Myricetin

One of the many Bioflavonoids, usually investigated as being more involved with anti-osteoporotic effects and bone health than other flavonoids like Kaempferol or Quercetin.

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Also Known As

3,3',4',5,5',7-hexahydroxyflavone


Do Not Confuse With

Myricitrin (the 3-O-rhamnoside of Myricetin), Myristin and Myristicin (components of Nutmeg), Myristica fragrans (the plant called 'Nutmeg')


Things to Note

  • Appears to be able to inhibit CYP2C9 and CYP3A4 activity (2-8mg/kg myricetin orally to rats)

Is a Form of


Caution Notice

Known to interact with enzymes of drug metabolism

Examine.com Medical Disclaimer
Table of Contents:


Edit1. Sources and Structure

1.1. Sources

Myricetin (3,3′,4′,5,5′,7-hexahydroxyflavone) is a bioflavonoid compound of the flavanol class.

Myricetin can be detected in numerous supplements including:

  • Blueberry leaves[1] and rose petals (Rosa damascena)[2]
  • Oranges (0.01mg/100g fruit weight)[3]
  • Sea Buckthorn at 27.1-161.7µg/g depending on the part of the plant assessed[4]
  • Chia seeds (Salvia hispanica) at 986.5µg/g[5]
  • Japanese raisin tree (Hovenia dulcis)[6]
  • Carob extract (Ceratonia siliqua) at 1486.0+/-61.9mg/kg[7]
  • Pistachio extract (Pistacia lentiscus) 1331.5+/-55.5mg/kg[7]
  • Grape Seed Extract (23.3+/-1.0mg/kg)[7]
  • Cruciferous vegetables such as broccoli (62.5+/-0.06mg/kg dry weight), cabbage (147.5+/-0.05mg/kg), chinese cabbage (31.0+/-0.10mg/kg), but not cauliflower nor kailan[8]
  • Peppers (capsicum family) including red chili (29.5+/-0.04mg/kg dry weight), green chili (11.5+/-0.02mg/kg), bell pepper (171.5+/-0.02mg/kg) and bird chili (236.0+/-0.03mg/kg);[8] bell peppers have previously been noted to have minimal levels[9]
  • Garlic (up to 693.0+/-0.05mg/kg dry weight,[8] but once undetectable[10]); not detected in other allium vegetables such as onion or chives[8]
  • Camellia sinensis (black tea tested) at 303.0+/-0.02mg/kg[8]
  • Asam gelugor (Garcinia atroviridus) at 77.0+/-0.07mg/kg[8]
  • Semambu (leaves; Calamus scipronum)853.0+/-0.06mg/kg dry weight[8]
  • Kesom (leaves; Polygonum  minus) 126.5+/-0.02mg/kg dry weight[8]
  • Maman (Gynandropsis gynandra) 129.0+/-0.09mg/kg dry weight[8]
  • Kadok (Piper sarmentosum) 55.5+/-0.07mg/kg dry weight[8]
  • Cashew shoots (Anacardium occidentale) at 188.0+/-0.01mg/kg dry weight[8]
  • French bean (Phaseolus vulgaris) at 47.0+/-0.04mg/kg dry weight[8]
  • Angular loofah (Luffa acutangula) at 433.5+/-0.04mg/kg dry weight[8]
  • Guava (Psidium guajava) at 549.5+/-0.05mg/kg dry weight[8]

1.2. Physicochemical Properties

Myricetin is chemically known as 3,3′,4′,5,5′,7-hexahydroxyflavone. It is thought to possess a larger antioxidant property than other flavonoids due to possessing three hydroxyl groups on the B ring (which, as they are beside each other, form catechol groups) and since the double bonded oxygen group is beside two hydroxyl groups, each of which can aid in mineral chelation in vitro.[11][12] There is a prooxidative effect possible with this structure as the catechol groups can form semi-quinone radicals following oxidation, and the 4-hydroxyl group on the C ring (to the right of the ketone) and the 4-hydroxyl on the B ring (middle hydroxyl) can form a quinine methide following oxidation.[12]

Secondary to the structure of Myricetin (depicted above), it possesses both prooxidative and antioxidative properties depending on the context of the system it is in. It is one of the more hydroxylated flavanol structures

Removing the right-most hydroxyl group (5'-hydroxyl) on the B ring creates Quercetin, and then removing the hydroxyl on the right side of the ketone group (on the C ring) from quercetin creates Luteolin. Working back to the myricetin structure, if you remove both the 3-hydroxyl and 5-hydroxyl groups (ie. not the middle one) on the B ring you get Kaempferol, and removing the hydroxyl to the right of the ketone group again will create Apigenin; the isomer for apigenin is Naringenin. Removing all hydroxyls from the B ring results in Galangin, and removing the 4-hydroxyl from the C ring then results in Chrysin.

1.3. Variants and Formulations

A variant of myricetin known as Dihydromyricetin (DHM; also known as Ampelopsin) is a major component of Hovenia dulcis.[6]

Various known glycosides include a 3-arabinogalactose (in Hibiscus sabdariffa calices[13]).


Edit2. Molecular Targets

2.1. PDEs

Myricetin has been noted to have inhibitory potential towards four of the five major phosphodiesterase (PDE) enzymes with IC50 values of 24.9+/-3.6µM (PDE1), 12.8+/-0.6µM (PDE2), 12.4+/-3.3µM (PDE3), 39.8+/-2.1µM (PDE4), and no significant inhibitory effect on PDE5 under 100µM.[14]


Edit3. Pharmacology

3.1. Phase I Enzyme Interactions

Myricetin has been noted to inhibit the aromatase enzyme (mediates the conversion of testosterone to estrogen) with an IC50 value of 10µM, a potency greater than most flavonoids and similar to gossypetin (11µM) but less than liquirtigenin (highest in Licorice) at 340nM.[15] When tested in human granulosa-like KGN cells, estrogen biosynthesis is inhibited by myricetin by 20% at 0.1-1μM, and this was less potent than the other tested flavonoid luteolin (IC50 1.17μM, although it worked via suppressing aromatase transcription rather than inhibiting the enzyme).[16]

Concentrations of 10µM myricetin have failed to inhibit estrogen biosynthesis[16] and 50µM failed to have an influence in the rat hippocampus.[17]

Myricetin has been noted to inhibit CYP3A4 (IC50 7.81μM) and CYP2C9 (IC50 13.5μM) assessed via a CYP inhibition test (GENTEST).[18]

P-glycoprotein appears to be inhibited by Myricetin in the concentration range of 3-30μM with no apparent concentration dependence to around a doubling at 10μM, as assessed via Rhodamine-123 retentionin MCF-7 cells.[18]

3.2. Drug Interactions

In rats given oral or intravenous tamoxifen, myricetin (2-8mg/kg orally 30 minutes prior to the drug, 400mcg/kg was ineffective) was able to increase the drugs oral Cmax (48.4–81.7%) and AUC0-∞ (41.8–74.4) with no significant influence on Tmax or half-life.[18] The metabolite 4-hydroxytamoxifen had its AUC decreased by 40.1% only at 8mg/kg myricetin.[18]


Edit4. Longevity

4.1. Non-Mammalian Interventions

Myricetin has been noted to prolong average (18%) and maximal (21.7%) lifespan in C. Elegans , which was a potency greater than other tested flavanols (quercetin, kaempferol, and naringenin) associated with reducing oxidative damage to the mitochondrial and proteins;[19] when tested in mev-1(kn1) mutants (reduced lifespan[20] associated with higher mitochondrial oxidative stress[21]) all flavonoids reduced mitochondrial oxidative stress (in a manner not related to DAF-16 translocation) yet only myricetin increased average lifespan (16%) in these mutants.[19] Oddly, all tested flavonoids were able to induce DAF-16 translocation.[19]

Elsewhere, DAF-16 (the human homologue is FOXO) was confirmed to modulate the effects of myricetin on increasing average lifespan (32.9%) in C. Elegans as there was no influence on SKN-1 (human homologue is Nrf2) and abolishign DAF-16 function prevented myricetin from enhancing lifespan.[11] There was no influence of myricetin on thermal stress to C. Elegans and food intake in C. Elegans was not altered (since a reduction in food intake via caloric restriction can increase lifespan).[11]

Myricetin appears to prolong lifespan in nematodes secondary to activating the DAF-16 (FOXO human homologue) pathway, and does not appear to increase stress resistance in nematodes


Edit5. Neurology

5.1. Melatonergic Neurotransmission

Myricetin has been found to be an inhibitor of the serotonin N-acetyltransferase (AANAT) enzyme, and secondary to this can suppress serum Melatonin concentrations during both waking and dark hours in rats.[22]


Edit6. Cardiovascular Health

6.1. Atherosclerosis

In an LDL oxidation assay, it was found that myricetin could inhibit LDL oxidation with an IC50 of 0.447µM, which was comparbale to quercetin and other flavonoids but greater than that of Vitamin C (1.45µM) and Vitamin E (2.4µM) as references and less than epigallocatechin-3-O-gallate (70nM).[23]


Edit7. Interactions with Glucose Metabolism

7.1. Blood Glucose

In studies done in rats with injected myricetin, it has been noted that myricetin decreases blood glucose levels in a dose-dependent manner and ameliorates the adverse effects of metabolic syndrome during co-ingestion.[24][25] The mechanism of action appears to be through potentiating insulin-dependent GLUT4 translocation via phosphatidylinositol 3-kinase (PI3K) and insulin receptor substrate-1 (IRS-1), although it has also been shown to improve blood glucose uptake independent of insulin.[26]

Similar to Kaempferol, myricetin seems to be able to reduce blood glucose levels by increasing myocyte uptake as well as increasing hepatic glycogen synthesis.[27]

The latter study was also via injection, and noted enhanced hepatic glycogen synthesis. Effects were noted at concentrations of 0.1uM-10.0uM, which correlated into an effective dose of 1.0mg/kg BW.


Edit8. Fat Mass and Obesity

8.1. Adipogenesis

Myricetin, like the Bioflavonoids Quercetin and catechin-gallate (one of the four catechins of Green Tea) have been shown to inhibit glucose uptake into cultured rat adipocytes; the opposite effect as is seen in myocytes.[28]


Edit9. Bone and Joint Health

9.1. Osteoblasts

In vitro studies suggest that myricetin is able to prevent oxidative damage in osteoblasts and potentially protect against osteoporosis by this mechanism and others (such as increased calcium deposition). This effect was noted at a concentration of 20uM.[29]


Edit10. Interactions with Hormones

10.1. Estrogen

Myricetin is able to activate the alpha subset of the estrogen receptor (ERα) in a concentration dependent manner between 10-1,000nM and activated genetic transcription thereof; myricetin competes with 17β-estradiol at both the ERα and ERβ receptors but only the former seems to be relevant, and all these effects were mimicked with a similar potency by Piceatannol.[30]


Edit11. Interactions with Oxidation

11.1. General

Relative to other flavonoids, those with three hydroxyls on the B ring appear to have highest antioxidant potency;[31] this means myricetin and robinetin, both of which slightly exceed the potency of quercetin and fisetin.[31][32]

Myricetin (786nM) is actually antagonistic to the antoxidative properties of naringenin (2.61μM) unless in the presence of Hesperidin (10.2μM) as assessed in an ORAC assay,[3] and when testing all three alongside each other they appear to be synergistic, and myricetin alone was synergistic with hesperidin.[3]


Edit12. Interactions with Cancer Metabolism

12.1. Prostate

When looking at dietary correlates, a higher myricetin intake appears to be associated with a reduced risk for prostate cancer.[33]

12.2. Pancreatic

When looking at dietary correlates, a higher myricetin intake appears to be associated with a reduced risk for pancreatic cancer.[34]


Edit13. Sexuality and Pregnancy

13.1. Fertility

In ejaculate from fertile men, incubating myricetin (10-100nM) increased sperm motility by 25-50% while 1µM caused a slight decline; similar trends were noted in viability where 10-100nM increase it by 20-30% relative to control.[35] This increase in seminal parameters was dependent on both estrogen receptors and PI3K/Akt, as it seens that myricetin (as well as 17β-estradiol itself[36]) influence estrogen signalling to phosphorylate Akt via PI3K, and the increased Akt phosphorylation increases cell viability.[35] There is also an increase in the acrosome reaction in these phytoestrogen treated sperm cells five-fold at 100nM only,[35] which is indicative of increased seminal fertility.[37]

References

  1. Abidov M, et al. Effect of Blueberin on fasting glucose, C-reactive protein and plasma aminotransferases, in female volunteers with diabetes type 2: double-blind, placebo controlled clinical study. Georgian Med News. (2006)
  2. Kumar N, et al. Reversed phase-HPLC for rapid determination of polyphenols in flowers of rose species. J Sep Sci. (2008)
  3. Freeman BL, Eggett DL, Parker TL. Synergistic and antagonistic interactions of phenolic compounds found in navel oranges. J Food Sci. (2010)
  4. Sharma UK, et al. Microwave-assisted efficient extraction of different parts of Hippophae rhamnoides for the comparative evaluation of antioxidant activity and quantification of its phenolic constituents by reverse-phase high-performance liquid chromatography (RP-HPLC). J Agric Food Chem. (2008)
  5. Chia Seeds as a Source of Natural Lipid Antioxidants
  6. Yoshikawa M, et al. Bioactive constituents of Chinese natural medicines. III. Absolute stereostructures of new dihydroflavonols, hovenitins I, II, and III, isolated from hoveniae semen seu fructus, the seed and fruit of Hovenia dulcis THUNB. (Rhamnaceae): inhibitory effect on alcohol-induced muscular relaxation and hepatoprotective activity. Yakugaku Zasshi. (1997)
  7. Vaya J, Mahmood S. Flavonoid content in leaf extracts of the fig (Ficus carica L.), carob (Ceratonia siliqua L.) and pistachio (Pistacia lentiscus L.). Biofactors. (2006)
  8. Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem. (2001)
  9. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands
  10. Beato VM, et al. Changes in phenolic compounds in garlic (Allium sativum L.) owing to the cultivar and location of growth. Plant Foods Hum Nutr. (2011)
  11. Büchter C, et al. Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16. Int J Mol Sci. (2013)
  12. Chobot V, Hadacek F. Exploration of pro-oxidant and antioxidant activities of the flavonoid myricetin. Redox Rep. (2011)
  13. Beltrán-Debón R, et al. The aqueous extract of Hibiscus sabdariffa calices modulates the production of monocyte chemoattractant protein-1 in humans. Phytomedicine. (2010)
  14. Ko WC, et al. Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochem Pharmacol. (2004)
  15. Paoletta S, et al. Screening of herbal constituents for aromatase inhibitory activity. Bioorg Med Chem. (2008)
  16. Lu DF, et al. Inhibitory Effect of Luteolin on Estrogen Biosynthesis in Human Ovarian Granulosa Cells by Suppression of Aromatase (CYP19). J Agric Food Chem. (2012)
  17. Monteiro R, et al. Red wine interferes with oestrogen signalling in rat hippocampus. J Steroid Biochem Mol Biol. (2008)
  18. Li C, et al. Effects of myricetin, an anticancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Eur J Drug Metab Pharmacokinet. (2011)
  19. Grünz G, et al. Structural features and bioavailability of four flavonoids and their implications for lifespan-extending and antioxidant actions in C. elegans. Mech Ageing Dev. (2012)
  20. Yanase S, Yasuda K, Ishii N. Adaptive responses to oxidative damage in three mutants of Caenorhabditis elegans (age-1, mev-1 and daf-16) that affect life span. Mech Ageing Dev. (2002)
  21. Senoo-Matsuda N, et al. A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans. J Biol Chem. (2001)
  22. Shin JC, et al. The flavonoid myricetin reduces nocturnal melatonin levels in the blood through the inhibition of serotonin N-acetyltransferase. Biochem Biophys Res Commun. (2013)
  23. Plant Flavonoids, Especially Tea Flavonols, Are Powerful Antioxidants Using an in Vitro Oxidation Model for Heart Disease
  24. Liu IM, et al. Improvement of insulin sensitivity in obese Zucker rats by myricetin extracted from Abelmoschus moschatus. Planta Med. (2007)
  25. Liu IM, et al. Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats. Life Sci. (2007)
  26. Liu IM, et al. Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats. Planta Med. (2005)
  27. Ong KC, Khoo HE. Effects of myricetin on glycemia and glycogen metabolism in diabetic rats. Life Sci. (2000)
  28. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes
  29. Lee KH, Choi EM. Myricetin, a naturally occurring flavonoid, prevents 2-deoxy-D-ribose induced dysfunction and oxidative damage in osteoblastic MC3T3-E1 cells. Eur J Pharmacol. (2008)
  30. Maggiolini M, et al. The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor alpha in human breast cancer cells. J Mol Endocrinol. (2005)
  31. The antioxidants of higher plants
  32. Flavonoid intake and risk of chronic diseases
  33. Flavonols and Pancreatic Cancer Risk
  34. Aquila S, et al. Red wine consumption may affect sperm biology: the effects of different concentrations of the phytoestrogen myricetin on human male gamete function. Mol Reprod Dev. (2013)
  35. Aquila S, et al. Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway. J Clin Endocrinol Metab. (2004)
  36. Tummon IS, et al. Total acrosin activity correlates with fertility potential after fertilization in vitro. Fertil Steril. (1991)

(Common misspellings for Myricetin include myrcetin, myrictin)

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