Myricetin
| |
| |
| Names | |
|---|---|
| IUPAC name
3,3′,4′,5,5′,7-Hexahydroxyflavone
| |
| Systematic IUPAC name
3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-1-benzopyran-4-one | |
| Other names
Cannabiscetin
Myricetol Myricitin | |
| Identifiers | |
3D model (JSmol)
|
|
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.007.695 |
| EC Number |
|
| KEGG | |
PubChemCID
|
|
| UNII | |
CompTox Dashboard(EPA)
|
|
| |
| |
| Properties | |
| C15H10O8 | |
| Molar mass | 318.237g·mol−1 |
| Density | 1.912 g/mL |
| Hazards | |
| GHSlabelling: | |
| |
| Warning | |
| H315,H319,H335 | |
| P261,P264,P271,P280,P302+P352,P304+P340,P305+P351+P338,P312,P321,P332+P313,P337+P313,P362,P403+P233,P405,P501 | |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
| |
Myricetinis a member of theflavonoidclass of polyphenolic compounds, with antioxidant properties.[1]Common dietary sources[2]include vegetables (includingtomatoes), fruits (includingoranges), nuts, berries, tea,[3]and red wine.[4]
Myricetin is structurally similar tofisetin,luteolin,andquercetinand is reported to have many of the same functions as these other members of theflavonolclass of flavonoids.[3]Reported average intake of myricetin per day varies depending on diet, but has been shown in the Netherlands to average 23 mg/day.[5]
Myricetin is produced from the parent compoundtaxifolinthrough the(+)-dihydromyricetinintermediate and can be further processed to formlaricitrinand thensyringetin,both members of the flavonol class of flavonoids.[6]Dihydromyricetin is frequently sold as a supplement and has controversial function as a partialGABAAreceptorpotentiator and treatment inAlcohol Use Disorder (AUD).Myricetin can alternatively be produced directly fromkaempferol,which is another flavonol.[6]
Sources
[edit]| Foods | Myricetin
(mg/100g) |
|---|---|
| carobfiber | 48[7] |
| fennelleaves, raw | 20[7] |
| parsley,fresh | 15[7] |
| goji berry,dried | 11[7] |
| bog blueberry,frozen | 7[7] |
| carobflour | 7[7] |
| cranberry | 7[7] |
| dock,raw | 6[7] |
| European black currant,raw | 6[7] |
| crowberry | 5[7] |
| rabbit-eye blueberry,raw | 5[7] |
| sweet potatoleaves, raw | 4[7] |
Oxidative Properties
[edit]Antioxidant
[edit]Antioxidantsare molecules present in fruits and vegetables that have been demonstrated to protect against some forms of cancer and cardiovascular disease. Biomolecules and cell structures can experience oxidative stress due to the presence and activity ofreactive oxygen species(ROS). ROS like •OH, •O2−,and H2O2are produced during cellular metabolism processes (aerobic respiration). ROS can damage lipids, DNA, and proteins.
Gradual but steady accretion of such damage can lead to the development of many diseases and conditions including thrombosis, diabetes, persistent inflammation, cancer, and atherosclerosis. Flavonoids including myricetin are able to scavenge for ROS and canchelateintracellular transition metal ions that ultimately produce ROS.[3]
Myricetin also enhances the effects of other antioxidants. Myricetin can induce the enzymeglutathione S-transferase(GST). GST has been suggested to protect cells against oxidative stress by protecting cells against free-radicals.In vitrostudies have shown that myricetin significantly increased GST activity.[3]
Pro-oxidant
[edit]Multiple studies have demonstrated that myricetin also has the potential to act as apro-oxidantdue to its tendency to undergoautoxidationdepending upon its environment[citation needed].It has been seen that when in the presence of cyanide, autoxidation is favored, resulting in superoxide, a byproduct characteristic of causing cellular damage[citation needed].However, sodium azide,superoxide dismutase,andcatalasehave been seen to inhibit the autoxidation of myricetin.[1]
Myricetin may also act as a pro-oxidant in its ability to increase the production ofhydroxy radicalsthrough reactions with Fe2+or Fe3+−EDTAandhydrogen peroxide[citation needed].The resulting hydroxy radicals are often linked to DNA degradation, however, there are doubts as to whether or not this damage would be significant when analyzedin vivosincein vitrostudies with bothbovineand humanserum albuminexhibited extensive protection against it.[1]
Myricetin's pro-oxidative capabilities can also be seen in its ability to act as an inhibitory agent againstglutathione reductase,which is responsible for regeneratingglutathione,a scavenger offree radicalsand peroxides.[1]
Potential health effects
[edit] | This sectionneeds morereliable medical referencesforverificationor relies too heavily onprimary sources.(May 2018) |  |
Anticarcinogen
[edit]Myricetin is also effective in protecting cells fromcarcinogenicmutation. Myricetin reduces the risk of skin tumorigenicity that is caused bypolycyclic aromatic hydrocarbonslikebenzo(a)pyrene,a highly carcinogenic compound. Myricetin provided protection against the formation of skin tumors in mice models after tumor initiating and tumor promoter agents were applied to the skin. On a more biochemical level, it was shown thattopicalapplication of myricetin to mice inhibited the binding of benzo(a)pyrenes to DNA and protein native to epidermal skin cells.[1]
Myricetin also has been shown to inhibit the act of genetic mutation as exhibited by theAmes test.This test showed that myricetin was more effective in preventing mutagenesis initiated by certain carcinogenic polycyclic aromatic hydrocarbons (benzo(a)pyrene, dibenzo(a,h)pyrene, and dibenzo(a,i)pyrene) as compared to others in which it was less effective in preventing against mutagenesis (benzo(a)pyrene 4, 5-oxide and the bay-region diol-epoxides of benzo(a)anthracene, chrysene, and benzo(c)phenathrene).[1]This data shows that myricetin is not unilaterally able to reduce the carcinogenic activity of all polycyclic aromatic hydrocarbons or even the more specific subclass of benzo(a)pyrenes. Myricetin’s exact biochemical activity is still not fully understood. Clearly there is a multifaceted, complex system involved in the anticarcinogenic activity displayed by myricetin that does not apply equally to all carcinogens of the same subfamily.
Mutagen
[edit]It has also been shown that myricetin can itself act as an agent of mutagenicity. Myricetin can produceframeshift mutationsin the genomes of particular strains ofSalmonella typhimurium.[1]In general, biochemical structural studies have shown that flavonoid structures cantautomerizein biological systems to become active mutagens.[1]
Interactions with DNA
[edit]Myricetin can act as apro-oxidantcompound when it interacts with DNA. Studies involvingin vitromodels have shown that myricetin causes the degradation of DNA. Additionally, myricetin, in the presence of Fe3+and Cu2+,intensified this DNA degradation. The antioxidants catalase, superoxide dismutase, mannitol, and sodium azide in combination with Cu2+increased the DNA degradation activity of myricetin. Myricetin was shown to createreactive oxygen speciesthat caused the DNA damage.[1]
It has been demonstrated that myricetin, depending on its concentration, displays different oxidizing effects on DNA. Polyphenols like myricetin are able to reduce (donate electrons to) Fe3+.Thus, this reaction yields a less oxidized (more reduced) form of the iron cation: Fe2+and a less reduced (more oxidized) form of myricetin.[1]This allows myricetin to form a complex with oxygen and biochemically target the DNA molecule. At higher and higher concentrations of myricetin, the rate of DNA damage has been shown to decrease.[1]A current hypothesis for why this occurs can be attributed to myricetin’s ability tochelateiron (Fe) (myricetin ligand forms two or more coordinate bonds to iron). Thesein vitrostudies cannot be correlated directly to human models and should not be extrapolated.
Myricetin also impacts the biochemical efficacy and binding ability of large intracellular biomolecules. Myricetin has been shown to inhibit viralreverse transcriptase,cellularDNA polymerase,and cellularRNA polymerase.[1]Inhibition of cellular DNA polymerases could have dangerous effects on the cell’s ability to replicate its genome and its progression through thecell cycle.Inhibition of cellular RNA polymerase could have deleterious effects on the cell’s capacity to transcribe and translate DNA and RNA to produce vital proteins for the cell. Researchers have found that myricetin has the ability to interfere in the RNA polymerase pathway in two different ways. InE. colimyricetin competitively inhibitedGTPsubstrate binding to RNA polymerase. In T7bacteriophagesmyricetin competitively inhibited DNA template binding to RNA polymerase.[1]
Antiviral
[edit]Myricetin has been seen to demonstrate antiviral activity against a number of viruses includingMoloney murine leukemia virus,Rauscher murine leukemia virus,and thehuman immunodeficiency virus.Its effects against the proliferation of viruses is thought to be a consequence of myricetin’s ability to inhibit the proper functioning ofreverse transcriptase.Myricetin was identified as acompetitive inhibitorof the reverse transcriptase of Rauscher murine leukemia virus and a partial competitor with respect to the human immunodeficiency virus.[1]Investigations into the activity of theHIV-1 strainwhen introduced to myricetin suggest the antiviral effects are derived from the inhibition of HIV-1integrase,however, there are suspicions that the inhibition is non-specific.[8]Structural analysis of myricetin and other flavonoids with observed antiviral effects indicate that the 3,4’ free hydroxyl groups likely are responsible for inhibition.[1]
Antithrombotic
[edit]Polyphenolssuch as myricetin may prevent oxidative stress-inducedplateletactivation/aggregation. Thus, consumption of antioxidants may serve an anti-thrombotic function. In addition to offering protection by neutralizing peroxide radicals and effectingthromboxaneproduction via thePTGS1pathway, polyphenols such as myricetin may target other platelet activation pathways, limiting fibrinogen’s ability to bind platelet surface receptors.[9]
Antidiabetic
[edit]Severalin vitroand animal studies have indicated the antidiabetic capabilities of myricetin; however, the evidence in clinical trials is less convincing. The flavonoid has been demonstrated to have a hypoglycemic effect by increasing the ability of adipocytes, as well as cells of the soleus muscle and liver of rats, to uptake glucose.[1][10]This insulinomimetic effect is hypothesized to be a consequence of myricetin's either direct or indirect interaction withGLUT4,however, no analysis has produced concrete conclusions detailing exactly from where this effect is derived. In the hepatocytes of rats suffering from diabetes, myricetin has been observed to increase the activity of glycogen synthase 1. In trials done onXenopus laevisoocytes, myricetin is thought to regulate the transport of glucose and fructose through the function of glucose transporter 2 (GLUT2) in sugar absorption. In addition, daily injections of myricetin into rats has been seen to be correlated with increased sensitivity to insulin, indicating the possibility of using a myricetin as treatment or protection against insulin resistance, a frequent cause of diabetes mellitus. In the mouse myoblast cell line known asC2C12,treatment with myricetin not only increased glucose uptake, but also enhancedlipogenesis,a result not seen from any of the other bioflavonoids tested.[10]
Although myricetin has not been concluded to have more than a neutral effect on humans, it has been used as a form of traditional medicine for diabetes in Northern Brazil and is hypothesized by the Finnish Mobile Clinic Health Examination Survey to potentially be correlated to the lower risk ofType 2 diabetesin individuals whose diets included higher than average amounts of myricetin. However, since studies in the United States, such as the Women's Health Study, do not confirm these results, there is doubt of whether or not the difference is risk can actually be accredited to myricetin and is not the result of the inability to fully control other variables such as racial background or inconsistencies in diet between participants.[10]
There is also evidence indicating that other characteristics of myricetin, such as its effect againstinflammation,oxidative stress,andhyperlipidemia,may be helpful to reduce or even prevent other clinical issues which arise fromdiabetes mellitus.[10]
Antiatherosclerotic
[edit]Antioxidants, including flavonoids such as myricetin, are often touted to reduce the risk ofatherosclerosis,the hardening of arteries associated with high cholesterol. However,in vivostudies are lacking andin vitrostudies are contradictory and do not support this claim. This claim is based on myricetin's proposed ability to increase LDL uptake by macrophages, which in theory would protect against atherosclerosis. This theoretical action of myricetin is not supported by experimental data.[11]It is also proposed that myricetin may have the ability as a potent flavonoid antioxidant to prevent LDL oxidation, thus slowing the body's local inflammatory response and delaying the appearance of the first fatty streak and onset of atherosclerosis.[12]
Although mechanisms relating to myricetin specifically have not been proven, a diet that is rich in fruits and vegetables, and therefore rich in antioxidants, correlates with a decreased risk of cardiovascular disease, including atherosclerosis.[13][14]
Neuroprotectant
[edit]It has also been shown that myricetin is effective in protecting neurons against oxidative stressors. Researchers have shown thatPC12 cellstreated with hydrogen peroxide (H2O2) as an oxidative stressor experience cell death due toapoptosis.When treated with myricetin, these oxidatively stressed cells displayed statistically significant increased cell survival.[15] It has been suggested that myricetin not only has oxygen radical scavenging abilities, but also inherent, specific cell-survival capacities. Other molecules known for oxygen radical scavenging (vitamin Eandboldine) did not successfully protect the cell models from oxidative stress and eventual cell death as effectively as myricetin and other biochemically related molecules.[15]
Anti-inflammatory
[edit]Myricetin, along with other lipoxygenase- and cyclooxygenase-blocker flavonoids are seen to have significant anti-inflammatory characteristics, demonstrated by their ability to reduceedemascaused by carrageenan and croton oil.[1]The anti-inflammatory nature of myricetin lies in its ability to inhibit the amplified production ofcytokinesthat occurs during inflammation. Testing on various types ofmacrophagecells, including RAW264.7, as well as on human synovialsarcomacells, demonstrated the inhibition of several kinds of cytokines, such asinterleukin-12andinterleukin-1β,through down-regulation of transcription factors and mediators involved in their production.[10]Other studies suggest that myricetin's anti-inflammatory nature could also potentially be dependent upon interfering in inflammatory signal pathways by inhibiting various kinases and, consequently, the function oftumor necrosis factor Alpha.[10][16]
Anti-platelet aggregation activity
[edit]Exposure to myricetin caused inhibition of rabbitplatelet aggregation,induced byadenosine diphosphate,arachidonic acid,collagenandplatelet activating factor(PAF). It inhibited specific receptor binding of PAF in rabbit platelets. The compound was found to be active againstthrombinandneutrophil elastase.In addition, A prostacyclin-stimulated rise in the levels of plateletadenosine 3',5'-cyclic monophosphate(cAMP) was stimulated by myricetin.[17]
Immunomodulatory activities
[edit]Myricetin's preclinicalimmunomodulatoryproperties are now becoming increasingly widely known.[18]It was discovered that myricetin may preventT-lymphocytestimulation in a mouse model by binding to anti-CD3 and anti-CD28monoclonal antibodiesimmobilised on beads. The inhibitory effect of myricetin on T cells, which was described in this study, was explained as beingmediatedvia extracellularH2O2production. Through the inhibition of NF-B binding activity, these natural compounds were reported to significantly reduce thelipopolysaccharide (LPS)-inducedinterleukin (IL)-12 production in mouse mainmacrophagesas well as the RAW264.7 monocytic cell-line.[19]Myricetin producedepithelial layercontractile reflexes in separate rataortic ringsat a concentration of 50 M.[20]This substance induces the synthesis ofcytosolicunbound calcium in culturedbovineendothelial cells. Myricetin suppressed the release of IL-2 protein from mouse EL-4 T cells that had been stimulated with phorbol 12-myristate 13-acetate (PMA) andionomycinin a daily dosage approach.[21]
References
[edit]- ^abcdefghijklmnopqOng KC, Khoo HE (August 1997). "Biological Effects of Myricetin".General Pharmacology.29(2): 121–126.doi:10.1016/S0306-3623(96)00421-1.PMID9251891.
- ^Holland, Thomas M.; Agarwal, Puja; Wang, Yamin; Leurgans, Sue E.; Bennett, David A.; Booth, Sarah L.;Morris, Martha Clare(2020-01-29)."Dietary flavonols and risk of Alzheimer dementia".Neurology.94(16): e1749–e1756.doi:10.1212/WNL.0000000000008981.ISSN0028-3878.PMC7282875.PMID31996451.
- ^abcdRoss JA, Kasum CM (July 2002). "Dietary Flavonoids: Bioavailability, Metabolic Effects, and Safety".Annual Review of Nutrition.22:19–34.doi:10.1146/annurev.nutr.22.111401.144957.PMID12055336.
- ^Basli A, Soulet S, Chaher N, Merillon JM, Chibane M, Monti JP, Richard T (July 2012)."Wine polyphenols: potential agents in neuroprotection".Oxidative Medicine and Cellular Longevity.2012:805762.doi:10.1155/2012/805762.PMC3399511.PMID22829964.
- ^Hollman PC, Katan MB (Dec 1999). "Health effects and bioavailability of dietary flavonols".Free Radical Research.31 Suppl: Suppl S75–80.doi:10.1080/10715769900301351.PMID10694044.
- ^abFlamini R, Mattivi F, De Rosso M, Arapitas P, Bavaresco L (Sep 2013)."Advanced knowledge of three important classes of grape phenolics: anthocyanins, stilbenes and flavonols".International Journal of Molecular Sciences.14(10): 19651–69.doi:10.3390/ijms141019651.PMC3821578.PMID24084717.
- ^abcdefghijkl"USDA Database for the Flavonoid Content of Selected Foods, Release 3"(PDF).U.S. Department of Agriculture. 2011.
- ^Cushnie T, Lamb A (November 2005)."Antimicrobial activity of flavonoids".International Journal of Antimicrobial Agents.26(5): 343–356.doi:10.1016/j.ijantimicag.2005.09.002.PMC7127073.PMID16323269.
- ^Santhakumar AB, Bulmer AC, Singh I (November 2013). "A review of the mechanisms and effectiveness of dietary polyphenols in reducing oxidative stress and thrombotic risk".Journal of Human Nutrition and Dietetics.27(1): 1–21.doi:10.1111/jhn.12177.hdl:10018/1029016.PMID24205990.
- ^abcdefLi Y, Ding Y (December 2012)."Minireview: Therapeutic potential of myricetin in diabetes mellitus".Food Science and Human Wellness.1:19–25.doi:10.1016/j.fshw.2012.08.002.
- ^Wedworth, SM (1995). "Dietary flavonoids in atherosclerosis prevention".Annals of Pharmacotherapy.29(6): 627–8.doi:10.1177/106002809502900614.PMID7663037.S2CID37311639.
- ^Berliner JA, Navab M, Fogelman AM (1995). "Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics".Circulation.91(9): 2488–96.doi:10.1161/01.CIR.91.9.2488.PMID7729036.
- ^Rice, BH (2014)."Dairy and Cardiovascular Disease: A Review of Recent Observational Research".Current Nutrition Reports.3(2): 130–138.doi:10.1007/s13668-014-0076-4.PMC4006120.PMID24818071.
- ^Kratz, M; Baars, T; Guyenet, S (Feb 2013). "The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease".European Journal of Nutrition.52(1): 1–24.doi:10.1007/s00394-012-0418-1.PMID22810464.S2CID1360916.
- ^abDajas F, Rivera-Megret, F (December 2003)."Neuroprotection by Flavonoids".Brazilian Journal of Medical and Biological Research.36(12): 1613–1620.doi:10.1590/S0100-879X2003001200002.PMID14666245.
- ^Gupta SC, Tyagi AK, Deshmukh-Tasker P, Hinojosa M, Prasad S, Aggarwal BB (October 2014). "Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols".Archives of Biochemistry and Biophysics.559:91–99.doi:10.1016/j.abb.2014.06.006.PMID24946050.
- ^Semwal, D. K.; Semwal, R. B.; Combrinck, S.; Viljoen, A. (2016)."Myricetin: A Dietary Molecule with Diverse Biological Activities".Nutrients.8(2): 90.doi:10.3390/nu8020090.PMC4772053.PMID26891321.
- ^Ghassemi-Rad, Javad; Maleki, Mahdis; Knickle, Allison F.; Hoskin, David W. (2018-05-10)."Myricetin-induced oxidative stress suppresses murine T lymphocyte activation".Cell Biology International.42(8): 1069–1075.doi:10.1002/cbin.10977.ISSN1065-6995.PMID29745443.S2CID13675528.
- ^Kang, Bok Yun; Kim, Seung Hyun; Cho, Daeho; Kim, Tae Sung (2005)."Inhibition of interleukin-12 production in mouse macrophagesvia decreased nuclear factor-κB DNA binding activity by myricetin, a naturally occurring flavonoid".Archives of Pharmacal Research.28(3): 274–279.doi:10.1007/bf02977791.ISSN0253-6269.PMID15832812.S2CID30554297.
- ^Jiménez, Rosario; Andriambeloson, Emile; Duarte, Juan; Andriantsitohaina, Ramaroson; Jiménez, José; Pérez-Vizcaino, Francisco; Zarzuelo, Antonio; Tamargo, Juan (August 1999)."Involvement of thromboxane A2in the endothelium-dependent contractions induced by myricetin in rat isolated aorta ".British Journal of Pharmacology.127(7): 1539–1544.doi:10.1038/sj.bjp.0702694.ISSN0007-1188.PMC1566141.PMID10455307.
- ^Cho, Young-Chang; Yoon, Goo; Lee, Kwang Youl; Choi, Hyun Jin; Kang, Bok Yun (September 2007)."Inhibition of Interleukin-2 Production by Myricetin in Mouse EL-4 T Cells".Archives of Pharmacal Research.30(9): 1075–1079.doi:10.1007/bf02980240.ISSN0253-6269.PMID17958323.S2CID40028977.