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Apigenin

Apigenin is a naturally occurring , a subclass of characterized by a trihydroxyflavone structure with hydroxyl groups at positions 4', 5, and 7, and the molecular formula C₁₅H₁₀O₅. It appears as a solid with a molecular weight of 270.24 g/mol and a of 345–350 °C, exhibiting solubility in , , and dilute alkalies. Abundantly present in various fruits (such as cherries and apples), vegetables (including and ), herbs (like ), and beverages (such as and ), apigenin contributes to the nutritional profile of many common dietary plants. As a , apigenin demonstrates potent antioxidant and anti-inflammatory properties, primarily through scavenging free radicals, regulating pro-inflammatory cytokines, and modulating signaling pathways like and MAPK. It has shown promising effects in disease prevention, including suppressing cancer progression via induction of , cell-cycle arrest, and inhibition of , while exhibiting low toxicity to normal cells. Additionally, apigenin supports cardiovascular , , and management of conditions such as , , and organ injuries in the liver, kidney, and heart by reducing and enhancing cellular repair mechanisms. Research highlights apigenin's potential in enhancing efficacy and improving through nanoformulations, addressing its moderate challenges for therapeutic applications. Its role in promoting sleep and mitigating aging-related effects further underscores its multifaceted pharmacological profile, positioning it as a key dietary for .

Chemistry

Structure and Properties

Apigenin is a , a class of compounds, characterized by the molecular formula C₁₅H₁₀O₅. It features a basic flavone backbone consisting of two phenyl rings (A and B) connected by a heterocyclic pyrone ring (C), with hydroxyl groups attached at the 5, 7, and 4' positions, making it 5,7,4'-trihydroxyflavone. The compound has a of 270.24 g/mol and appears as a crystalline solid, often isolated as needles when crystallized from aqueous . It has a of 345–350 °C. Apigenin exhibits negligible in water (approximately 2.35 μg/mL), but it is soluble in organic solvents such as (DMSO, up to 54 mg/mL) and (1 mg/mL in hot ). In terms of spectral properties, apigenin displays characteristic UV-Vis absorption maxima at 269 nm and 340 nm in , corresponding to its conjugated aromatic system, which contributes to its yellow coloration. Historically, this pigmentation has led to its use as a natural for textiles, particularly in mordanting with to produce fast colors resistant to . Apigenin demonstrates basic stability under physiological conditions, remaining intact in rat plasma for up to 24 hours at room temperature and at least 4 weeks when frozen. Its reactivity includes the formation of conjugates, such as glucuronides and sulfates, through phase II metabolic processes, which enhance its solubility and facilitate excretion.

Biosynthesis

Apigenin is synthesized in plants via the phenylpropanoid pathway, a core metabolic route for secondary metabolites that begins primarily with the amino acid L-phenylalanine, though L-tyrosine serves as an alternative precursor in certain species through bifunctional enzymes. The pathway initiates with phenylalanine ammonia-lyase (PAL) or tyrosine ammonia-lyase (TAL), which deaminate these amino acids to yield trans-cinnamic acid or p-coumaric acid, respectively. Cinnamic acid is then hydroxylated by cinnamate 4-hydroxylase (C4H) to p-coumaric acid if starting from phenylalanine. This p-coumaric acid is subsequently activated by 4-coumarate:CoA ligase (4CL) to form p-coumaroyl-CoA, the key intermediate that branches into flavonoid biosynthesis. From p-coumaroyl-CoA, chalcone synthase (CHS) catalyzes the condensation with three molecules of to produce naringenin , the first committed flavonoid precursor. (CHI) then cyclizes naringenin chalcone to the flavanone naringenin through stereospecific isomerization. The final conversion to apigenin occurs via flavone synthase (FNS), which performs oxidative dehydration and aromatization of naringenin; in the family, this is mediated by the soluble FNS I, a Fe²⁺/2-oxoglutarate-dependent dioxygenase. Biosynthesis of apigenin exhibits tissue-specific regulation, particularly in species like (Petroselinum crispum), where FNS I expression is prominent in leaves and glandular structures to support accumulation. Genetic factors, including tandem duplications of flavanone 3-hydroxylase (F3H) leading to FNS I neofunctionalization, contribute to clustered biosynthetic in genomes, such as in and , enhancing pathway efficiency. Environmental cues like UV-B radiation and modulate pathway by upregulating key enzymes such as FNS and CHS, thereby increasing apigenin as a protective response against .

Occurrence

Natural Sources

Apigenin occurs in high concentrations in plants of the family, notably (Petroselinum crispum), where dried leaves can contain up to 45 mg/g dry weight, primarily as the aglycone and glycosides. (Apium graveolens) also accumulates significant amounts, with concentrations reaching 0.79 mg/g in seeds and 0.24 mg/g in aerial parts like leaves and stems. In the family, apigenin is prominent in (), constituting approximately 68% of total in dried flowers, with overall contents of 3–5 mg/g dry weight. Various species, such as A. annua and A. vestita, contain apigenin in their aerial parts and roots, often as C- and O-glycosides, with accumulation varying by species and environmental factors. Herbs like ( vulgare) accumulate up to 14 mg/g total apigenin in dried samples, while () shows lower levels around 0.04 mg/g in dried leaves. Ecologically, apigenin contributes to and , absorbing UV-B radiation to protect tissues from photodamage, as demonstrated in where synthase enzymes produce apigenin in response to UV exposure. As part of pigments, it also aids in attraction by enhancing flower coloration and signaling in species like .

Glycosides

Apigenin occurs in nature predominantly as glycosides, where sugar moieties are attached to the flavonoid core, forming O-glycosides or C-glycosides that modify its chemical properties. Major glycosides include apigetrin (apigenin-7-O-glucoside), an O-linked form with a glucose attached at the 7-position of the B-ring; vitexin (apigenin-8-C-glucoside), a C-linked variant with glucose bound directly to the 8-position of the A-ring; isovitexin (apigenin-6-C-glucoside), similarly C-linked but at the 6-position; and rhoifolin (apigenin-7-O-rutinoside), featuring a (rutinose, composed of and glucose) at the 7-position. Another notable example is apiin, a complex O-glycoside with an apiosyl-glucose unit at the 7-position. These glycosides are formed in through the action of UDP-glycosyltransferases (UGTs), enzymes that catalyze the transfer of activated sugars, such as UDP-glucose or UDP-rhamnose, to specific hydroxyl (for O-glycosides) or carbon (for C-glycosides) positions on the apigenin aglycone, typically at sites 5, 7, or 6/8. This enhances the molecule's water —up to several orders of magnitude higher than the aglycone (which has a solubility of approximately 0.00135 mg/mL)—and improves against degradation, facilitating storage and transport within tissues. In terms of distribution, apigenin glycosides are widespread in various plant families, with specific prevalence in certain species; for instance, and isovitexin are abundant in leaves (e.g., up to 2.78 mg/g for related isomers), while apiin predominates in seeds and leaves of plants like . Rhoifolin occurs in fruits and herbs such as . Analytical identification of these glycosides commonly employs coupled with (HPLC-MS), which separates and characterizes them based on retention times, mass-to-charge ratios, and fragmentation patterns, enabling precise quantification in plant extracts. Compared to the free aglycone form, glycosylated apigenin exhibits superior due to increased , allowing better and uptake in biological systems, though the exact mechanisms vary by type. In plants, these conjugates serve as storage forms of the , acting as inactive reservoirs that can be hydrolyzed to release active aglycones during stress responses, such as UV exposure or attack, thereby contributing to and metabolic regulation.

Dietary Aspects

Food Sources

Apigenin is most abundantly found in certain edible herbs and vegetables, with parsley serving as one of the richest sources. Dried parsley contains approximately 4503 mg of apigenin per 100 g, while fresh parsley provides about 215 mg per 100 g. Celery hearts contribute around 19 mg per 100 g, making them a notable vegetable source. In chamomile flowers, used to prepare tea, apigenin constitutes up to 68% of the total flavonoids. Dietary exposure to apigenin varies significantly based on food preparation methods. Drying concentrates apigenin levels in herbs like parsley by removing water content, whereas fresh forms retain lower concentrations due to higher moisture. For beverages such as chamomile tea, brewing time influences extraction; longer steeping (e.g., 5-10 minutes) can increase apigenin yield from 1.5 mg to 5 mg per cup, depending on flower quality and water temperature. Herbs like parsley and thyme, vegetables including celery and artichokes, and herbal teas collectively account for the majority of apigenin in typical diets. Global dietary intake estimates indicate that apigenin is a minor component of overall consumption. In the average diet, daily apigenin intake ranges from 0.13 to 1.35 mg among middle-aged and , while in it averages 4.23 mg per day. These levels reflect moderate contributions from everyday foods rather than high-dose sources. Several factors influence apigenin concentrations in foods. practices, such as and sunlight exposure, can vary levels by up to 20-30% across growing regions. Seasonal differences affect , with higher accumulation in summer-harvested and . Processing methods, including thermal treatments like or , lead to losses of 10-50% due to at elevated temperatures or pH shifts above 5.

Absorption and Metabolism

Apigenin exhibits low oral , estimated at approximately 5-10% in humans, primarily attributed to its poor water solubility (around 2.16 μg/mL) and extensive first-pass . Following dietary intake, apigenin is mainly absorbed in the , particularly the and , through passive across the , with involvement of efflux transporters such as (P-gp) and multidrug resistance-associated protein 2 (ABCC2) that can limit uptake. This process is saturable and occurs within 3.9 to 24 hours post-ingestion, resulting in peak plasma concentrations of about 127 nM in human studies. In terms of metabolism, apigenin undergoes phase I oxidation primarily in the liver via enzymes, including and , leading to hydroxylated metabolites such as . Phase II conjugation follows, with extensive and sulfation by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) in the liver and intestine, producing water-soluble conjugates like apigenin glucuronides and sulfates. For dietary glycosides, such as apigenin-7-glucoside, play a crucial role in initial deglycosylation through beta-glucosidase activity in the colon, releasing free aglycone apigenin for subsequent absorption; this microbial transformation enhances overall compared to the intact . Enterohepatic recirculation of these conjugates, via biliary back into the intestine, further prolongs systemic exposure. Excretion of apigenin occurs predominantly through as conjugated metabolites (accounting for about 51% of the dose in preclinical models) and to a lesser extent via (around 12%), with unabsorbed portions eliminated directly in the gut. The half-life of apigenin is approximately 4-8 hours in s, reflecting rapid clearance, though terminal elimination can extend longer due to recirculation and tissue distribution. Chronic dietary intake may lead to potential accumulation in tissues like the liver, as evidenced by detection in models up to 9 days post-dose, underscoring the need for further studies on long-term .

Biological Effects

Pharmacological Mechanisms

Apigenin exerts effects primarily through its interaction with the type A (GABA_A) receptor, where it binds competitively to the site located at the α-γ subunit interface, thereby enhancing GABA-mediated chloride influx and hyperpolarization of neurons. studies using recombinant GABA_A receptors (e.g., α1β2γ2 subtypes) demonstrate that apigenin acts as a , enhancing GABA-induced currents at concentrations around 1-10 μM. This is consistent with its moderate affinity (Ki ≈ 4-30 μM) for the site as measured by displacement of radiolabeled in rat brain membranes. Animal models, such as elevated plus-maze tests in mice, confirm this mechanism, showing dose-dependent activity (e.g., 0.5-5 mg/kg orally) that aligns with site involvement, as effects in related studies are reversed by the . Early reports indicated conflicting potency data, with some suggesting insensitivity to and potential allosteric modulation outside the classical site; however, post-2020 structural analyses of -GABA_A interactions, including cryo-EM models of flavone-bound receptors, have clarified that apigenin's effects arise from site occupancy with subtype-specific variations (e.g., stronger potentiation at α2/3-containing receptors). In terms of anti-inflammatory actions, apigenin inhibits key enzymes in the pathway, including (COX-2) and (LOX), thereby reducing and production that drive . For instance, in (LPS)-stimulated macrophages, apigenin (10-50 μM) suppresses COX-2 expression and activity by 40-60%, as evidenced by decreased PGE2 release in vitro and in models of acute (e.g., carrageenan-induced paw edema). Similarly, it exhibits weak but measurable LOX inhibition ( ≈ 100 μM for 5-LOX in cell-free assays), contributing to reduced in activated neutrophils. Complementing these enzymatic effects, apigenin activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, promoting translocation of Nrf2 to the and upregulation of genes such as oxygenase-1 (HO-1) and NAD(P)H 1 (NQO1). In oxidative stress models, like H2O2-treated human melanocytes or rat kidney cells under high-fat diet conditions, apigenin (5-20 μM) enhances Nrf2 nuclear accumulation by 2-3 fold, mitigating (ROS) and without altering levels directly. Apigenin also modulates estrogen signaling by interacting with estrogen receptors (ERα and ERβ) and inhibiting , the enzyme converting androgens to estrogens. It acts as a selective ER modulator, preferentially activating ERβ (EC50 ≈ 10 μM in reporter assays) over ERα, which promotes antiproliferative effects in ER-positive cells like lines. In vitro binding studies show apigenin displaces from ERβ with higher affinity (Ki ≈ 50 μM) than ERα, leading to recruitment of corepressors and suppression of estrogen-responsive genes in MCF-7 cells. Concurrently, apigenin inhibits aromatase activity (IC50 ≈ 0.5-10 μM in microsomal assays from placental ), reducing biosynthesis by up to 70% in preclinical models of hormone-dependent cancers. In immune cells, such as macrophages and mast cells, apigenin interferes with nuclear factor-κB (NF-κB) signaling by inhibiting IκB kinase (IKK) phosphorylation and p65 nuclear translocation, thereby attenuating pro-inflammatory production (e.g., TNF-α, IL-6 reduced by 50-80% at 20-50 μM in LPS-challenged models). Animal studies corroborate this, with oral apigenin (20 mg/kg) suppressing NF-κB activation in TRAMP mouse prostates, linking it to reduced immune-mediated .

Health Applications and Safety

Apigenin has been investigated for its potential and -promoting effects, primarily through studies on extracts containing the compound. Clinical trials involving tea or extracts, standardized to apigenin content, have demonstrated mild reductions in anxiety symptoms and improvements in quality, particularly in individuals with or , at doses equivalent to 50-100 mg of apigenin daily. A 2024 of randomized controlled trials confirmed these benefits, noting decreased awakenings and better maintenance, though effects were modest and more pronounced in short-term use. In , apigenin exhibits anti-proliferative effects by inducing in and cells through inhibition of the PI3K/Akt pathway. Limited evidence comes from Phase I trials, such as a pilot study in high-risk patients testing apigenin supplementation from sources, which assessed safety and tolerability without reporting significant adverse events or efficacy endpoints yet. Another early-phase trial explored its role in gastrointestinal cancers, highlighting potential chemopreventive actions but emphasizing the need for further validation. Neuroprotective properties of apigenin have been observed in models, where it reduces amyloid-beta deposition and inhibits hyperphosphorylation, thereby mitigating neuronal damage. A 2023 study in animal models demonstrated apigenin's ability to lower amyloid-beta levels and improve cognitive function, supporting its role in attenuating and oxidative stress associated with the disease. For applications, apigenin shows promise in management, with animal studies indicating suppression of progression via enhanced mitophagy and reduced pyroptosis. Human observational data link higher intake, including apigenin, to lower risk, while a clinical study using oil rich in apigenin glycosides reported significant relief in patients. Apigenin is (GRAS) by the FDA when consumed as part of extracts, with no major observed in up to doses of 50 mg/kg body weight. Rare side effects include allergic reactions in sensitive individuals, similar to those from . It may interact with CYP450 substrates, such as sedatives, by inhibiting enzymes like and CYP4F2, potentially enhancing their effects or leading to ; caution is advised with concurrent use. Subacute toxicity studies report a (NOAEL) of 75 mg/kg for apigenin glycosides, with an LD50 exceeding 4800 mg/kg in . Despite these findings, evidence gaps persist, including the lack of large-scale randomized controlled trials (RCTs) to confirm clinical across applications. Recent 2024 reviews highlight advancements in delivery systems, such as nanoemulsions and nanoparticles, which improve apigenin's poor and stability, potentially enabling higher therapeutic doses with reduced gastrointestinal inactivation. As of 2025, comprehensive reviews continue to affirm apigenin's multifaceted pharmacological profile and explore emerging applications in neurodegeneration, , and bone protection.