Apigenin

Last Updated: September 28 2022

One of the bioflavonoids, apigenin appears to be catered towards reducing anxiety and causing sedation. Found in chamomile tea, alcoholic beverages, and Bacopa Monnieri, apigenin is unstable by itself yet stable when consumed via foods and herbs.

Apigenin is most often used for


1.

Sources and Composition

1.1

Sources and Structure

Apigenin is a flavone compound found almost ubiquitously in plant compounds. It is most commonly isolated in abundance from the plant Matricaria recutita L, or Asteraceae.

Some of the more popular and abundant sources include chamomile tea[1] grapefruits, onions, oranges and some spices such as parsley.[2] and is also found in higher levels (relative to other foods) in celery, yarrow, tarragon, cilantro, foxglove, coneflower, licorice, flax, passion flower, horehound, spearmint, basil, and oregano.[3][4] It is also found in red wine[5] and beer[6] and is an active ingredient in the memory herb Gingko Biloba.[4] Chamomile is approximately 0.8-1.2% apigenin by weight.[2]

In food and herbal sources, the active apigenin is found in the form of various acylated derivates and Apigenin-7-O-glucoside.[7][8]

1.2

Physicochemical Properties

Apigenin itself is a low molecular weight (270.24) with a very high melting point (347.5)[4] It is very insoluble in water by itself, but can become soluble in dilute potassium hydrochloride or DimethylSulfoxide (DMSO).[4] The food borne apigenin, apigenin-7-O-glucoside, has increased water solubility via its carbohydrate containing bond.[9] Chemicular apigenin is highly unstable, although the food bound sources are more stable in normal environments.[10][11]

1.3

Formulations and Variants

A glycoside is a term used to refer to a molecule connected to sugar molecules. Glycosides tend to exist in plants as a storage form, and upon human consumption they can either be hydrolyzed into the molecule and sugars (two separate things to make note of) or remain bound together. For example, Cyanidin is a molecule while Cyanidin-3-O-Glucoside is a glycoside thereof that has some unique properties and can be detected in the blood after oral ingestion

Glycoside is a term that does not discriminate the sugar in concern, whereas the term glucoside may be used to refer to the same thing if the sugar is glucose

Apigenin-7-O-Apiosylglucoside (Apigenin bound at the 7-carbon to a glucose which is then bound to apiose, a pentacyclic sugar[12])

Apigenin bound to a glucose molecule at the 8 carbon is known as Vitexin, with the full name of Apigenin-8-O-glucoside.

Apigenin-7-O-Glucoside is known as Apigentrin.

Apigenin bound to a glucose molecule at the 6 carbon yields Apigenin-6-O-Glucoside and is also known as Isovitexin, homovitexin, or saponaretin.

Isovitexin can be further bound to another glucose at the 7 carbon to create Apigenin-6,7-Diglucoside, also known as Saponarin.

Apigenin bound to Neohesperidose (a disaccharide of Rhamnose and Glucose bound via an oxygen) results in a compound known as Rhoifolin

7-Methoxyapigenin is a molecule where the hydroxyl (-OH) group at the 7-carbon is replaced by a methoxy group (-OCH3).

If 7-Methoxyapigenin is bound to a glucose at the 6-carbon, it is known as Swertish; a diglucoside at this carbon results in Spinosin. If the glucose or diglucoside are bound to the 8-carbon, Puerarin and Isospinosin result (respectively); these 7-Methyoapigenin glycosides are known components of Ziziphus Jujuba

2.

Pharmacology

2.1

Distribution

Upon ingestion of apigenin, it is rapidly metabolized via UDP glucuronosyltransferase UGT1A1 and released into serum as glucuroside and sulfate conjugates.[4][13] It has a half-life of 91.8 hours, and apigenin appears in the blood 24 hours after initial ingestion.[13] It is mostly excreted via the urine in the form of glucurosides and sulfate conjugates, but there is some fecal excretion as well due to enterohepatic ejection.

3.

Neurology

3.1

GABAergic Neurotransmission

Apigenin possesses anxiolytic effects by acting as a benzodiazepine ligand, and has no muscle relaxant or sedative effects at normal dosages (3-10mg/kg bodyweight) but sedation was observed at 3 and 10-fold said dose.(30-100mg/kg bodyweight)[14]

3.2

Neurooxidation

Apigenin, in the form of Biapigenin, can exert a neuroprotective effect against excitotoxicity and prevent calcium build-up in neural mitochondria.[15]

4.

Interactions with Glucose Metabolism

4.1

Type II Diabetes

Apigenin and two glucopyranoside glycosides of Apigenin, from the plant Cephalotaxus sinensis of the Plum Yew family, have been shown to exert anti-diabetic effects in the body by potentiating the GLUT4 response to insulin.[16]

5.

Inflammation and Immunology

5.1

Macrophages

Apigenin exerts its anti-inflammatory effects via suppressing the induction of NO-synthase and COX2 enzymes in macrophages via lipopolysacchraide influence.[17] Apigenin also has inhibitory effects on Interleukin-4 production.[18][19] Apigenin may also suppress TNFa elevations via interference with NF-kb transcription[20] and potentially TNFa induced upregulation of adhesion molecule 1.[21]

6.

Interactions with Hormones

6.1

Testosterone

Apigenin can inhibit both aromatase and 17β-hydroxysteroid dehydrogenase (17β-HSD) with the inhibition of 17β-HSD being unique to apigenin and 3 other tested flavonoids (chrysin, genistein and naringenin)[22] and apigenin possessing an IC50 of 300nM (0.3μM). The IC50 of Apigenin on aromatase is approximately 2.9μM (most potent tested flavonoid on aromatase was 7-Hydroxyflavone at 0.21uM, outperforming the reference aminoglutethimide at 1.2uM[22]) and both of these enzymes are involved in testosterone synthesis at different stages.

Apigenin has been noted to directly block signalling through the thromboxane A2 (TBXA2) receptor in testicular leydig cells, reducing the ability of the TBXA2-COX2 pathway to induce a repressor protein known as DAX-1; as DAX-1 normally suppresses the transcription of a rate-limiting step of protein synthesis known as steroidogenic acute regulatory (StAR) protein, apigenin indirectly increased StAR activity and testosterone synthesis (induced by cAMP) in these cells.[23] This effect was concentration-dependent between 5-10μM with no effect at 1μM.[23]

Apigenin has been noted to modify a receptor (TBXA2) and an enzyme's activity (aromatase) in a manner which would be conducive to increasing testosterone activity, both at relatively low concentrations. It is uncertain what oral dose this translates to at this moment in time

6.2

Estrogen

Apigenin at 20μM in DU-125 and MDA-MB-231 breast cancer cells appears to inhibit proliferation and in yeast assays activated both subunits of the estrogen receptor (ERα and ERβ) but activated ERβ at a lower concentration (100nM) while activating ERβ to a higher degree than ERα at higher concentrations (1μM).[24]

6.3

Cortisol

In isolated human H295R adrenal cells, 12.5μM of Apigenin decreased cortisol to 47.5% of control (being outperformed by both soy isoflavones) with significant efficacy at 6μg/mL and greater.[25]

7.

Interaction with Cancer Metabolism

7.1

Angiogenesis

Apigenin has been noted to bind to the VEGF receptors including VEGFR1 (hydrogen bonding at Glu878, Cys912, and Asp1040) and VEGFR2 (Lys868, Cys919, Asp1046) which are similar to the binding sites as the angiogenesis inhibitor Axitinib while the mean binding energy of Apigenin (−8.56kcal/mol and −9.01kcal/mol on VEGFR1 and VEGFR2, respectively) was lower than Axitinib (−12.38kcal/mol and −12.20kcal/mol).[26]

7.2

Mechanisms

Apigenin is known as one of the bioflavonoid compounds in which has high selectivity to induce selective apoptosis of cancer cells in vivo.[27] Like other bioflavonoid compounds apigenin can reduce oxidative stress, induce cell cycle inhibition, increase hepatic detoxification enzyme efficacy, and act as anti-inflammatory to a degree.[28][29]

Laboratory animal studies suggest that apigenin exerts anti-mutagenic properties that occur in response to exogenous toxins and bacteria[30][31] and plays direct roles in metal chelation, free radical scavenging, and induction of phase II detoxification enzymes such as glutathione.[32][33] It is also an inhibitor of the enzyme ornithine decarboxylase, which may promote some tumor growth.[34]

The presence of Apigenin in vivo seems to exert acute protective effects against carcinogenic insults as well.[35][36]

Other receptor targets of apigenin that may influence carcinogenesis include Heat Shock Proteins[37], telomerase[38], fatty acid synthase[39], the aryl hydrocarbon receptor[40], casein kinase 2 alpha[41], HER2/neu[42], and matrix metalloproteinases[43] It is also a relatively weak xanthine oxidase inhibitor.[44]

According to Shukla and Gupta, there is very little evidence to date to suggest that apigenin promotes adverse metabolic reactions in vivo when consumed as part of a normal diet.[2] Apigenin beneficially affects most types of cancer.

8.

Safety and Toxicity

8.1

General

Apigenin, in doses consumed via food intake, not apparent toxicity has been reported.[10][11]

References
2.^Shukla S, Gupta SApigenin: a promising molecule for cancer preventionPharm Res.(2010 Jun)
3.^Birt DF, Hendrich S, Wang WDietary agents in cancer prevention: flavonoids and isoflavonoidsPharmacol Ther.(2001 May-Jun)
5.^Bevilacqua L, Buiarelli F, Coccioli F, Jasionowska RIdentification of compounds in wine by HPLC-tandem mass spectrometryAnn Chim.(2004 Sep-Oct)
7.^Svehliková V, Bennett RN, Mellon FA, Needs PW, Piacente S, Kroon PA, Bao YIsolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita (L.) Rauschert)Phytochemistry.(2004 Aug)
11.^Hollman PC, Katan MBHealth effects and bioavailability of dietary flavonolsFree Radic Res.(1999 Dec)
12.^Meyer H, Bolarinwa A, Wolfram G, Linseisen JBioavailability of apigenin from apiin-rich parsley in humansAnn Nutr Metab.(2006)
13.^Gradolatto A, Basly JP, Berges R, Teyssier C, Chagnon MC, Siess MH, Canivenc-Lavier MCPharmacokinetics and metabolism of apigenin in female and male rats after a single oral administrationDrug Metab Dispos.(2005 Jan)
14.^Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini ACApigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effectsPlanta Med.(1995 Jun)
16.^Li W, Dai RJ, Yu YH, Li L, Wu CM, Luan WW, Meng WW, Zhang XS, Deng YLAntihyperglycemic effect of Cephalotaxus sinensis leaves and GLUT-4 translocation facilitating activity of its flavonoid constituentsBiol Pharm Bull.(2007 Jun)
18.^Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, Kuwahara Y, Ohkawara T, Hagihara K, Yamadori T, Shima Y, Ogata A, Kawase I, Tanaka TFlavonoids and related compounds as anti-allergic substancesAllergol Int.(2007 Jun)
19.^Yano S, Umeda D, Yamashita T, Ninomiya Y, Sumida M, Fujimura Y, Yamada K, Tachibana HDietary flavones suppresses IgE and Th2 cytokines in OVA-immunized BALB/c miceEur J Nutr.(2007 Aug)
21.^Panés J, Gerritsen ME, Anderson DC, Miyasaka M, Granger DNApigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivoMicrocirculation.(1996 Sep)
22.^Le Bail JC, Laroche T, Marre-Fournier F, Habrioux GAromatase and 17beta-hydroxysteroid dehydrogenase inhibition by flavonoidsCancer Lett.(1998 Nov 13)
23.^Li W, Pandey AK, Yin X, Chen JJ, Stocco DM, Grammas P, Wang XEffects of apigenin on steroidogenesis and steroidogenic acute regulatory gene expression in mouse Leydig cellsJ Nutr Biochem.(2011 Mar)
24.^Mak P, Leung YK, Tang WY, Harwood C, Ho SMApigenin suppresses cancer cell growth through ERbetaNeoplasia.(2006 Nov)
25.^Ohno S, Shinoda S, Toyoshima S, Nakazawa H, Makino T, Nakajin SEffects of flavonoid phytochemicals on cortisol production and on activities of steroidogenic enzymes in human adrenocortical H295R cellsJ Steroid Biochem Mol Biol.(2002 Mar)
26.^Seo EJ, Kuete V, Kadioglu O, Krusche B, Schröder S, Greten HJ, Arend J, Lee IS, Efferth TAntiangiogenic activity and pharmacogenomics of medicinal plants from traditional korean medicineEvid Based Complement Alternat Med.(2013)
28.^O'Prey J, Brown J, Fleming J, Harrison PREffects of dietary flavonoids on major signal transduction pathways in human epithelial cellsBiochem Pharmacol.(2003 Dec 1)
29.^Surh YJCancer chemoprevention with dietary phytochemicalsNat Rev Cancer.(2003 Oct)
30.^Khan TH, Jahangir T, Prasad L, Sultana SInhibitory effect of apigenin on benzo(a)pyrene-mediated genotoxicity in Swiss albino miceJ Pharm Pharmacol.(2006 Dec)
35.^Birt DF, Mitchell D, Gold B, Pour P, Pinch HCInhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoidAnticancer Res.(1997 Jan-Feb)
38.^Menichincheri M, Ballinari D, Bargiotti A, Bonomini L, Ceccarelli W, D'Alessio R, Fretta A, Moll J, Polucci P, Soncini C, Tibolla M, Trosset JY, Vanotti ECatecholic flavonoids acting as telomerase inhibitorsJ Med Chem.(2004 Dec 16)
41.^Kim JS, Eom JI, Cheong JW, Choi AJ, Lee JK, Yang WI, Min YHProtein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemiaClin Cancer Res.(2007 Feb 1)
44.^Lin CM, Chen CT, Lee HH, Lin JKPrevention of cellular ROS damage by isovitexin and related flavonoidsPlanta Med.(2002 Apr)