Butein (2′,3,4,4′-Tetrahydroxychalcone): A Comprehensive Reference
1. Identity, Chemical Description, and Natural Sources
1.1 Chemical Identity
Butein is chemically described as 2′,3,4,4′-tetrahydroxychalcone, a chalcone derivative produced by species from several diverse botanical families, including the Anacardiaceae, Asteraceae, and Fabaceae. An alternative but equivalent systematic name is (E)-1-(2′,4′-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one. Its CAS registry number is 487-52-5. The compound belongs to the chalconoid class of open-chain flavonoids: a chalcone moiety consists of two aromatic rings, also known as 1,3-diaryl-2-propen-1-ones, connected by a 3-carbon-unsaturated carbonyl system — a kind of open-chain flavonoid.
Biosynthetically, butein is synthesized in plants by a series of reactions of three molecules of malonyl-CoA and a single molecule of p-coumaroyl-CoA in the presence of enzymes such as chalcone synthase and chalcone reductase to produce isoliquiritigenin; isoliquiritigenin then undergoes hydroxylation by the action of chalcone-3-hydroxylase to produce butein.
1.2 Botanical Sources
Butein is found in a very large variety of botanical sources belonging to different families, such as Asteraceae (e.g., Coreopsis lanceolata L., Dahlia variabilis Desf.), Asparagaceae (e.g., Sansevieria liberica), Anacardiaceae (e.g., Semecarpus anacardium L.), Fabaceae (e.g., Butea frondosa Roxb., Butea monosperma Taub., Acacia pycnantha Benth.), Pinaceae (e.g., Abies pindrow Royle), Solanaceae (e.g., Solanum lycopersicum Lam.), and others. It can also be found in Toxicodendron vernicifluum (formerly Rhus verniciflua), Dahlia, Butea (Butea monosperma), and Coreopsis.
Additional important sources documented in the scientific literature include the heartwood of Dalbergia odorifera, the stem bark of cashews (Semecarpus anacardium), and the herb Caragana jubata. Butein is present in numerous plants, including the stem bark of cashews (Semecarpus anacardium), and herbs such as Caragana jubata and the heartwood of Dalbergia odorifera.
1.3 Discovery and Isolation History
The compound was first isolated and identified in 1904 from the flowers of Butea frondosa, in the form of a yellow colouring pigment (Perkin and Hummel, 1904). However, Perkin and Everest (1918) proposed that butein is not produced by B. frondosa, but rather that it is a biotransformation product of butin that is formed during the drying or extraction of the flowers. Schmid and Seebald (1932) subsequently purified butein from flowers of Dahlia variabilis.
1.4 Common Forms and Preparations
Butein is a reputed food additive and a common ingredient of botanicals used in herbal medicine formulations, particularly in Asian countries. The compound is used as a food additive in various countries, including Korea. In research and supplement contexts, butein is available as an isolated pure compound. Butein possesses extensive anticancer properties but has limited use due to issues like low bioavailability, rapid systemic clearance, and low water solubility; to overcome these challenges, innovative novel delivery technologies such as bioengineering, nanoformulations, and encapsulation have been investigated.
2. Traditional and Historical Use
2.1 Asian Medicinal Traditions
Butein has a long history of traditional use in Japan, Korea, and China as an analgesic, antibiotic, antithrombotic, anticancer, and anti-inflammatory agent. Butein belongs to the chalcone family of flavonoids and was isolated from several plants including Toxicodendron vernicifluum, Semecarpus anacardium, Dalbergia odorifera, and Butea monosperma; all of these plants have been used in various systems of traditional medicine, such as Siddha, Ayurveda, Korean, Chinese, and Iranian, for curing inflammatory diseases, atherosclerosis, hepatic disorders, ulcers, gout, eye diseases, rheumatic pain, dementia, bleeding, cough, and cancers.
These source plants have been used in the treatment of gastritis, atherosclerosis, and various other diseases such as inflammatory diseases, hepatic disorders, cancers, bleeding, and cough, and also as a pain killer, antioxidant, and antibacterial agent.
2.2 Ayurvedic Use
Butea monosperma — one of the richest botanical sources of butein — has an extensive history in Ayurvedic practice. Flower, stem bark, root bark, and leaves of Butea monosperma possess diverse chemical constituents such as butrin, isobutrin, and isocoreopsin, which showed a wide range of biological activities such as antioxidant, anti-inflammatory, anticonvulsant, antidiabetic, hepatoprotective, anti-gout, ameliorative, anti-obese, anti-hyperglycemic, anti-nociceptive, anthelmintic, and chemopreventive activities. Plant flowers are a good source of colour which is traditionally used in religious rituals.
2.3 Food Use
The compound is also used as a food additive in various countries, including Korea; plant extracts containing butein as an active ingredient are widely used as traditional medicines. Its role as a natural pigment — imparting yellow coloration — means it has been incorporated into food and dyeing traditions in several Asian countries.
3. Key Active Constituents and Established Mechanisms of Action
3.1 Structural Basis of Activity
Although a simple polyphenol, butein exhibits a range of pharmacological properties, most notably acting as a potent protein tyrosine kinase inhibitor and as an antineoplastic agent. The four hydroxyl groups at positions 2′, 3, 4, and 4′ of the chalcone scaffold are widely understood to underlie many of its bioactivities through hydrogen bonding and radical-scavenging properties.
3.2 NF-κB Pathway Inhibition
Butein inhibits the production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, as well as the production of nitric oxide (NO) and prostaglandin E2 (PGE2) through the NF-κB signaling pathway. It has been shown to affect multiple molecular targets, including the master transcription factor nuclear factor-κB and its downstream molecules; moreover, since it acts on multiple pathways, the chances of non-responsiveness and resistance development are reduced.
3.3 SIRT1 Activation
Butein is a sirtuin-activating compound, a chemical compound having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. Activation of silent information regulator 1 (SIRT1) inhibits apoptosis, oxidation, and inflammation, thus alleviating sepsis-induced multi-organ injuries. In the context of cancer, butein increases the activity of SIRT1 to enhance the functional mitochondrial pool.
3.4 PI3K/Akt/mTOR and MAPK Pathways
The role of butein in disease treatment mainly lies in its ability to specifically target key signaling pathways, including NF-κB, TNF-α, PI3K/Akt/mTOR, p53, MAPK, and several other signaling cascades involved in growth, metabolism, inflammation, oxidative homeostasis, chemoresistance, and apoptosis.
3.5 Nrf2/ARE and HO-1 Activation
Butein-mediated HO1 (heme oxygenase-1) expression, induced via Nrf2 activation, is involved in its neuroprotective action; the upregulation of Nrf2-induced HO1 expression contributes to the neurocytoprotective and anti-inflammatory effects of butein.
3.6 Protein Tyrosine Kinase Inhibition
Butein has been recognised for its ability to inhibit the enzyme protein tyrosine kinase, thereby preventing phosphorylation and affording protection against some cancers and inflammatory diseases. The compound displays inhibitory effects against the EGFR in HepG2 cells and against the tyrosine-specific protein kinase activities of the EGFR.
3.7 Antioxidant Mechanisms
Butein had a chain-breaking antioxidant mechanism with higher activity than reference α-tocopherol, particularly concerning the stoichiometry or peroxyl radical-trapping (n = 3.7 ± 1.1 vs. 2.0 for tocopherol). Butein can effectively reduce lipid peroxidation and superoxide anion production in rat liver microsomes by its inherent antioxidant capacity, thus preventing free radical-induced cytotoxicity. Butein also protects rat primary hepatocytes from oxidative damage by promoting glutamate cysteine ligase expression and glutathione levels.
3.8 Aldose Reductase and Advanced Glycation End-Product Inhibition
Butein has antioxidative, aldose reductase, and advanced glycation end-product (AGE) inhibitory effects. Inhibition of aldose reductase — the first enzyme of the polyol pathway — is considered relevant to preventing diabetic complications such as neuropathy, retinopathy, and cataracts.
3.9 Aromatase Inhibition
Buteins possess a high ability to inhibit the aromatase process in the human body; for this reason, the use of these compounds in the treatment of breast cancer on the estrogen basis has been explored.
3.10 Anti-Angiogenic Mechanisms
Butein inhibited serum- and vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and tube formation of human endothelial progenitor cells (EPCs) in a concentration-dependent manner without cytotoxic effect. Furthermore, butein markedly abrogated VEGF-induced vessel sprouting from aortic rings and suppressed microvessel formation in the Matrigel implant assay in vivo.
4. Scientific Evidence by Area of Use
Important overarching limitation: Based on numerous preclinical studies, butein shows significant therapeutic potential against various diseases; nevertheless, well-designed clinical studies are urgently needed to validate the preclinical findings. The following subsections reflect the current state of the evidence, which is predominantly in vitro and animal-based.
4.1 Anticancer Activity
Evidence Base
Anticancer research on butein is extensive but remains at the preclinical stage. In vitro and in vivo studies have shown that butein may induce apoptotic cell death in various human cancer cells. As yet, no published human clinical trials of isolated butein for cancer treatment have been identified in peer-reviewed literature.
Breast Cancer
A study demonstrated that butein inhibition of reactive oxygen species (ROS) production results in suppression of breast cancer growth; different breast cancer cell lines were treated with butein and then subjected to cell viability and apoptosis assays, and butein-sensitive or -resistant breast cancer cells were injected into mammary fat pads of immunocompromised mice and then butein was injected; breast cancer cells were categorized on the basis of butein sensitivity; butein reduced viabilities of different breast cancer cells, while not affecting those of HER2-positive breast cancer cells.
Cervical Cancer
Two cervical cancer cell lines, C-33A and SiHa, were treated with butein at different dosages for different durations, with assessment by MTT assay revealing that butein exerted cytotoxicity in both cell lines in a dose- and time-dependent fashion. Butein treatment modulated expression of Bcl-2 and IAP family proteins in cervical cancer cells.
Ovarian Cancer
Butein decreased the growth of ovarian cancer cells in xenograft tumor models; it inhibited STAT3 phosphorylation and induced FoxO3a accumulation in the nucleus by inhibiting IL-6 signaling; the anticancer activity of butein was mediated by blocking the IL-6/IL-6Rα interaction and suppressing IL-6 bioactivity via interfering with the IL-6/STAT3/FoxO3a pathway.
Oral Squamous Cell Carcinoma
Butein exhibited potent anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects in oral squamous cell carcinoma (OSCC) cells; it suppressed the expression of NF-κB and NF-κB-regulated gene products such as COX-2, survivin, and MMP-9, which are involved in the regulation of processes like proliferation, survival, invasion, and metastasis of OSCC cells. In vivo validation was noted as critical before moving to clinical trials.
Cutaneous Squamous Cell Carcinoma
In vitro experiments demonstrated that butein inhibited the proliferation and migration of human cSCC cell line A431 with an IC50 of 43 μM and induced dose-dependent apoptosis; in a nude mouse xenograft model, treatment with butein at 10, 20, and 40 mg/kg reduced tumor volume by 39.21%, 63.44%, and 79.05%, respectively, without affecting body weight.
Skin Carcinoma
Further investigation revealed that butein arrests cell cycle progression, increases reactive oxygen species (ROS) generation, and disrupts the mitochondrial membrane potential (MMP), leading to both apoptotic and necrotic cell death; butein also possesses good oral bioavailability, drug-like properties, and high gastrointestinal absorption in prediction studies, while it did not alter human erythrocyte integrity in an ex vivo study.
Overall Characterization
Butein possesses extensive anticancer properties with wide applications in the chemotherapeutic field; however, it has limited use due to issues like low bioavailability, rapid systemic clearance, and low water solubility. The evidence base for anticancer effects is entirely preclinical (in vitro cell line studies and rodent xenograft models). No human clinical trial data exist.
4.2 Anti-Inflammatory Activity
Butein exhibits a broad spectrum of bioactivities, including promising antineoplastic, antioxidant, and anti-inflammatory activities in both in vitro and in vivo models. Butein significantly decreased TNF-α-induced monocyte cell adhesion to lung epithelial cells in a dose-dependent manner; it also inhibited the protein and mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecules. These findings are from cell-culture and animal models; no clinical trial data on anti-inflammatory endpoints in humans have been published.
4.3 Neuroprotection and Neurological Disorders
Butein has been found to have neuroprotective properties against scopolamine-induced Alzheimer's disease in rats; it reduces cognitive impairment and biochemical and neurobehavioral changes caused by scopolamine; the neuroprotective effect of butein may be attributed to its anti-inflammatory and antioxidant properties.
In a mouse model of sepsis-induced brain injury, butein administered intraperitoneally at 10 mg/kg saved mice from sepsis-induced lethality by increasing the 7-day survival rate after cecal ligation and puncture surgery; butein treatment enhanced SIRT1 signaling, thus decreasing Ac-NF-κB, Ac-FOXO1, and Ac-p53 levels, attenuating brain injury by decreasing cerebral edema, maintaining blood-brain barrier integrity, inhibiting neuronal apoptosis, and decreasing pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and oxidative stress in both serum and cerebral cortex tissues.
All current neuroprotective evidence is derived from animal studies. No human clinical trial data exist for neurological indications.
4.4 Hepatoprotection and Liver Disease
Liver Fibrosis
Butein, a polyphenolic compound extracted from the stem bark of cashews and Rhus verniciflua, has been shown to suppress liver fibrosis induced by carbon tetrachloride and to inhibit myofibroblastic differentiation of rat hepatic stellate cells (HSCs). Its derivative, with improved bioavailability, has been shown to have a potent antiproliferative effect mediated by the activation of ERK, with ERK activation leading to the transcriptional activation of AP-1 and, consequently, to heme oxygenase 1 expression in hepatic stellate cells.
A nanoformulation study employed a vitamin A-modified solid lipid nanoparticle system to improve hepatic delivery: butein was encapsulated inside novel VA-modified solid lipid nanoparticles (VA-SLNs), and negatively charged SLNs with a mean diameter of 150 nm and entrapment efficacy of 75% were successful in liver fibrosis amelioration.
Non-Alcoholic Steatohepatitis (NASH)
Butein treatment resulted in significant amelioration of glucolipid metabolism dysregulation, hepatic inflammation, and liver fibrosis in a mouse model, potentially mediated through modulation of the PDE4/cAMP/p-CREB signaling pathway; in in vitro experimental models, butein effectively attenuated lipid-induced oxidative stress in HepG2 cells and reduced inflammatory and fibrotic responses in LX-2 cells. These findings establish the protective effects of butein against NASH progression through PDE4/cAMP/p-CREB pathway modulation, supporting its potential as a therapeutic candidate for NASH treatment pending further clinical validation.
Chemotherapy-Induced Hepatotoxicity
In a rat model, male albino rats were divided into groups (of 7 animals each): control, 5-FU, and two butein-pretreated groups (50 and 100 mg/kg/day, orally for 14 days) before a single intraperitoneal dose of 150 mg/kg 5-FU. Butein offered dose-dependent hepatoprotection against 5-FU-induced liver injury through the attenuation of oxidative stress, suppression of pro-inflammatory and apoptotic markers, and upregulation of antioxidant defenses.
All hepatoprotective evidence is from in vitro and rodent models. No human clinical data exist.
4.5 Antidiabetic and Metabolic Effects
Butein has antioxidative, aldose reductase, and advanced glycation end-product inhibitory effects, all of which are mechanistically relevant to managing diabetic complications. The diabetic complications induced by hyperglycaemia are also driven by AGE formation; butein has been investigated for inhibition of the glycation of α-crystallin as an approach to prevention of retinopathy; the aggregation of lens proteins induced by glycation is one of the key drivers of diabetic retinopathy and development of diabetic cataracts.
Antidiabetic, antinephritic, anti-angiogenic, neuroprotective, antimicrobial, anti-hypertensive, and hepatoprotective properties have also been attributed to butein. This evidence is exclusively preclinical. No human clinical trial data have been published specifically for butein in diabetes or metabolic disease.
4.6 Cardiovascular Effects
As a chalcone derivative and plant polyphenol from the heartwood of Dalbergia odorifera, Caragana jubata, and Rhus verniciflua, butein has been identified to have wide-ranging pharmacological effects including antioxidant, anticancer, anti-inflammatory, and antimicrobial properties. In a rat model of chronic heart failure, butein was studied for its ability to reduce oxidative stress injury via ERK/Nrf2 signaling. In preclinical settings, it was shown to improve the treatment outcome of several chronic diseases including inflammation, neurological disorders, neoplasms, and atherosclerosis, and most of these actions were accomplished by the inhibition of NF-κB and its downstream targets. Evidence is limited to animal studies.
4.7 Antioxidant Activity
Butein and homobutein are bioactive polyhydroxylated chalcones widespread in dietary plants whose antioxidant properties require mechanistic definition. Kinetic studies in lipid micelles showed that butein had a chain-breaking mechanism with higher antioxidant activity than the reference α-tocopherol, particularly concerning the stoichiometry of peroxyl radical trapping (n = 3.7 ± 1.1 vs. 2.0 for tocopherol). These results were obtained in in vitro lipid-oxidation assays.
4.8 Antimicrobial Properties
Butein, isolated from plants with profound medicinal use, has inherent antioxidant, anti-inflammatory, anticancer, antinephritic, antidiabetic, and antibacterial properties. Specific antimicrobial study details are not extensively published in human-focused literature; this area also remains preclinical.
4.9 Senolytic and Anti-Aging Activity
Butein increases resistance to oxidative stress and lifespan with positive effects on the risk of age-related diseases in Caenorhabditis elegans. Research into butein's sirtuin-activating properties (SIRT1 activation) has generated interest in its potential contribution to longevity pathways, but this remains at the basic science level with no human clinical confirmation.
5. Body Systems and Health Areas Associated with Butein
- Oncology: Multiple cancer cell lines studied in vitro; xenograft models in rodents; no clinical trials.
- Nervous System: Neuroprotection against oxidative stress, neuroinflammation, and Alzheimer's-like models in rodents.
- Liver / Hepatic System: Hepatoprotection, anti-fibrotic, anti-NASH effects in rodent and cell-culture models.
- Metabolic / Endocrine System: Antidiabetic, aldose reductase inhibition, AGE inhibition; preclinical.
- Cardiovascular System: Anti-atherosclerotic, anti-oxidative stress in heart failure models; preclinical.
- Immune System / Inflammation: NF-κB inhibition, cytokine suppression; preclinical.
- Endocrine (Estrogenic) System: Aromatase inhibition; preclinical interest in estrogen-dependent breast cancer.
- Skin: Tyrosinase inhibition (potential depigmenting), anticancer effects in skin carcinoma cell lines.
- Kidney: Antinephritic properties attributed in preclinical studies.
6. Dosage Forms and Reported Dosages
No clinically validated dosage regimen for humans exists. The following doses are derived exclusively from the experimental literature:
- In vitro studies: Typically at experimental doses of 10–100 µM in cell culture systems.
- Rodent xenograft model (cutaneous SCC): Butein was administered at 10, 20, and 40 mg/kg, reducing tumor volume by 39.21%, 63.44%, and 79.05%, respectively, without affecting body weight.
- Mouse sepsis model: Butein administered intraperitoneally at 10 mg/kg.
- Rat hepatotoxicity model: Butein administered orally at 50 and 100 mg/kg/day for 14 days before a toxic insult.
- Human dosages: No clinically studied dosages in humans are available due to the absence of human trials.
7. Pharmacokinetics and Bioavailability
A study reported that butein is a weakly basic compound that showed higher solubility in the basic pH range, indicating that the intestine is the major site of absorption.
In a study, the binding association of butein with human serum albumin (HSA) and its pharmacodynamics were assessed; investigators observed that butein binds to HSA mostly through hydrophobic interactions and effectively penetrates liposomes, thus enabling successful permeation into cell membranes.
Bioavailability is considered limited due to low aqueous solubility (lipophilic character), susceptibility to rapid phase II metabolism (glucuronidation and sulfation), and potential gut microbial transformation.
Butein's inherent challenges related to bioavailability in physiological environments necessitate innovative formulation strategies; developing delivery systems that enhance solubility, prolong circulation time, and ensure targeted delivery to specific tissues or organs could optimize its therapeutic impact. To this end, innovative novel delivery technologies such as bioengineering, nanoformulations, and encapsulation have been investigated.
8. Safety Considerations and Interactions
8.1 Overall Safety Profile
Long-term safety and potential toxicities associated with prolonged butein consumption require meticulous evaluation. Rigorous clinical investigations are needed to validate its safety, efficacy, and optimal dosing regimens in diverse patient populations; designing well-controlled trials that account for the multifaceted actions of butein and its potential interactions with other medications will be essential for establishing its clinical utility.
8.2 Hepatic Considerations from Source Plants
Toxicodendron vernicifluum (the lacquer tree), one of the richest botanical sources of butein, is itself known to be an allergenic and potentially hepatotoxic plant in crude form; however, this toxicity is attributed to urushiol and related constituents rather than to butein specifically. Butein as an isolated compound has been studied preclinically and found to be hepatoprotective rather than hepatotoxic, but the systemic safety profile of the isolated compound at higher or prolonged doses has not been formally evaluated in humans.
8.3 Interactions with Chemotherapy
The flavonoids butein and its analogues have been implicated as the active constituents behind the liver-protective effects of Butea monosperma extracts in experimental hepatotoxicity models. While this suggests a potentially protective role alongside some chemotherapeutic agents, the interaction of butein with cytotoxic drugs in clinical settings has not been evaluated.
8.4 Estrogenic/Anti-Estrogenic Considerations
Buteins possess a high ability to inhibit the aromatase process in the human body. This mechanism implies a potential to reduce circulating estrogen levels and could theoretically interact with hormone-sensitive conditions or medications. No clinical interaction data are available.
8.5 Bioavailability and Dose-Related Concerns
Potential dose-dependent adverse effects may be mitigated by improved delivery systems. Further, long-term safety and potential toxicities associated with prolonged butein consumption require meticulous evaluation. The existing preclinical animal studies used doses in the range of 10–100 mg/kg body weight without reporting significant acute toxicity, but these findings cannot be directly extrapolated to human clinical use.
8.6 Absence of Established Regulatory Status
As of the time this article was compiled, butein as an isolated compound has not received approval as a drug or received a formally established maximum safe dose from any major regulatory authority (FDA, EMA, WHO). It is consumed as part of whole-plant preparations and food products in several Asian countries, where its use is traditional, but no pharmacopoeial monograph specific to isolated butein has been identified in the sources available.
References
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