a carbon-carbon bond) is resistant to hydrolysis by intestinal and hepatic glycosidases. This means that isovitexin is primarily absorbed intact rather than being converted to its aglycone (apigenin) in the gastrointestinal tract.

The glucose moiety enhances water solubility but reduces passive diffusion across cell membranes due to its hydrophilicity. Absorption occurs primarily through active transport mechanisms, including sodium-dependent glucose transporters (SGLTs) and possibly other transporters. Once absorbed, isovitexin undergoes limited phase II metabolism, primarily glucuronidation and sulfation, though to a lesser extent than many other flavonoids due to its already glycosylated structure. The C-glycosidic bond also makes isovitexin less susceptible to efflux by P-glycoprotein transporters in the intestine, which may partially compensate for its limited passive diffusion.

In animal studies, isovitexin has demonstrated tissue distribution to various organs, including the liver, kidneys, and brain, though brain penetration is limited due to its hydrophilicity. The presence of other compounds in herbal extracts, particularly from passion flower and bamboo leaves, may influence isovitexin’s bioavailability through various mechanisms, including competitive inhibition of metabolic enzymes or transporters.

Nanoemulsion formulations – can increase bioavailability by 3-10 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects isovitexin from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexes – enhance lipid solubility and membrane permeability, Microemulsions – provide a stable delivery system with enhanced solubility, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, Solid dispersion techniques – enhance dissolution rate and solubility, Co-administration with other flavonoids that may compete for metabolic enzymes, potentially extending isovitexin’s half-life, Nanoparticle formulations – improve stability and targeted delivery, particularly relevant for neuroprotective and anxiolytic applications

Isovitexin is best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. The presence of other flavonoids may enhance isovitexin’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For anxiety and stress, taking isovitexin 30-60 minutes before stressful situations may help manage acute symptoms, while consistent daily dosing is recommended for chronic anxiety. For sleep support, taking isovitexin 30-60 minutes before bedtime may help promote relaxation and sleep onset.

For antioxidant and anti-inflammatory effects, timing is less critical than consistency of use, though divided doses throughout the day may maintain more consistent blood levels due to isovitexin’s relatively short half-life (approximately 2-4 hours in animal studies). For metabolic support, taking isovitexin before meals may enhance its effects on postprandial glucose levels through α-glucosidase and α-amylase inhibition. Enhanced delivery formulations like nanoemulsions or liposomes 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. Traditional use of passion flower containing isovitexin often involves preparing it as a tea or tincture, which may have different absorption characteristics compared to modern extract formulations.

When consumed as a tea, the hot water extraction efficiently extracts isovitexin due to its good water solubility, but the absence of lipids may limit absorption compared to when taken with a meal.

• Gastrointestinal discomfort (mild, uncommon)
• Nausea (rare)
• Dizziness (rare)
• Headache (rare)
• Mild sedation (uncommon, primarily with higher doses)
• Allergic reactions (rare)
• Drowsiness (uncommon, dose-dependent)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential mild sedative effects and interactions with anesthetics)
• Individuals with known allergies to plants in the Passifloraceae family (for passion flower-derived isovitexin) or Poaceae family (for bamboo-derived isovitexin)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)
• Individuals taking medications that act on the central nervous system (due to potential additive effects)

• Benzodiazepines and other sedatives (potential for additive sedative effects due to isovitexin’s mild GABAA receptor modulation)
• Antidepressants, particularly SSRIs and MAOIs (potential for interactions due to isovitexin’s effects on serotonergic neurotransmission)
• Anticonvulsant medications (potential for interactions due to isovitexin’s effects on GABA and glutamate systems)
• Cytochrome P450 substrates (limited evidence suggests potential mild inhibition of certain CYP enzymes)
• Antidiabetic medications (may enhance blood glucose-lowering effects)
• Antioxidant medications (potential for additive effects with other antioxidants)
• Alcohol (potential for additive sedative effects)
• Drugs requiring active transport for absorption (potential competition for transporters)

Due to limited human clinical data on isolated isovitexin, a definitive upper limit has not been established. Based on safety data for passion flower and bamboo leaf extracts (which contain isovitexin) and animal toxicity studies, doses up to 50 mg of isovitexin daily or 800 mg of standardized extract daily appear to be well-tolerated in most individuals. For general supplementation, doses exceeding these levels are not recommended without medical supervision due to potential drug interactions and limited long-term safety data at higher doses. It’s important to note that isovitexin has demonstrated a favorable safety profile in both preclinical and limited clinical studies, with a wide therapeutic window.

Acute toxicity studies in animals have shown very low toxicity, with LD50 values well above any reasonable supplemental dose. The presence of other bioactive compounds in herbal extracts may contribute to the overall safety profile, making it difficult to establish precise upper limits for isolated isovitexin. Traditional use of passion flower in moderate doses has a long history of safe use, further supporting the generally favorable safety profile of isovitexin-containing preparations.

Isovitexin itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Plant extracts containing isovitexin, such as passion flower and bamboo leaf extracts, 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 isovitexin specifically.

Passion flower is generally recognized as safe (GRAS) when used in traditional amounts as an herb or supplement.

Eu: In the European Union, isovitexin is not approved as a medicinal product. However, passion flower extracts containing isovitexin are regulated as traditional herbal medicinal products under Directive 2004/24/EC in several EU countries, allowing them to be sold with specific health claims related to traditional use. The European Medicines Agency (EMA) has published a community herbal monograph on passion flower, recognizing its traditional medicinal use for relief of mild symptoms of mental stress and to aid sleep.

Germany: In Germany, passion flower extracts are approved by Commission E (the German regulatory authority for herbs) for nervousness and sleep disorders. They are available as registered herbal medicinal products with specific therapeutic indications.

Uk: In the United Kingdom, passion flower products may be registered as Traditional Herbal Medicinal Products (THMPs) under the Traditional Herbal Medicines Registration Scheme, allowing them to be sold with specific health claims based on traditional use, such as ‘a traditional herbal medicinal product used for the temporary relief of symptoms associated with stress, such as mild anxiety and to aid sleep, based on traditional use only.’

Canada: Health Canada regulates passion flower extracts as Natural Health Products (NHPs). Several products containing these extracts have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims, including ‘traditionally used in Herbal Medicine as a sleep aid’ and ‘helps relieve restlessness and nervousness.’ Bamboo leaf extracts are also regulated as NHPs. Isolated isovitexin is not specifically approved as a standalone ingredient.

Australia: The Therapeutic Goods Administration (TGA) regulates passion flower and bamboo leaf 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. Isovitexin as an isolated compound is not specifically regulated.

China: In China, bamboo leaves (Zhu Ye) are officially listed in the Chinese Pharmacopoeia as a traditional Chinese medicine. They are approved for clearing heat, resolving phlegm, and calming the spirit. Various formulations containing bamboo leaves are approved for medicinal use. Isovitexin as an isolated compound is primarily used in research rather than as an approved therapeutic agent.

Japan: In Japan, bamboo leaves and passion flower are recognized as medicinal plants and are included in some traditional Japanese medicine formulations. Isovitexin as an isolated compound is not specifically regulated for therapeutic use.

Medium

Isolated isovitexin is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $200-$600 per 10-25 mg, making

it prohibitively expensive for regular supplementation. Standardized passion flower extracts containing isovitexin along with other flavonoids typically cost $0.25-$1.00 per day for basic extracts and $1.00-$2.50 per day for premium, highly standardized formulations. Standardized bamboo leaf extracts containing isovitexin typically cost $0.30-$1.20 per day for basic extracts and $1.20-$3.00 per day for premium formulations. Dried passion flower for tea preparation is the most cost-effective option, typically costing $0.15-$0.50 per day, though

it provides less consistent and potentially lower amounts of isovitexin.

The cost-effectiveness of isovitexin must be evaluated in the context of herbal extracts containing it, as isolated isovitexin is not practically available for regular supplementation due to its high cost and limited commercial availability. For anxiety and sleep support, passion flower extracts containing isovitexin offer good value compared to both pharmaceutical anxiolytics and many other herbal alternatives. The anxiolytic effects are generally milder than benzodiazepines but come with significantly fewer side effects and no risk of dependence, making them a cost-effective option for mild to moderate anxiety and sleep disturbances. For antioxidant and anti-inflammatory benefits, there are likely more cost-effective options than isovitexin-containing extracts, as many other botanical antioxidants have similar potency at lower costs.

For neuroprotective effects, the value proposition is promising based on preclinical studies, but clinical evidence is still lacking. The long-term benefits for neurodegenerative conditions would need to be substantial to justify ongoing supplementation costs. For liver and kidney protection, bamboo leaf extracts containing isovitexin offer moderate value compared to other hepatoprotective and nephroprotective supplements. The preclinical evidence is promising, but more clinical studies are needed to fully establish their efficacy in humans.

When comparing the cost-effectiveness of passion flower and bamboo leaf extracts containing isovitexin to other supplements with similar indications: For anxiety and sleep, passion flower extracts are generally less expensive than many specialized anti-anxiety supplements like L-theanine or specific adaptogenic herbs, while offering comparable benefits for mild to moderate anxiety. For neuroprotection, they are comparably priced to other neuroprotective botanicals like Bacopa monnieri or Ginkgo biloba, but with less clinical evidence supporting their use. The most cost-effective way to consume isovitexin is through traditional passion flower tea, which can be prepared from dried herb at a fraction of the cost of processed extracts. However, the concentration of isovitexin and other active compounds may be lower and less consistent in tea preparations compared to standardized extracts.

Enhanced delivery systems such as nanoemulsions, liposomes, or SEDDS offer better bioavailability and potentially superior therapeutic outcomes, which may justify their higher cost for specific health conditions, particularly those affecting the central nervous system where clinical benefits have been suggested by preclinical research.

Pure isovitexin is moderately stable, with a typical shelf life of 2-3 years when properly stored. The C-glycosidic bond (where the glucose is directly attached to the C-6 position of apigenin via a carbon-carbon bond) provides better stability compared to O-glycosides, as it is resistant to hydrolysis by acids and enzymes. Standardized herbal extracts containing isovitexin, such as passion flower or bamboo leaf extracts, typically have a shelf life of 1-2 years from the date of manufacture. Dried herb material (e.g., passion flower, bamboo leaves) properly stored can maintain acceptable isovitexin content for 1-2 years.

Tea preparations have a much shorter shelf life, with optimal potency maintained for only a few hours after preparation. Enhanced delivery formulations such as nanoemulsions or liposomes generally have shorter shelf lives of 1-2 years, depending on the specific 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 isovitexin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure isovitexin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

For dried herb material (e.g., passion flower, bamboo leaves), store in airtight containers away from light and moisture to preserve the isovitexin content. The addition of antioxidants such as vitamin E or ascorbic acid to formulations can help prevent oxidation and extend shelf life. Enhanced delivery formulations may have specific storage requirements provided by the manufacturer, which should be followed carefully to maintain stability and potency. Avoid repeated freeze-thaw cycles, particularly for liquid formulations, as this can destabilize the product.

Exposure to UV light and sunlight – causes photodegradation, though the C-glycosidic bond provides better stability compared to O-glycosides, High temperatures (above 30°C) – accelerates decomposition, Moisture – can promote hydrolysis (though to a lesser extent than with O-glycosides) and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, particularly affecting the hydroxyl groups, pH extremes – isovitexin is most stable at slightly acidic to neutral pH (5-7), with increased degradation in strongly acidic or alkaline conditions, Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – while the C-glycosidic bond is resistant to glycosidases, other enzymes may affect the flavone structure, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with isovitexin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Isovitexin itself was not identified or isolated until the modern era, but it is a constituent of several plants that have been used in traditional medicine systems for centuries. While the specific contribution of isovitexin to the traditional uses of these plants was unknown to ancient practitioners, it is now recognized as one of the bioactive compounds in these historically important medicinal materials. Isovitexin is primarily found in passion flower (Passiflora species) and bamboo leaves, both of which have rich histories in traditional medicine across various cultures. Passion flower has been used by indigenous peoples of the Americas for centuries before European contact.

Native American tribes, including the Aztecs, Maya, and various North American groups, used passion flower for its calming and sedative properties. The Aztecs used passion flower as a sedative and to treat insomnia, nervousness, and epilepsy. Various indigenous tribes in North America used passion flower to treat wounds, earaches, liver problems, and as a mild pain reliever. When European explorers arrived in the Americas in the 16th century, they quickly learned about passion flower from indigenous peoples and brought it back to Europe.

The plant was named ‘passion flower’ by Spanish missionaries who saw in its unique flower structure symbols of the Passion of Christ. By the 17th century, passion flower was being used in European herbal medicine for its calming and sleep-promoting effects. In the 19th and early 20th centuries, passion flower was included in various pharmacopeias and was commonly prescribed for nervousness, insomnia, and epilepsy. It was officially listed in the United States National Formulary from 1916 to 1936 and in the British Herbal Pharmacopoeia.

Bamboo leaves have been used in traditional Asian medicine, particularly in China, Korea, and Japan, for thousands of years. In Traditional Chinese Medicine (TCM), bamboo leaves (Zhu Ye) were first documented in the ‘Shennong Bencao Jing’ (Divine Farmer’s Classic of Materia Medica) around 200-300 CE. They were classified as herbs that clear heat, resolve phlegm, and calm the spirit. Bamboo leaves were traditionally used to treat fevers, coughs, phlegm, and irritability.

In Korean traditional medicine, bamboo leaves were used for similar purposes as in TCM, with additional applications for treating hypertension and diabetes. In Japanese Kampo medicine, bamboo leaves were included in various formulations for treating respiratory conditions and fevers. Rice, another source of isovitexin, has been a staple food in various cultures for thousands of years and was also used in traditional medicine systems. In TCM, rice bran was used to improve digestion and treat gastrointestinal disorders.

In Ayurvedic medicine, rice preparations were used for their cooling and nourishing properties. Mung bean, which also contains isovitexin, has been used in traditional Asian medicine for its detoxifying and cooling properties. In TCM, mung bean was used to clear heat, detoxify the body, and treat conditions associated with heat and toxicity, such as fevers, skin eruptions, and food poisoning. Isovitexin was first isolated and characterized in the mid-20th century as part of the scientific investigation into the active components of these traditional medicinal plants.

Its structure was elucidated as apigenin-6-C-glucoside, identifying it as a C-glycosylflavone with a unique carbon-carbon bond between the flavone backbone and the glucose moiety. Modern scientific interest in isovitexin began to grow in the late 20th and early 21st centuries as research revealed its antioxidant, anti-inflammatory, anxiolytic, and neuroprotective properties. The discovery of isovitexin’s effects on GABA and serotonin systems has provided scientific explanations for some of the traditional uses of passion flower, particularly its applications in anxiety and sleep disorders. Today, passion flower extracts containing isovitexin are used in various herbal formulations, particularly in Europe and North America, for treating anxiety, insomnia, and nervous disorders.

Bamboo leaf extracts containing isovitexin are increasingly being studied and used for their antioxidant, anti-inflammatory, and potential neuroprotective properties.