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Wikipedia

Genistein

February 02, 2023

Not to be confused with Genistin.

Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen.[1]

Genistein
Names
IUPAC name
4′,5,7-Trihydroxyisoflavone
Preferred IUPAC name
5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one
Identifiers
  • 446-72-0 Y
3D model (JSmol)
  • Interactive image
263823
ChEBI
  • CHEBI:28088 Y
ChEMBL
  • ChEMBL44 Y
ChemSpider
  • 4444448 Y
DrugBank
  • DB01645 Y
ECHA InfoCard 100.006.524
EC Number
  • 207-174-9
  • 2826
KEGG
  • D11680 Y
  • C06563
  • 5280961
UNII
  • DH2M523P0H Y
  • DTXSID5022308
  • InChI=1S/C15H10O5/c16-9-3-1-8(2-4-9)11-7-20-13-6-10(17)5-12(18)14(13)15(11)19/h1-7,16-18H Y
    Key: TZBJGXHYKVUXJN-UHFFFAOYSA-N Y
  • InChI=1/C15H10O5/c16-9-3-1-8(2-4-9)11-7-20-13-6-10(17)5-12(18)14(13)15(11)19/h1-7,16-18H
    Key: TZBJGXHYKVUXJN-UHFFFAOYAH
  • Oc1ccc(cc1)C\3=C\Oc2cc(O)cc(O)c2C/3=O
Properties
C15H10O5
Molar mass 270.240 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)

It was first isolated in 1899 from the dyer's broom, Genista tinctoria; hence, the chemical name. The compound structure was established in 1926, when it was found to be identical with that of prunetol. It was chemically synthesized in 1928.[2] It has been shown to be the primary secondary metabolite of the Trifolium species and Glycine max L.[3]

Natural occurrences

Isoflavones such as genistein and daidzein are found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea being the primary food source,[4][5] also in the medicinal plants, Flemingia vestita[6] and F. macrophylla,[7][8] and coffee.[9] It can also be found in Maackia amurensis cell cultures.[10]

Biological effects

Besides functioning as an antioxidant and anthelmintic, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Isoflavones also produce non-hormonal effects.[citation needed]

Molecular function

Genistein influences multiple biochemical functions in living cells:

Activation of PPARs

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

The main known activity of genistein is tyrosine kinase inhibitor, mostly of epidermal 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

Genistein may act as direct antioxidant, similar to many other isoflavones, and thus may alleviate damaging effects of free radicals in tissues.[24][25]

The same molecule of genistein, similar to many other isoflavones, by generation of free radicals poison topoisomerase II, an enzyme important for maintaining DNA stability.[26][27][28]

Human cells turn on beneficial, detoxifying Nrf2 factor in response to genistein insult. This pathway may be responsible for observed health maintaining properties of small doses of genistein.[29]

Anthelmintic

The root-tuber peel extract of the leguminous plant Flemingia vestita is the traditional anthelmintic of the Khasi tribes of India. While investigating its anthelmintic activity, genistein was found to be the major isoflavone responsible for the deworming property.[6][30] Genistein was subsequently demonstrated to be highly effective against intestinal parasites such as the poultry cestode Raillietina echinobothrida,[30] the pork trematode Fasciolopsis buski,[31] and the sheep liver fluke Fasciola hepatica.[32] It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and glycogenolysis,[33][34] and disturbing the Ca2+ homeostasis and NO activity in the parasites.[35][36] It has also been investigated in human tapeworms such as Echinococcus multilocularis and E. granulosus metacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.[37]

Atherosclerosis

Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte-endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis.[38]

Cancer links

Genistein and other isoflavones have been identified as angiogenesis inhibitors, and found to inhibit the uncontrolled cell growth of cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Various studies have found that moderate doses of genistein have inhibitory effects on cancers of the prostate,[39][40] cervix,[41] brain,[42] breast[39][43][44] and colon.[17] It has also been shown that genistein makes some cells more sensitive to radio-therapy.;[45] although, timing of phytoestrogen use is also important.[45]

Genistein's chief method of activity is as a tyrosine kinase inhibitor. Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein.[27][46] The observation that transition of normal lymphocytes from quiescence (G0) to the G1 phase of the cell cycle is particularly sensitive to genistein prompted the authors to suggest that this isoflavone may be potential immunosuppressant.[47] Genistein has been used to selectively target pre B-cells via conjugation with an anti-CD19 antibody.[48]

Studies on rodents have found genistein to be useful in the treatment of leukemia, and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.[49]

Estrogen receptor — more cancer links

Due to its structure similarity to 17β-estradiol (estrogen), genistein can compete with it and bind to estrogen receptors. However, genistein shows much higher affinity toward estrogen receptor β than toward estrogen receptor α.[50]

Data from in vitro and in vivo research confirms that genistein can increase rate of growth of some ER expressing 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 of tamoxifen and letrozole - 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

Isoflavones can act like estrogen, stimulating development and maintenance of female characteristics, or they can block cells from using cousins of estrogen. In vitro studies have shown genistein to induce apoptosis of 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

Genistein was, among other flavonoids, found to be a strong topoisomerase inhibitor, similarly to some chemotherapeutic anticancer drugs ex. etoposide and doxorubicin.[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 other flavonoids is suspected to increase risk of infant leukemia when consumed during pregnancy.[63][64]

Sanfilippo syndrome treatment

Genistein decreases pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro animal 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, autophagy may explain the observed efficiency of the substance as autophagy is significantly impaired in the disease.[66][67]

Cognition

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

See also

References

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February 02, 2023
genistein, confused, with, genistin, this, article, multiple, issues, please, help, improve, discuss, these, issues, talk, page, learn, when, remove, these, template, messages, this, article, relies, excessively, references, primary, sources, please, improve, . Not to be confused with Genistin This article has multiple issues Please help improve it or discuss these issues on the talk page Learn how and when to remove these template messages This article relies excessively on references to primary sources Please improve this article by adding secondary or tertiary sources Find sources Genistein news newspapers books scholar JSTOR February 2020 Learn how and when to remove this template message This article needs more medical references for verification or relies too heavily on primary sources Please review the contents of the article and add the appropriate references if you can Unsourced or poorly sourced material may be challenged and removed Find sources Genistein news newspapers books scholar JSTOR June 2012 Learn how and when to remove this template message Genistein C15H10O5 is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones It is described as an angiogenesis inhibitor and a phytoestrogen 1 Genistein NamesIUPAC name 4 5 7 TrihydroxyisoflavonePreferred IUPAC name 5 7 Dihydroxy 3 4 hydroxyphenyl 4H 1 benzopyran 4 oneIdentifiersCAS Number 446 72 0 Y3D model JSmol Interactive imageBeilstein Reference 263823ChEBI CHEBI 28088 YChEMBL ChEMBL44 YChemSpider 4444448 YDrugBank DB01645 YECHA InfoCard 100 006 524EC Number 207 174 9IUPHAR BPS 2826KEGG D11680 YC06563PubChem CID 5280961UNII DH2M523P0H YCompTox Dashboard EPA DTXSID5022308InChI InChI 1S C15H10O5 c16 9 3 1 8 2 4 9 11 7 20 13 6 10 17 5 12 18 14 13 15 11 19 h1 7 16 18H YKey TZBJGXHYKVUXJN UHFFFAOYSA N YInChI 1 C15H10O5 c16 9 3 1 8 2 4 9 11 7 20 13 6 10 17 5 12 18 14 13 15 11 19 h1 7 16 18HKey TZBJGXHYKVUXJN UHFFFAOYAHSMILES Oc1ccc cc1 C 3 C Oc2cc O cc O c2C 3 OPropertiesChemical formula C 15H 10O 5Molar mass 270 240 g mol 1Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Y verify what is Y N Infobox references It was first isolated in 1899 from the dyer s broom Genista tinctoria hence the chemical name The compound structure was established in 1926 when it was found to be identical with that of prunetol It was chemically synthesized in 1928 2 It has been shown to be the primary secondary metabolite of the Trifolium species and Glycine max L 3 Contents 1 Natural occurrences 2 Biological effects 2 1 Molecular function 2 2 Activation of PPARs 2 3 Tyrosine kinase inhibitor 2 4 Redox active not only antioxidant 2 5 Anthelmintic 2 6 Atherosclerosis 2 7 Cancer links 2 8 Estrogen receptor more cancer links 2 9 Effects in males 2 10 Carcinogenic and toxic potential 2 11 Sanfilippo syndrome treatment 2 12 Cognition 3 Related compounds 4 See also 5 References 6 External linksNatural occurrences EditIsoflavones such as genistein and daidzein are found in a number of plants including lupin fava beans soybeans kudzu and psoralea being the primary food source 4 5 also in the medicinal plants Flemingia vestita 6 and F macrophylla 7 8 and coffee 9 It can also be found in Maackia amurensis cell cultures 10 Biological effects EditBesides functioning as an antioxidant and anthelmintic many isoflavones have been shown to interact with animal and human estrogen receptors causing effects in the body similar to those caused by the hormone estrogen Isoflavones also produce non hormonal effects citation needed Molecular function Edit Genistein influences multiple biochemical functions in living cells full agonist of ERb EC50 7 62 nM and to a much lesser extent 20 fold full agonist 11 or partial agonist of ERa 12 agonist of G protein coupled estrogen receptor affinity of 133 nM 13 14 activation of peroxisome proliferator activated receptors PPARs inhibition of several tyrosine kinases inhibition of topoisomerase inhibition of AAAD direct antioxidation with some pro oxidative features activation of Nrf2 antioxidative response stimulation of autophagy 15 16 17 inhibition of the mammalian hexose transporter GLUT1 contraction of several types of smooth muscles modulation of CFTR channel potentiating its opening at low concentration and inhibiting it a higher doses inhibition of cytosine methylation inhibition of DNA methyltransferase 18 inhibition of the glycine receptor inhibition of the nicotinic acetylcholine receptor 19 Activation of PPARs Edit Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms a d and g 20 For example membrane bound PPARg binding assay showed that genistein can directly interact with the PPARg 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 is tyrosine kinase inhibitor mostly of epidermal 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 direct antioxidant similar to many other isoflavones and thus may alleviate damaging effects of free radicals in tissues 24 25 The same molecule of genistein similar to many other isoflavones by generation of free radicals poison topoisomerase II an enzyme important for maintaining DNA stability 26 27 28 Human cells turn on beneficial detoxifying Nrf2 factor 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 the leguminous plant Flemingia vestita is the traditional anthelmintic of the Khasi tribes of India While investigating its anthelmintic activity genistein was found to be the major isoflavone responsible for the deworming property 6 30 Genistein was subsequently demonstrated to be highly effective against intestinal parasites such as the poultry cestode Raillietina echinobothrida 30 the pork trematode Fasciolopsis buski 31 and the sheep liver fluke Fasciola hepatica 32 It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and glycogenolysis 33 34 and disturbing the Ca2 homeostasis and NO activity in the parasites 35 36 It has also been investigated in human tapeworms such as Echinococcus multilocularis and E granulosus metacestodes that genistein and its derivatives Rm6423 and Rm6426 are potent cestocides 37 Atherosclerosis Edit Genistein protects against pro inflammatory factor induced vascular endothelial barrier dysfunction and inhibits leukocyte endothelium interaction thereby modulating vascular inflammation a major event in the pathogenesis of atherosclerosis 38 Cancer links Edit Genistein and other isoflavones have been identified as angiogenesis inhibitors and found to inhibit the uncontrolled cell growth of cancer most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival growth factors Various studies have found that moderate doses of genistein have inhibitory effects on cancers of the prostate 39 40 cervix 41 brain 42 breast 39 43 44 and colon 17 It has also been shown that genistein makes some cells more sensitive to radio therapy 45 although timing of phytoestrogen use is also important 45 Genistein s chief method of activity is as a tyrosine kinase inhibitor Tyrosine kinases are less widespread than their ser thr counterparts but implicated in almost all cell growth and proliferation signal cascades Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein 27 46 The observation that transition of normal lymphocytes from quiescence G0 to the G1 phase of the cell cycle is particularly sensitive to genistein prompted the authors to suggest that this isoflavone may be potential immunosuppressant 47 Genistein has been used to selectively target pre B cells via conjugation with an anti CD19 antibody 48 Studies on rodents have found genistein to be useful in the treatment of leukemia 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 17b estradiol estrogen genistein can compete with it and bind to estrogen receptors However genistein shows much higher affinity toward estrogen receptor b than toward estrogen receptor a 50 Data from in vitro and in vivo research confirms that genistein can increase rate of growth of some ER expressing 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 of tamoxifen and letrozole 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 like estrogen stimulating development and maintenance of female characteristics or they can block cells from using cousins of estrogen In vitro studies have shown genistein to induce apoptosis of 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 other flavonoids found to be a strong topoisomerase inhibitor similarly to some chemotherapeutic anticancer drugs ex etoposide and doxorubicin 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 other flavonoids is suspected to increase risk of infant leukemia when consumed during pregnancy 63 64 Sanfilippo syndrome treatment Edit Genistein decreases pathological accumulation of glycosaminoglycans in Sanfilippo syndrome In vitro animal 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 autophagy may explain the observed efficiency of the substance as autophagy is 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 EditGenistin is the 7 O beta D glucoside of genistein citation needed Wighteone can be described as 6 isopentenyl genistein KBU2046 under investigation for prostate cancer 69 70 B43 genistein an anti CD19 antibody linked to genistein e g for leukemia 71 See also Edit S Equol Liquiritigenin MenerbaReferences Edit Sail Vibhavari Hadden M Kyle 2012 01 01 Desai Manoj C ed Chapter Eighteen Notch Pathway Modulators as Anticancer Chemotherapeutics Annual Reports in Medicinal Chemistry vol 47 Academic Press pp 267 280 doi 10 1016 B978 0 12 396492 2 00018 7 retrieved 2020 09 14 Walter E D 1941 Genistin an Isoflavone Glucoside and its Aglucone Genistein from Soybeans Journal of the American Chemical Society 63 12 3273 76 doi 10 1021 ja01857a013 Popiolkiewicz Joanna Polkowski Krzysztof Skierski 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David C Ballabio Andrea 2007 A block of autophagy in lysosomal storage disorders Human Molecular Genetics 17 1 119 29 doi 10 1093 hmg ddm289 PMID 17913701 Giampieri Francesca Godos Justyna Caruso Giuseppe Owczarek Marcin Jurek Joanna Castellano Sabrina Ferri Raffaele Caraci Filippo Grosso Giuseppe 2022 05 30 Dietary Phytoestrogen Intake and Cognitive Status in Southern Italian Older Adults Biomolecules 12 6 760 doi 10 3390 biom12060760 ISSN 2218 273X PMC 9221352 PMID 35740885 Xu Li Farmer Rebecca Huang Xiaoke Pavese Janet Voll Eric Irene Ogden Biddle Margaret Nibbs Antoinette Valsecchi Matias Scheidt Karl Bergan Raymond 2010 Abstract B58 Discovery of a novel drug KBU2046 that inhibits conversion of human prostate cancer to a metastatic phenotype Cancer Prevention Research 3 12 Supplement B58 doi 10 1158 1940 6207 PREV 10 B58 New Drug Stops Spread of Prostate Cancer Press release Northwestern University April 3 2012 Retrieved September 27 2014 Chen Chun Lin Levine Alexandra Rao Asha O Neill Karen Messinger Yoav Myers Dorothea E Goldman Frederick Hurvitz Carole Casper James T Uckun Fatih M 1999 Clinical Pharmacokinetics of the CD19 Receptor Directed Tyrosine Kinase Inhibitor B43 Genistein in Patients with B Lineage Lymphoid Malignancies The Journal of Clinical Pharmacology 39 12 1248 55 doi 10 1177 00912709922012051 PMID 10586390 S2CID 24445516 External links Edit Wikimedia Commons has media related to Genistein Compound Summary at NCBI PubChem Fact Sheet at Zerobreastcancer Archived 2021 04 21 at the Wayback Machine Information at Phytochemicals Chemical Compound Review at Wikigenes Information at Chemicalbook Description at SpringerReference Description at NCI Drug Dictionary Retrieved from https en wikipedia org w index php title Genistein amp oldid 1136730486, wikipedia, wiki, book, books, library,

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