Luteolin

• Anti-inflammatory
• Antioxidant
• Neuroprotective
• Anti-cancer

• Pain reduction
• Blood glucose regulation
• Cardiovascular support
• Immune modulation
• Hepatoprotective
• Anti-allergic

Luteolin exerts its diverse biological effects through multiple molecular mechanisms and signaling pathways. As a potent antioxidant, luteolin directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), including superoxide anions, hydroxyl radicals, hydrogen peroxide, and peroxynitrite. This direct scavenging activity is primarily attributed to the hydroxyl groups in its structure, particularly the catechol moiety (3′,4′-dihydroxy) in the B-ring and the 5,7-dihydroxy groups in the A-ring. Beyond direct scavenging, luteolin enhances the endogenous antioxidant defense system by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.

Upon activation, Nrf2 translocates to the nucleus and binds to antioxidant response elements (AREs), promoting the expression of antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and γ-glutamylcysteine synthetase (γ-GCS). Luteolin also exhibits metal-chelating properties, binding transition metals like iron and copper that can catalyze oxidative reactions, thereby preventing lipid peroxidation and oxidative damage to cellular components. The anti-inflammatory effects of luteolin are mediated through multiple pathways. It potently inhibits the nuclear factor-kappa B (NF-κB) signaling pathway, a master regulator of inflammatory responses.

Luteolin blocks the phosphorylation and degradation of inhibitor of kappa B (IκB), preventing NF-κB translocation to the nucleus and subsequent transcription of pro-inflammatory genes. Additionally, luteolin inhibits the mitogen-activated protein kinase (MAPK) pathways, including p38 MAPK, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), which are involved in inflammatory signal transduction. These actions result in decreased production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8). Luteolin also inhibits the activity of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), reducing the production of prostaglandins and excessive nitric oxide associated with inflammation.

Furthermore, luteolin modulates the activity of phospholipase A2 (PLA2), decreasing the release of arachidonic acid and subsequent production of inflammatory mediators. In the context of neuroprotection, luteolin crosses the blood-brain barrier to a limited extent and exerts multiple beneficial effects on neuronal cells. It protects neurons from oxidative stress-induced damage by scavenging free radicals and enhancing antioxidant defenses. Luteolin inhibits microglial activation and the release of pro-inflammatory mediators in the central nervous system, reducing neuroinflammation.

It also modulates various neurotransmitter systems, including cholinergic, dopaminergic, and GABAergic pathways, potentially improving cognitive function. Additionally, luteolin inhibits the aggregation of amyloid-beta peptides and tau protein, which are implicated in Alzheimer’s disease pathogenesis. It also promotes the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), supporting neuronal survival and plasticity. The anti-cancer properties of luteolin involve multiple mechanisms.

It induces cell cycle arrest by modulating the expression of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors such as p21 and p27. Luteolin triggers apoptosis (programmed cell death) in cancer cells through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways, involving activation of caspases and regulation of Bcl-2 family proteins. It inhibits cancer cell proliferation by suppressing various signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, MAPK/ERK, and Janus kinase/signal transducer and activator of transcription (JAK/STAT). Luteolin also inhibits angiogenesis (formation of new blood vessels) by downregulating vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), thereby limiting tumor growth and metastasis.

Furthermore, luteolin exhibits epigenetic effects by inhibiting DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), potentially reversing aberrant epigenetic modifications associated with cancer. In metabolic regulation, luteolin influences glucose metabolism through several mechanisms. It enhances insulin sensitivity by activating the insulin receptor substrate-1 (IRS-1) and PI3K/Akt signaling pathway, promoting glucose uptake in peripheral tissues. Luteolin inhibits alpha-glucosidase and alpha-amylase, enzymes involved in carbohydrate digestion, thereby slowing glucose absorption.

It also protects pancreatic beta cells from oxidative stress-induced damage and stimulates insulin secretion. Additionally, luteolin activates AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, which promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.

The optimal therapeutic dosage of luteolin is not firmly established due to limited clinical trials. Based on available research and clinical practice, dosages typically range from 50 mg to 300 mg per day. For general health maintenance and antioxidant support, lower doses of 50-100 mg daily may be sufficient. Higher doses are typically used for specific therapeutic purposes and should be guided by healthcare professionals.

General Timing: Luteolin is typically taken with meals to enhance absorption and reduce potential gastrointestinal side effects. For twice-daily dosing, morning and evening administration with food is recommended.

Specific Considerations: For conditions involving allergic responses, consistent daily timing helps maintain stable blood levels. For sleep-related benefits, taking the last dose with dinner or early evening may be beneficial.

Tablets Capsules: Most common form, typically available in 50 mg, 100 mg, and occasionally 200 mg strengths.

Powder: Allows for flexible dosing but has a bitter taste. Typically mixed with juice or smoothies to mask flavor.

Combination Products: Often combined with other flavonoids (quercetin, rutin) or antioxidants. Dosages vary by formulation.

For those new to luteolin supplementation, starting with a lower dose (50 mg daily) for the first week and gradually increasing to the target therapeutic dose can help minimize potential digestive discomfort or other side effects.

Some practitioners recommend cycling luteolin (e.g., 4-6 weeks on, 1-2 weeks off) to prevent potential tolerance, though there is limited scientific evidence supporting this approach.

It’s important to note that optimal dosing guidelines for luteolin are still evolving as research continues. Many recommendations are based on preclinical studies, limited clinical trials, and clinical experience rather than large-scale human studies.

Luteolin has relatively poor oral bioavailability (approximately 4-6%) due to its low water solubility, limited intestinal absorption, and extensive first-pass metabolism. The planar structure and multiple hydroxyl groups contribute to its limited absorption in the small intestine.

Intestinal Metabolism: In the intestine, luteolin undergoes extensive metabolism by intestinal microflora and intestinal enzymes. Bacterial metabolism includes dehydroxylation, demethylation, and ring cleavage reactions. Intestinal enzymes primarily catalyze phase II conjugation reactions, including glucuronidation and sulfation.

Hepatic Metabolism: After absorption, luteolin undergoes further metabolism in the liver, primarily through phase II conjugation reactions. The main metabolic pathways include glucuronidation (mediated by UDP-glucuronosyltransferases), sulfation (mediated by sulfotransferases), and methylation (mediated by catechol-O-methyltransferases).

Primary Metabolites: Luteolin-7-O-glucuronide, Luteolin-3′-O-glucuronide, Luteolin-4′-O-glucuronide, Luteolin-7-O-sulfate, 3′-O-Methylluteolin (diosmetin), Various mixed conjugates (glucuronide-sulfates)

Peak Plasma Time: For standard luteolin, peak plasma concentrations of metabolites occur approximately 1-2 hours after oral administration, reflecting rapid metabolism. The parent compound is typically detected at very low concentrations in plasma.

Half Life: The elimination half-life of luteolin metabolites ranges from 3-4 hours for the parent compound to 8-18 hours for various metabolites, with considerable individual variation.

Protein Binding: Approximately 85-95% of circulating luteolin and its metabolites are bound to plasma proteins, primarily albumin.

Blood Brain Barrier: Luteolin can cross the blood-brain barrier to a limited extent, with brain concentrations typically reaching 5-10% of plasma levels. Enhanced delivery systems like liposomes or nanoparticles may improve CNS penetration.

Target Tissues: After absorption, luteolin and its metabolites distribute to various tissues, with higher concentrations observed in the liver, kidneys, and intestines. Lower concentrations are found in the brain, heart, and skeletal muscle.

Accumulation: Limited evidence of significant tissue accumulation with regular dosing, though some metabolites may have longer residence times in specific tissues.

Luteolin and its metabolites undergo enterohepatic circulation, where conjugated metabolites are excreted in bile, deconjugated by intestinal bacteria, and reabsorbed. This process extends the presence of active compounds in the body.

For optimal absorption, luteolin should be taken with meals, preferably those containing some fat content. Dividing the daily dose into two administrations (morning and evening with meals) may help maintain more consistent blood levels of active metabolites. Consistency in timing from day to day helps maintain stable therapeutic effects.

Luteolin has a generally favorable safety profile based on available research, though long-term human studies are limited. As a naturally occurring flavonoid present in many foods, luteolin is generally recognized as safe for most individuals when used appropriately. However, its potent biological activities warrant caution, particularly at higher doses or in certain populations.

• Known hypersensitivity to luteolin or other flavonoids
• Bleeding disorders (use with caution due to potential antiplatelet effects)
• Scheduled surgery (discontinue at least 2 weeks before due to potential anticoagulant effects)
• Pregnancy and lactation (insufficient safety data, use only if clearly needed and under medical supervision)
• Hormone-sensitive conditions (due to potential estrogenic effects)
• Severe liver or kidney disease (use with caution due to limited elimination data)

Pregnancy: Category C – Animal reproduction studies have shown adverse effects on the fetus, and there are no adequate well-controlled studies in humans. Use only if potential benefit justifies potential risk to the fetus.

Lactation: Limited data available. It is unknown if luteolin is excreted in human milk. Use caution and consider risk-benefit ratio.

Pediatric: Limited safety data available for pediatric use. Some clinical studies have used luteolin-containing formulations in children with autism spectrum disorders with acceptable safety profiles, but long-term safety data are lacking.

Geriatric: No specific dose adjustments required, but start at lower doses and monitor for side effects due to potential decreased renal/hepatic function and increased likelihood of drug interactions.

Renal Impairment: Use with caution in moderate to severe renal impairment. Consider reduced dosing.

Hepatic Impairment: Use with caution in moderate to severe hepatic impairment. Consider reduced dosing.

Acute Toxicity: Luteolin has low acute toxicity. Animal studies show LD50 values greater than 5,000 mg/kg body weight, indicating a wide margin of safety.

Chronic Toxicity: Long-term studies in humans are limited. Animal studies have not identified significant toxicity concerns at therapeutic doses. Monitoring liver function with long-term use may be prudent.

Genotoxicity: Available studies do not indicate significant genotoxic potential at therapeutic doses.

Carcinogenicity: No evidence of carcinogenic potential in available studies. Some research suggests potential anti-cancer properties.

No official upper limit has been established. Clinical studies have used doses up to 300 mg daily without significant adverse effects. Doses above 500 mg daily have not been well studied and are not recommended without medical supervision due to potential for increased risk of side effects and drug interactions.

For long-term use (>3 months), consider periodic monitoring of liver function, complete blood count, and blood pressure, particularly at higher doses.

Limited data on overdose. Expected symptoms may include severe gastrointestinal disturbances, hypotension, and potential liver stress. Supportive care is the primary management approach.

Classification: Dietary Supplement

Approval Status: Not approved as a drug in the United States. Marketed as a dietary supplement under DSHEA (Dietary Supplement Health and Education Act) regulations.

Permitted Claims: Structure/function claims related to antioxidant support, inflammatory response, and cellular health are permitted with appropriate disclaimer. Disease claims (such as treating autism, cancer, or inflammatory conditions) are not allowed without drug approval.

Restrictions: Must comply with dietary supplement GMP (Good Manufacturing Practices) regulations. Cannot be marketed with claims to treat, cure, or prevent specific diseases.

Increasing Scrutiny: Growing regulatory attention to quality control and standardization of botanical supplements, including luteolin-containing products.

Evidence Requirements: Increasing emphasis on clinical evidence to support health claims, with regulatory bodies requiring more robust scientific substantiation.

Safety Monitoring: Enhanced post-market surveillance systems for dietary supplements in many jurisdictions, potentially affecting luteolin products.

United States: Must include standard supplement facts panel, appropriate structure/function claim disclaimers, and cannot make disease claims.

European Union: Must comply with food supplement labeling regulations, including ingredient listing, recommended daily dose, warning statements, and no unauthorized health claims.

General Requirements: Most jurisdictions require batch/lot numbers, expiration dates, storage conditions, and manufacturer information.

Clinical Trials: Several registered clinical trials investigating luteolin for various conditions, including autism spectrum disorders, allergic conditions, and inflammatory disorders. Most are small-scale or early-phase studies.

Investigational New Drug: Some luteolin derivatives or formulations may be under investigation as potential pharmaceutical agents, though most remain in preclinical or early clinical stages.

Enhanced Formulations: Novel delivery systems for luteolin (liposomal, nanoparticle, etc.) may face additional regulatory scrutiny as they could alter the absorption, distribution, metabolism, and excretion profiles.

Combination Products: Products combining luteolin with other bioactives may face more complex regulatory pathways, particularly if synergistic effects are claimed.

Personalized Nutrition: Emerging regulatory frameworks for personalized nutrition may impact how luteolin supplements are recommended and marketed based on individual genetic or metabolic profiles.

2024-07-10

Medium to High

Luteolin supplements tend to be moderately to highly priced compared to many other dietary supplements. This is due to the relatively complex extraction and purification processes required, limited commercial sources, and growing demand. Enhanced bioavailability formulations and pharmaceutical-grade products typically command premium prices.

Standard Luteolin: $30-60 USD for 100-200 mg daily dose, $1.00-2.00 USD per day for standard formulations, Basic luteolin supplements are moderately priced but may have limited bioavailability. Quality can vary significantly in this price range.

Enhanced Bioavailability Formulations: $60-120 USD for 100-200 mg daily dose, $2.00-4.00 USD per day, Liposomal, phytosomal, or nanoparticle formulations command premium prices but may offer improved absorption and efficacy.

Combination Products: $40-90 USD for products combining luteolin with other flavonoids or antioxidants, $1.30-3.00 USD per day, Products combining luteolin with complementary compounds like quercetin, rutin, or PEA may offer better value through synergistic effects.

Specialized Formulations: $70-150 USD for specialized formulations targeting specific conditions (e.g., neuroinflammatory disorders), $2.30-5.00 USD per day, These products often include multiple active ingredients and enhanced delivery systems, justifying higher prices if efficacy is demonstrated.

Regional Variations: Prices vary significantly by country and region. European and Japanese products tend to be more expensive than those manufactured in the United States or India.

Vs Other Flavonoids: Luteolin is typically more expensive than common flavonoids like quercetin (30-50% higher) and rutin (50-100% higher), comparable to resveratrol, and less expensive than specialized flavonoids like fisetin or pterostilbene.

Vs Other Supplements: Luteolin is moderately to highly priced compared to other specialty supplements. It is typically more expensive than basic supplements like vitamin C or B vitamins, comparable to mid-range supplements like CoQ10 or alpha-lipoic acid, and less expensive than premium supplements like NMN or certain medicinal mushroom extracts.

Vs Pharmaceuticals: For conditions where luteolin may provide benefit, such as inflammatory or neurological disorders, it is generally less expensive than prescription medications, though efficacy comparisons are limited by insufficient clinical data.

Formulation Selection: For most conditions, standard luteolin supplements provide reasonable value. Enhanced bioavailability formulations may be worth the additional cost for individuals with absorption issues or those who haven’t responded adequately to standard formulations.

Dosing Strategies: Starting with lower doses (50-100 mg daily) and titrating up based on response may optimize cost-effectiveness. For some conditions, intermittent dosing or cycling may provide benefits while reducing costs.

Combination Approach: Using luteolin in combination with complementary compounds (e.g., quercetin, omega-3 fatty acids) may enhance efficacy and provide better overall value than higher doses of luteolin alone.

Purchasing Tips: Bulk purchases may reduce per-dose cost, Subscription services often offer 10-20% discounts, Look for sales or promotional discounts from reputable suppliers, Consider combination products if you would otherwise purchase multiple supplements separately

When evaluating cost-efficiency, consider the potential long-term savings from preventing progression of certain conditions or reducing the need for more expensive interventions. These indirect savings may significantly outweigh the direct costs of luteolin supplementation in some cases.

Standard luteolin supplements typically have a shelf life of 2-3 years when stored properly. The actual stability can vary based on formulation, packaging, and storage conditions.

Temperature: Store at room temperature (15-25°C or 59-77°F). Avoid exposure to temperatures above 30°C (86°F), as higher temperatures can accelerate degradation through oxidation and other chemical reactions.

Humidity: Keep in a dry place with relative humidity below 60%. Luteolin can absorb moisture, which may lead to hydrolysis and degradation.

Light: Protect from direct light, especially sunlight and UV radiation, which can cause photodegradation. Luteolin is particularly susceptible to photodegradation due to its flavonoid structure with conjugated double bonds.

Container: Keep in the original container, preferably in opaque or amber bottles with tight-fitting lids. Blister packs provide good protection against moisture and light.

Special Considerations: Some formulations may include stabilizers such as vitamin C, vitamin E, or other antioxidants to extend shelf life by protecting against oxidation.

Tablets: Generally stable with shelf life of 2-3 years. Film-coated tablets offer better protection against moisture and oxidation. Inclusion of antioxidants like vitamin C or vitamin E can enhance stability.

Capsules: Moderately stable with shelf life of 2-3 years. Vegetable capsules may be more susceptible to moisture than gelatin capsules. Oxygen absorbers in packaging can improve stability.

Powders: Less stable than solid dosage forms, with shelf life typically 1-2 years due to increased surface area exposed to environmental factors. Should be stored with desiccants.

Liquid Extracts: Least stable form with shelf life of 6-12 months. Often contain preservatives and antioxidants to extend stability. Glycerin-based extracts tend to be more stable than alcohol-based ones.

Liposomal Formulations: Moderate stability with shelf life of 1-2 years. The phospholipid encapsulation provides some protection against degradation but introduces potential for lipid oxidation.

Synthesis Methods

Natural Sources

Quality Considerations

Sustainability

Market Trends

Ancient Medicine: While luteolin itself was not identified until the 20th century, plants rich in luteolin have been used in traditional medicine systems for centuries. Perilla leaves (Perilla frutescens), one of the richest sources of luteolin, have been used in traditional Chinese and Japanese medicine for respiratory conditions, allergies, and inflammatory disorders.

Folk Remedies: Chamomile (Matricaria chamomilla), containing significant amounts of luteolin, has a long history of use in European folk medicine for digestive issues, inflammation, and anxiety. Celery seed, another luteolin-rich source, was used in Mediterranean traditional medicine for arthritis, gout, and as a diuretic.

Initial Discovery: Luteolin was first isolated and identified in the late 19th century from the plant Reseda luteola (weld), which was historically used as a yellow dye. The name ‘luteolin’ is derived from the Latin ‘luteus’, meaning ‘yellow’.

Structural Elucidation: The complete chemical structure of luteolin was elucidated in the early 20th century. Its classification as a flavone with a specific hydroxylation pattern (3′,4′,5,7-tetrahydroxyflavone) was established through chemical analysis and later confirmed by spectroscopic methods.

Early Research: Initial scientific interest in luteolin was primarily in the context of plant pigmentation and taxonomy. Its biological activities began to be investigated more thoroughly in the mid-20th century.

1950s-1970s: Early research focused on the chemical properties and botanical distribution of luteolin. Limited studies began to explore its potential biological activities, particularly its antioxidant properties.

1980s-1990s: Increased research into the biological activities of flavonoids in general, with growing interest in luteolin’s antioxidant and anti-inflammatory properties. Studies began to elucidate its mechanisms of action at the molecular level.

2000s-2010s: Significant expansion of research into luteolin’s therapeutic potential, with studies exploring its effects on cancer, inflammation, neurological disorders, and metabolic conditions. Mechanisms of action were more thoroughly characterized, and initial clinical studies began.

2010s-Present: Growing interest in luteolin’s potential applications for neuroinflammatory conditions, including autism spectrum disorders and neurodegenerative diseases. Increased focus on improving bioavailability and developing novel delivery systems. Expansion of clinical research, though still limited compared to preclinical studies.

Early Products: Initial commercial products containing luteolin were primarily plant extracts rather than isolated luteolin. These included perilla leaf extract, celery seed extract, and artichoke leaf extract, which were marketed for various health benefits.

Supplement Formulations: Isolated luteolin supplements began to appear in the market in the early 2000s, initially at relatively low doses and often combined with other flavonoids. More recently, higher-dose formulations and enhanced bioavailability products have been developed.

Specialized Formulations: Development of specialized formulations targeting specific conditions, particularly neuroinflammatory disorders. Notable examples include luteolin-containing formulations for autism spectrum disorders, which have gained attention following clinical research in this area.

Pharmaceutical Interest: Growing pharmaceutical interest in luteolin as a lead compound for drug development, particularly for anti-inflammatory, neuroprotective, and anticancer applications. Several derivatives and analogs are under investigation.

Regional Variations: Plants rich in luteolin, such as perilla, have significant cultural importance in East Asian countries, where they are used both as food and medicine. In Mediterranean regions, luteolin-containing herbs like thyme, oregano, and parsley are integral to culinary traditions and folk medicine.

Modern Perception: In contemporary wellness culture, luteolin is increasingly recognized as a beneficial flavonoid, though it has not yet achieved the widespread recognition of some other flavonoids like quercetin or resveratrol.

Late 19th century: First isolation of luteolin from the plant Reseda luteola, Early 20th century: Elucidation of luteolin’s complete chemical structure, 1990s: Identification of key molecular mechanisms underlying luteolin’s anti-inflammatory effects, 2000s: Discovery of luteolin’s potential neuroprotective properties and ability to cross the blood-brain barrier, 2013: Publication of clinical study on luteolin-containing formulation for autism spectrum disorders, expanding interest in its neuroinflammatory applications, 2010s-2020s: Development of enhanced bioavailability formulations, including liposomal and nanoparticle delivery systems

Early Sources: Initially obtained through extraction from dye plants like Reseda luteola, primarily for research purposes rather than commercial production.

Modern Sources: Commercial production now relies primarily on extraction from perilla leaves, celery seed, and artichoke leaves, which offer higher yields and more economical processing.

Extraction Methods: Early extraction methods used simple solvent extraction with alcohol or water. More sophisticated methods using selective solvents and purification techniques developed over time.

Synthetic Approaches: While total chemical synthesis of luteolin has been achieved, it has not been commercially viable compared to extraction from natural sources.

Luteolin has moderate evidence supporting its biological activities, particularly its antioxidant and anti-inflammatory effects, which are well-established in preclinical studies. Clinical evidence for specific therapeutic applications is emerging but still limited. Most research consists of in vitro and animal studies, with a growing but still modest number of human clinical trials. The quality of available clinical studies varies, with many being small-scale, short-duration, or using combination products rather than isolated luteolin.

Clinical trial evaluating luteolin supplementation in children with autism spectrum disorders (NCT04873921), Study of luteolin for allergic rhinitis and asthma (NCT03582826), Investigation of luteolin-containing formulation for cognitive function in healthy aging (ISRCTN17542563)

Long-term safety and efficacy data beyond 6 months of treatment, Optimal dosing strategies for different conditions, Comparative effectiveness studies against standard treatments for inflammatory and neurological conditions, Well-designed clinical trials for emerging applications such as neuroprotection and metabolic disorders, Studies on enhanced bioavailability formulations and their clinical outcomes, Research on potential synergistic effects with other flavonoids and antioxidants

Development and clinical testing of enhanced bioavailability formulations, Larger, well-designed clinical trials for specific conditions, particularly neuroinflammatory and allergic disorders, Investigation of optimal dosing regimens and treatment durations, Exploration of synergistic combinations with other bioactive compounds, Long-term safety studies, particularly in special populations