Sinensetin

• Anti-inflammatory
• Anticancer
• Metabolic regulation
• Antioxidant

• Neuroprotective
• Hepatoprotective
• Antimicrobial
• Diuretic
• Bone protection

Sinensetin, a pentamethoxyflavone found primarily in citrus peels and Orthosiphon aristatus (Java tea), exerts its diverse biological effects through multiple molecular pathways. As an anti-inflammatory agent, sinensetin 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. Recent research has identified a novel anti-inflammatory mechanism where sinensetin binds to Bach1, a transcriptional repressor, preventing its degradation and thereby inhibiting the expression of pro-inflammatory genes.

This Bach1-mediated mechanism has been particularly implicated in sinensetin’s protective effects against periodontitis and potentially other inflammatory conditions. In cancer cells, sinensetin demonstrates multiple anticancer mechanisms. It induces apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways by modulating the expression of Bcl-2 family proteins, activating caspases, and promoting cytochrome c release. Sinensetin inhibits cancer cell proliferation by arresting the cell cycle at G0/G1 phase through regulation of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors such as p21 and p27.

It also suppresses cancer cell migration and invasion by inhibiting matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT). A particularly significant mechanism of sinensetin’s anticancer activity is its ability to modulate multidrug resistance (MDR) transporters, including P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP). By inhibiting these efflux transporters, sinensetin can enhance the intracellular accumulation and efficacy of chemotherapeutic agents, potentially overcoming drug resistance in cancer cells. The antioxidant properties of sinensetin are primarily attributed to its ability to indirectly enhance endogenous antioxidant defense systems rather than direct radical scavenging.

Unlike hydroxylated flavonoids, sinensetin’s methoxy groups limit its direct radical scavenging capacity. Instead, it activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to increased expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1). In metabolic regulation, sinensetin improves insulin sensitivity and glucose metabolism by activating AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma (PPAR-γ). It also enhances adiponectin production and reduces leptin resistance, contributing to improved metabolic homeostasis.

Additionally, sinensetin has been shown to inhibit adipogenesis and lipid accumulation in adipocytes, suggesting potential applications in obesity management. In the central nervous system, sinensetin exhibits neuroprotective effects through multiple mechanisms. It reduces oxidative stress and neuroinflammation, which are key contributors to neurodegenerative diseases. Sinensetin also modulates neurotransmitter systems and promotes neuronal survival through activation of survival signaling pathways such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.

In bone metabolism, sinensetin has been shown to inhibit osteoclastogenesis and bone resorption by suppressing receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced signaling pathways. This mechanism contributes to its potential benefits for bone health and conditions like osteoporosis and periodontitis. Sinensetin also exhibits diuretic effects, which are attributed to its ability to inhibit Na+/K+/2Cl- cotransporter activity in the kidney, promoting sodium and water excretion. This mechanism explains its traditional use in conditions requiring increased urine output.

The highly methoxylated structure of sinensetin contributes to its lipophilicity and ability to penetrate cell membranes, which enhances its intracellular effects and potentially its therapeutic efficacy. However, this same characteristic limits its water solubility and oral bioavailability, necessitating various formulation strategies to enhance its absorption and therapeutic potential.

Optimal dosage ranges for sinensetin in humans have not been well established through clinical trials. Most studies use citrus peel extracts or Orthosiphon aristatus (Java tea) extracts standardized to contain specific percentages of polymethoxyflavones (PMFs), including sinensetin. Based on preclinical studies and limited human research, typical daily doses range from 30-150 mg of sinensetin or 500-2000 mg of standardized extract containing 3-8% PMFs.

For Orthosiphon aristatus extracts, which are traditionally used as diuretics and for metabolic conditions, typical doses contain approximately 5-30 mg of sinensetin daily.

Sinensetin has poor oral bioavailability, estimated at approximately 1-5% in animal studies, primarily due to its extremely low water solubility, extensive first-pass metabolism in the liver, and efflux by P-glycoprotein transporters in the intestine.

Despite its lipophilic nature, which theoretically should enhance membrane permeability, the poor aqueous solubility significantly limits its dissolution in the gastrointestinal tract and subsequent absorption. Once absorbed, sinensetin undergoes extensive metabolism, primarily through demethylation and conjugation reactions, forming various metabolites that may contribute to its biological activities. Interestingly, sinensetin itself is an inhibitor of P-glycoprotein and other drug efflux transporters, which may lead to complex pharmacokinetic interactions

when co-administered with other compounds that are substrates for

these transporters.

Nanoemulsion formulations – can increase bioavailability by 5-15 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects sinensetin from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexation – enhances lipid solubility and membrane permeability, Microemulsions – provide a stable delivery system with enhanced solubility, Combination with piperine – inhibits intestinal metabolism and may enhance absorption, Co-administration with medium-chain triglycerides or other lipids – enhances solubility and lymphatic transport, 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 sinensetin’s half-life

Sinensetin is best absorbed when taken with meals containing fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. The presence of other citrus flavonoids may enhance sinensetin’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For diuretic effects, morning dosing is recommended to avoid nighttime urination. For metabolic conditions, consistent daily dosing is important, with some evidence suggesting that divided doses may maintain more consistent blood levels due to sinensetin’s relatively short half-life (approximately 2-4 hours in animal studies).

When used as an adjunct to cancer therapy, timing relative to chemotherapy administration may be critical due to sinensetin’s effects on drug transporters. In some cases, administration of sinensetin before chemotherapy may enhance the efficacy of the chemotherapeutic agent by inhibiting efflux transporters, but this should only be done under medical supervision due to the potential for complex drug interactions. Enhanced 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.

• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Increased urination (due to diuretic effects)
• Allergic reactions (rare)
• Potential electrolyte imbalances with high doses or prolonged use (due to diuretic effects)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects)
• Bleeding disorders (due to potential antiplatelet activity)
• Hormone-sensitive conditions (due to potential effects on hormone metabolism)
• Individuals taking medications metabolized by CYP450 enzymes (due to potential interactions)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)
• Individuals with electrolyte imbalances or taking diuretic medications (due to sinensetin’s diuretic effects)
• Individuals undergoing chemotherapy (unless specifically recommended by oncologist, due to potential drug interactions)

• Chemotherapeutic agents (may increase bioavailability and potentially toxicity due to inhibition of drug efflux transporters)
• P-glycoprotein substrates (may alter drug transport and absorption)
• Cytochrome P450 substrates (may affect metabolism of drugs metabolized by CYP1A2, CYP2C9, CYP2D6, and CYP3A4)
• Diuretic medications (may enhance diuretic effects, potentially leading to excessive fluid loss and electrolyte imbalances)
• Anticoagulant and antiplatelet medications (may enhance bleeding risk due to potential antiplatelet effects)
• Antihypertensive medications (may enhance blood pressure-lowering effects)
• Statins (potential for increased bioavailability and risk of side effects)
• Immunosuppressants (may interfere with therapeutic effects through immunomodulatory actions)
• Antidiabetic medications (may enhance blood glucose-lowering effects)

Due to limited human clinical data, a definitive upper limit has not been established. Based on animal toxicity studies, doses up to 150-200 mg/kg body weight have been used without significant adverse effects, suggesting a relatively high safety margin. For human supplementation, doses exceeding 200 mg of sinensetin or 2500 mg of standardized extract daily are not recommended without medical supervision due to potential drug interactions, diuretic effects, and limited long-term safety data.

Sinensetin itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Citrus peel extracts and Orthosiphon aristatus (Java tea) extracts containing sinensetin 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 sinensetin specifically.

Sinensetin is generally recognized as safe (GRAS) as a component of citrus fruits and their extracts when used in food applications.

Eu: In the European Union, sinensetin is not approved as a medicinal product. Citrus peel extracts and Orthosiphon aristatus extracts containing sinensetin may be sold as food supplements, subject to the general food safety regulations. The European Medicines Agency (EMA) has issued a monograph on Orthosiphon aristatus folium (Java tea leaf), recognizing its traditional use as a diuretic for minor urinary complaints, based on long-standing use. The European Food Safety Authority (EFSA) has not issued specific health claims for sinensetin. Sinensetin is permitted as a food flavoring component derived from natural sources.

Canada: Health Canada regulates citrus peel extracts and Orthosiphon aristatus extracts containing sinensetin as Natural Health Products (NHPs). Several products have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims related to traditional use. Orthosiphon aristatus is listed in the Natural Health Products Ingredients Database with approved claims for use as a diuretic and for urinary tract health. Isolated sinensetin is not specifically approved as a standalone ingredient.

Australia: The Therapeutic Goods Administration (TGA) regulates citrus peel extracts and Orthosiphon aristatus 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. Orthosiphon aristatus is recognized in the TGA’s list of substances that may be used in listed medicines with claims related to its traditional use as a diuretic and for urinary tract health.

Indonesia: In Indonesia, where Orthosiphon aristatus (locally known as ‘Kumis Kucing’) is native and widely used, it is officially recognized in the Indonesian Herbal Pharmacopoeia. Various formulations containing this herb are approved for specific indications based on traditional use and modern research. It is one of the most important medicinal plants in the traditional Jamu medicine system.

Malaysia: The Malaysian National Pharmaceutical Regulatory Agency recognizes Orthosiphon aristatus (locally known as ‘Misai Kucing’) as a traditional medicinal herb. It is listed in the Malaysian Herbal Monograph with approved traditional uses for kidney and bladder disorders, diabetes, and hypertension.

Japan: Citrus peel is included in several Kampo medicine formulations approved by the Ministry of Health, Labour and Welfare for specific indications. Sinensetin as an isolated compound is not specifically regulated for therapeutic use. The Japanese Ministry of Health, Labour and Welfare permits sinensetin as a natural component of food flavorings derived from citrus.

Medium to high

Isolated sinensetin is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $300-$600 per 10-25 mg, making

it prohibitively expensive for regular supplementation. Standardized citrus peel extracts containing sinensetin along with other polymethoxyflavones typically cost $0.50-$2.00 per day for basic extracts and $2.00-$5.00 per day for premium, highly standardized formulations. Orthosiphon aristatus (Java tea) extracts standardized for sinensetin content typically cost $0.30-$1.50 per day for basic extracts and $1.50-$4.00 per day for premium, highly standardized formulations. Dried Orthosiphon aristatus herb for tea preparation is the most economical form, costing approximately $0.10-$0.30 per day.

The cost-effectiveness of sinensetin must be evaluated in the context of the extracts containing it, as isolated sinensetin is not practically available for regular supplementation due to its high cost and limited commercial availability. For diuretic effects and urinary tract health, Orthosiphon aristatus (Java tea) extracts or dried herb preparations offer the best value, with centuries of traditional use supporting their efficacy for these applications. The dried herb for tea preparation is particularly cost-effective, though the sinensetin content may be less consistent than in standardized extracts. For anti-inflammatory, metabolic, and potential anticancer benefits, citrus peel extracts may offer better value due to their higher content of complementary polymethoxyflavones like tangeretin and nobiletin, which work synergistically with sinensetin.

Basic citrus peel extracts provide good value for general health maintenance and mild inflammatory conditions. However, their effectiveness is limited by poor bioavailability of the active compounds. Premium extracts with standardized polymethoxyflavone content provide more consistent results but at a higher price point. For specific applications like adjunctive cancer therapy (to potentially enhance the efficacy of chemotherapeutic agents), the higher cost of premium standardized extracts may be justified by the potential benefits, though this should only be considered under medical supervision.

Enhanced delivery formulations such as nanoemulsions, liposomes, or SEDDS offer the best therapeutic potential due to significantly improved bioavailability (5-15 fold increase), potentially justifying their higher cost for specific health conditions. When comparing the cost-effectiveness of extracts containing sinensetin to other botanical supplements with similar indications, they generally offer competitive value. For diuretic effects, Orthosiphon aristatus extracts are comparable in cost and efficacy to other herbal diuretics like dandelion leaf. For anti-inflammatory and metabolic benefits, citrus peel extracts are generally less expensive than many specialized botanical extracts with similar applications.

Pure sinensetin is relatively stable compared to hydroxylated flavonoids due to its pentamethoxylated structure, which reduces its susceptibility to oxidation. When properly stored, isolated sinensetin may maintain stability for 2-3 years. Standardized extracts containing sinensetin typically have a shelf life of 1-2 years from the date of manufacture. Orthosiphon aristatus (Java tea) dried herb or tea preparations containing sinensetin generally have a shelf life of 1-2 years when properly stored.

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 sinensetin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure sinensetin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

For Orthosiphon aristatus dried herb, store in airtight containers away from light and moisture to preserve the active compounds. 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 less rapidly than hydroxylated flavonoids, High temperatures (above 30°C) – accelerates decomposition and may cause demethylation, Moisture – can promote hydrolysis and microbial growth, particularly in dried herb preparations and liquid formulations, Oxygen exposure – leads to oxidation, though the methoxy groups provide some protection compared to hydroxyl groups, pH extremes – sinensetin 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 sinensetin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Sinensetin 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 sinensetin to the traditional uses of these plants was unknown to ancient practitioners, it is now recognized as one of the key bioactive compounds in these historically important medicinal materials. Sinensetin is found in two main traditional medicinal sources: citrus peels and Orthosiphon aristatus (Java tea, cat’s whiskers). In Traditional Chinese Medicine (TCM), dried citrus peels, known as ‘Chen Pi’ (primarily from Citrus reticulata), have been used for over 2,000 years.

They were classified as herbs that regulate qi (vital energy), dispel dampness, and resolve phlegm. Citrus peels were traditionally used to treat digestive disorders, coughs with phlegm, abdominal distension, and nausea. The first documented medicinal use of citrus peels appears in the ancient Chinese pharmacopeia ‘Shennong Bencao Jing’ (Divine Farmer’s Materia Medica), compiled around 200-250 CE. During the Tang Dynasty (618-907 CE), citrus peels were recognized for their ability to ‘break up stagnation’ and improve digestion.

The famous physician Sun Simiao included detailed descriptions of citrus peel applications in his work ‘Qianjin Yaofang’ (Thousand Golden Prescriptions). In the Ming Dynasty (1368-1644 CE), the renowned physician Li Shizhen further documented the medicinal properties of various citrus peels in his monumental work ‘Bencao Gangmu’ (Compendium of Materia Medica). Orthosiphon aristatus (Java tea) has a rich history of use in Southeast Asian traditional medicine, particularly in Indonesia, Malaysia, Thailand, and Vietnam. It has been used for centuries as a diuretic and to treat kidney stones, urinary tract infections, diabetes, hypertension, and rheumatism.

In Indonesian traditional medicine (Jamu), it is known as ‘Kumis Kucing’ (cat’s whiskers) and is one of the most important medicinal plants. In Malaysian traditional medicine, it is called ‘Misai Kucing’ and is similarly used for urinary and kidney disorders. The Dutch colonists in Indonesia recognized the medicinal value of Java tea and introduced it to Europe in the early 19th century, where it became known as ‘Java tea’ and was used primarily as a diuretic and for kidney and bladder complaints. Sinensetin 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.

It was identified as a polymethoxyflavone, a class of compounds that has attracted scientific interest due to their unique biological properties and potential therapeutic applications. Modern scientific interest in sinensetin began to grow in the late 20th and early 21st centuries as research revealed its anti-inflammatory, diuretic, and potential anticancer properties. A significant breakthrough in sinensetin research came in the early 2010s when it was discovered to be an inhibitor of drug efflux transporters, which opened new avenues for research into its potential applications in cancer therapy and drug resistance. Recent studies have particularly focused on sinensetin’s novel anti-inflammatory mechanism involving Bach1, its effects on bone health, and its potential applications in metabolic disorders.

Limited meta-analyses specifically on sinensetin; most analyses focus on citrus flavonoids or polymethoxyflavones as a group., A systematic review of Orthosiphon aristatus (Java tea) for urinary tract and kidney disorders included analysis of sinensetin as one of its active components, concluding that there is moderate evidence supporting its diuretic effects (Arafat et al., Journal of Ethnopharmacology, 2018).

Several preclinical studies investigating sinensetin’s potential in cancer therapy, particularly focusing on its ability to reverse multidrug resistance, Research on novel delivery systems to enhance sinensetin’s bioavailability and targeted delivery, Investigations into sinensetin’s potential for bone health and periodontal disease, Studies on the metabolic effects of sinensetin in models of obesity and nonalcoholic fatty liver disease, Limited early-phase clinical trials evaluating standardized extracts containing sinensetin for inflammatory conditions and metabolic disorders