Apigenin

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Apigenin is a Bioflavonoids compound (specifically a flavone) which is found in a wide variety of plants and herbs. It is very abundant in chamomile tea, and exerts Anxiety-reducing effects when consumed in these high doses. At even higher doses, it may be sedative.

Apigenin is also a very potent anti-cancer compound. It beneficially protects against a wide variety of cancers with high selectivity for cancer cells as opposed to non-cancerous cells. It also has a very high safety threshold, and active (anti-cancer) doses can be gained through consuming a vegetable and fruit rich diet.

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For general health and well-being, doses found in multiple servings of fruits and vegetables is adequate.

For anxiolytic effects, doses in the range of 3-10mg/kg bodyweight are effective without sedation, and higher doses induce sedation in addition to reductions in anxiety.

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Edit1. Sources and composition

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]

1.1. Structure

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]

Edit2. Notable Glycosides and Conjugates

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

2.1. Apigenin-7-O-Apioglucoside (Apiin)

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

2.2. Apigenin-8-O-Glucoside (Vitexin)

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

2.3. Apigenin-7-O-Glucoside (Apigentrin)

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

2.4. Apigenin-6-O-Glucoside (Isovitexin)

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.

2.5. Apigenin-7-O-Neohesperoside (Rhoifolin)

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

2.6. 7-Methoxyapigenin

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

Edit3. Pharmacology

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.

Edit4. Neurology

Apigenin possesses anxiolytic effects by acting as a benxodiazepine 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]

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

Edit5. Interactions with Glucose Metabolism

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]

Edit6. Inflammation and Immunology

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]

Edit7. Interactions with Hormones

7.1. Enzymatic Interactions

Apigenin can inhibit both aromatase and 17β-hydroxysteroid dehydrogenase, with the inhibition of 17β-HSD being unique to apigenin and 3 other tested flavonoids (Chrysin, genistein and naringenin)^[22] with an IC₅₀ of 0.3μM; the IC₅₀ of Apigenin on aromatase was 2.9μM (most potent tested compound on aromatase being 7-Hydroxyflavone at 0.21uM, outperforming aminoglutethimide at 1.2uM)^[22]

7.2. Testosterone

Apigenin appears to be an antagonist of the Thromboxane A2 receptor on Leydig cells. The activation of this receptor induces DAX-1 expression that negatively regulates StAR protein expression and subsequently reduces testosterone secretion, while inhibition of this receptor preserves StAR protein content in response to Thromboxane A2.^[23]

7.3. Estrogen

Apigenin at 20uM 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 (1uM).^[24]

7.4. Cortisol

In isolated human H295R adrenal cells, 12.5uM of Apigenin decreased cortisol to 47.5% of control (being outperformed by both Soy Isoflavones) with significant efficacy at 6ug/mL and greater.^[25]

Edit8. Interaction with Cancer Metabolism

Apigenin is known as one of the Bioflavonoids compounds in which has high selectivity to induce selective apoptosis of cancer cells in vivo.^[26] 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.^[27][28]

Laboratory animal studies suggest that apigenin exerts anti-mutagenic properties that occur in response to exogenous toxins and bacteria^[29][30] and plays direct roles in metal chelation, free radical scavenging, and induction of phase II detoxification enzymes such as glutathione.^[31][32] It is also an inhibitor of the enzyme ornithine decarboxylase, which may promote some tumor growth.^[33]

The presence of Apigenin in vivo seems to exert acute protective effects against carcinogenic insults as well.^[34][35]

Other receptor targets of apigenin that may influence carcinogenesis include Heat Shock Proteins^[36], telomerase^[37], fatty acid synthase^[38], the aryl hydrocarbon receptor^[39], casein kinase 2 alpha^[40], HER2/neu^[41], and matrix metalloproteinases^[42] It is also a relatively weak xanthine oxidase inhibitor.^[43]

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.

Edit9. Safety and Toxicity

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

References

1. McKay DL, Blumberg JB. A review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.). Phytother Res. (2006)
2. Shukla S, Gupta S. Apigenin: a promising molecule for cancer prevention. Pharm Res. (2010)
3. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. (2001)
4. Patel D, Shukla S, Gupta S. Apigenin and cancer chemoprevention: progress, potential and promise (review). Int J Oncol. (2007)
5. Bevilacqua L, et al. Identification of compounds in wine by HPLC-tandem mass spectrometry. Ann Chim. (2004)
6. Gerhäuser C. Beer constituents as potential cancer chemopreventive agents. Eur J Cancer. (2005)
7. Svehliková V, et al. Isolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita (L.) Rauschert). Phytochemistry. (2004)
8. Polyphenols: food sources and bioavailability
9. Tolstikova TG, Khvostov MV, Bryzgalov AO. The complexes of drugs with carbohydrate-containing plant metabolites as pharmacologically promising agents. Mini Rev Med Chem. (2009)
10. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr. (2002)
11. Hollman PC, Katan MB. Health effects and bioavailability of dietary flavonols. Free Radic Res. (1999)
12. Meyer H, et al. Bioavailability of apigenin from apiin-rich parsley in humans. Ann Nutr Metab. (2006)
13. Gradolatto A, et al. Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug Metab Dispos. (2005)
14. Viola H, et al. Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Med. (1995)
15. Silva B, et al. Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults. Neurotox Res. (2008)
16. Li W, et al. Antihyperglycemic effect of Cephalotaxus sinensis leaves and GLUT-4 translocation facilitating activity of its flavonoid constituents. Biol Pharm Bull. (2007)
17. Liang YC, et al. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis. (1999)
18. Kawai M, et al. Flavonoids and related compounds as anti-allergic substances. Allergol Int. (2007)
19. Yano S, et al. Dietary flavones suppresses IgE and Th2 cytokines in OVA-immunized BALB/c mice. Eur J Nutr. (2007)
20. Choi JS, et al. Flavones mitigate tumor necrosis factor-alpha-induced adhesion molecule upregulation in cultured human endothelial cells: role of nuclear factor-kappa B. J Nutr. (2004)
21. Panés J, et al. Apigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivo. Microcirculation. (1996)
22. Le Bail JC, et al. Aromatase and 17beta-hydroxysteroid dehydrogenase inhibition by flavonoids. Cancer Lett. (1998)
23. Li W, et al. Effects of apigenin on steroidogenesis and steroidogenic acute regulatory gene expression in mouse Leydig cells. J Nutr Biochem. (2011)
24. Mak P, et al. Apigenin suppresses cancer cell growth through ERbeta. Neoplasia. (2006)
25. Ohno S, et al. Effects of flavonoid phytochemicals on cortisol production and on activities of steroidogenic enzymes in human adrenocortical H295R cells. J Steroid Biochem Mol Biol. (2002)
26. Gupta S, Afaq F, Mukhtar H. Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun. (2001)
27. O'Prey J, et al. Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochem Pharmacol. (2003)
28. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. (2003)
29. Khan TH, et al. Inhibitory effect of apigenin on benzo(a)pyrene-mediated genotoxicity in Swiss albino mice. J Pharm Pharmacol. (2006)
30. Kuo ML, Lee KC, Lin JK. Genotoxicities of nitropyrenes and their modulation by apigenin, tannic acid, ellagic acid and indole-3-carbinol in the Salmonella and CHO systems. Mutat Res. (1992)
31. Myhrstad MC, et al. Flavonoids increase the intracellular glutathione level by transactivation of the gamma-glutamylcysteine synthetase catalytical subunit promoter. Free Radic Biol Med. (2002)
32. Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. (2000)
33. Wei H, et al. Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice. Cancer Res. (1990)
34. Birt DF, et al. Inhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoid. Anticancer Res. (1997)
35. Van Dross R, et al. The chemopreventive bioflavonoid apigenin modulates signal transduction pathways in keratinocyte and colon carcinoma cell lines. J Nutr. (2003)
36. Osada M, Imaoka S, Funae Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein. FEBS Lett. (2004)
37. Menichincheri M, et al. Catecholic flavonoids acting as telomerase inhibitors. J Med Chem. (2004)
38. Brusselmans K, et al. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J Biol Chem. (2005)
39. Reiners JJ Jr, Clift R, Mathieu P. Suppression of cell cycle progression by flavonoids: dependence on the aryl hydrocarbon receptor. Carcinogenesis. (1999)
40. Kim JS, et al. Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res. (2007)
41. Way TD, Kao MC, Lin JK. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem. (2004)
42. Kim MH. Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. J Cell Biochem. (2003)
43. Lin CM, et al. Prevention of cellular ROS damage by isovitexin and related flavonoids. Planta Med. (2002)

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