Myricetin

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]

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.

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]).

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]

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]

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 C_max (48.4–81.7%) and AUC_0-∞ (41.8–74.4) with no significant influence on T_max or half-life.^[18] The metabolite 4-hydroxytamoxifen had its AUC decreased by 40.1% only at 8mg/kg myricetin.^[18]

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

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]

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]

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.

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]

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]

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]

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]

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

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

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]