Genistein
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Names | |
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IUPAC name
4′,5,7-Trihydroxyisoflavone
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Systematic IUPAC name
5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one | |
Identifiers | |
3D model (JSmol)
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263823 | |
ChEBI | |
ChEMBL | |
ChemSpider | |
DrugBank | |
ECHA InfoCard | 100.006.524 |
EC Number |
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KEGG | |
PubChemCID
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UNII | |
CompTox Dashboard(EPA)
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Properties | |
C15H10O5 | |
Molar mass | 270.240g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
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Genistein(C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known asisoflavones.It is described as anangiogenesis inhibitorand aphytoestrogen.[1]
It was first isolated in 1899 from thedyer's broom,Genista tinctoria;hence, the chemical name. The compound structure was established in 1926, when it was found to be identical with that ofprunetol.It was chemically synthesized in 1928.[2]It has been shown to be the primary secondary metabolite of theTrifoliumspecies andGlycine max.[3]
Natural occurrences
[edit]Isoflavones such as genistein anddaidzeinare found in a number of plants includinglupin,fava beans,soybeans,kudzu,andpsoraleabeing the primary food source,[4][5]also in themedicinal plants,Flemingia vestita[6]andF. macrophylla,[7][8]andcoffee.[9]It can also be found inMaackia amurensiscell cultures.[10]
Biological effects
[edit]Besides functioning as anantioxidantandanthelmintic,manyisoflavoneshave been shown to interact withanimalandhumanestrogen receptors,causing effects in the body similar to those caused by thehormone estrogen.Isoflavonesalso produce non-hormonal effects.[citation needed]
Molecular function
[edit]Genistein influences multiplebiochemicalfunctions in living cells:
- full agonistofERβ(EC50= 7.62 nM) and, to a much lesser extent (~20-fold),full agonist[11]orpartial agonistofERα[12]
- agonist ofG protein-coupled estrogen receptor(affinity of 133 nM)[13][14]
- activation of peroxisome proliferator-activated receptors (PPARs)
- inhibition of severaltyrosine kinases
- inhibition oftopoisomerase
- inhibition ofAAAD
- direct antioxidation with some pro oxidative features
- activation ofNrf2antioxidative response
- stimulation ofautophagy[15][16][17]
- inhibition of the mammalianhexosetransporterGLUT1
- contraction of several types ofsmooth muscles
- modulation of CFTR channel, potentiating its opening at low concentration and inhibiting it a higher doses.
- inhibition of cytosine methylation
- inhibition ofDNA methyltransferase[18]
- inhibition of theglycine receptor
- inhibition of thenicotinic acetylcholine receptor[19]
Activation of PPARs
[edit]Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms, α, δ, and γ.[20]For example, membrane-bound PPARγ-binding assay showed that genistein can directly interact with the PPARγ ligand binding domain and has a measurable Ki of 5.7 mM.[21]Gene reporter assays showed that genistein at concentrations between 1 and 100 uM activated PPARs in a dose dependent way in KS483 mesenchymal progenitor cells, breast cancer MCF-7 cells, T47D cells and MDA-MD-231 cells, murine macrophage-like RAW 264.7 cells, endothelial cells and in Hela cells. Several studies have shown that both ERs and PPARs influenced each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.[20][22][23]
Tyrosine kinase inhibitor
[edit]The main known activity of genistein istyrosine kinase inhibitor,mostly ofepidermal growth factor receptor(EGFR). Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades.[citation needed]
Redox-active—not only antioxidant
[edit]Genistein may act as directantioxidant,similar to many otherisoflavones,and thus may alleviate damaging effects offree radicalsin tissues.[24][25]
The same molecule of genistein, similar to many otherisoflavones,by generation of free radicals poisontopoisomeraseII, an enzyme important for maintaining DNA stability.[26][27][28]
Human cells turn on beneficial, detoxifyingNrf2factor in response to genistein insult. This pathway may be responsible for observed health maintaining properties of small doses of genistein.[29]
Anthelmintic
[edit]The root-tuber peel extract of theleguminous plantFlemingia vestitais the traditionalanthelminticof theKhasi tribesof India. While investigating its anthelmintic activity, genistein was found to be the majorisoflavoneresponsible for thedewormingproperty.[6][30]Genistein was subsequently demonstrated to be highly effective againstintestinal parasitessuch as thepoultrycestodeRaillietina echinobothrida,[30]theporktrematodeFasciolopsis buski,[31]and thesheep liver flukeFasciola hepatica.[32]It exerts its anthelmintic activity by inhibiting the enzymes ofglycolysisandglycogenolysis,[33][34]and disturbing theCa2+ homeostasisandNOactivity in theparasites.[35][36]It has also been investigated inhuman tapewormssuch asEchinococcus multilocularisandE. granulosusmetacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potentcestocides.[37]
Atherosclerosis
[edit]Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibitsleukocyte-endotheliuminteraction, thereby modulating vascular inflammation, a major event in thepathogenesisofatherosclerosis.[38]
Cancer links
[edit]Genistein and otherisoflavoneshave been identified asangiogenesis inhibitors,and found to inhibit the uncontrolled cell growth ofcancer,most likely by inhibiting the activity of substances in the body that regulatecell divisionand cell survival (growth factors). Various studies have found that moderate doses of genistein have inhibitory effects oncancersof theprostate,[39][40]cervix,[41]brain,[42]breast[39][43][44]andcolon.[17]It has also been shown that genistein makes some cells more sensitive to radio-therapy.;[45]although, timing ofphytoestrogenuse is also important.[45]
Genistein's chief method of activity is as atyrosine kinase inhibitor.Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Inhibition ofDNA topoisomerase IIalso plays an important role in the cytotoxic activity of genistein.[27][46]The observation that transition of normal lymphocytes from quiescence (G0) to the G1phase of the cell cycle is particularly sensitive to genistein prompted the authors to suggest that thisisoflavonemay be potentialimmunosuppressant.[47]Genistein has been used to selectively target pre B-cells viaconjugation with an anti-CD19 antibody.[48]
Studies on rodents have found genistein to be useful in the treatment ofleukemia,and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.[49]
Estrogen receptor — more cancer links
[edit]Due to its structure similarity to 17β-estradiol (estrogen), genistein can compete with it and bind toestrogen receptors.However, genistein shows much higher affinity towardestrogen receptor βthan towardestrogen receptor α.[50]
Data fromin vitroandin vivoresearch confirms that genistein can increase rate of growth of someERexpressing breast cancers. Genistein was found to increase the rate of proliferation of estrogen-dependent breast cancer when not cotreated with an estrogen antagonist.[51][52][53]It was also found to decrease efficiency oftamoxifenandletrozole- drugs commonly used in breast cancer therapy.[54][55]Genistein was found to inhibit immune response towards cancer cells allowing their survival.[56]
Effects in males
[edit]Isoflavones can act likeestrogen,stimulating development and maintenance of female characteristics, or they can block cells from using cousins of estrogen. In vitro studies have shown genistein to induceapoptosisof testicular cells at certain levels, thus raising concerns about effects it could have on male fertility;[57]however, one study found that isoflavones had "no observable effect on endocrine measurements, testicular volume or semen parameters over the study period." in healthy males given isoflavone supplements daily over a 2-month period.[58]
Carcinogenic and toxic potential
[edit]Genistein was, among otherflavonoids,found to be a strongtopoisomerase inhibitor,similarly to some chemotherapeutic anticancer drugs ex.etoposideanddoxorubicin.[26][59]In high doses it was found to be strongly toxic to normal cells.[60]This effect may be responsible for both anticarcinogenic and carcinogenic potential of the substance.[28][61]It was found to deteriorate DNA of cultured blood stem cells, which may lead to leukemia.[62]Genistein among otherflavonoidsis suspected to increase risk of infant leukemia when consumed during pregnancy.[63][64]
Sanfilippo syndrome treatment
[edit]Genistein decreases pathological accumulation ofglycosaminoglycansinSanfilippo syndrome.In vitroanimal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by adequate dose of genistein.[65]Genistein was found to also possess toxic properties toward brain cells.[60]Among many pathways stimulated by genistein,autophagymay explain the observed efficiency of the substance asautophagyis significantly impaired in the disease.[66][67]
Cognition
[edit]A study looking at Italians older than 50 found that those with the highest genistein intake had the lowest odds of cognitive impairment.[68]
Related compounds
[edit]- Genistinis the 7-O-beta-D-glucosideof genistein.[citation needed]
- Wighteonecan be described as 6-isopentenylgenistein
- KBU2046under investigation forprostate cancer.[69][70]
- B43-genistein,an anti-CD19antibody linked to genistein e.g. forleukemia.[71]
See also
[edit]References
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External links
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