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 An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical dru ...

and a

phytoestrogen A phytoestrogen is a plant-derived xenoestrogen (see estrogen) not generated within the endocrine system, but consumed by eating plants or manufactured foods. Also called a "dietary estrogen", it is a diverse group of naturally occurring nonster ...

. 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. It has been shown to be the primary secondary metabolite of the ''Trifolium'' species and ''Glycine max L''.

Natural occurrences

Isoflavones such as genistein and daidzein are found in a number of plants including

lupin ''Lupinus'', commonly known as lupin, lupine, or regionally bluebonnet etc., is a genus of plants in the legume family Fabaceae. The genus includes over 199 species, with centers of diversity in North and South America. Smaller centers occur ...

fava bean ''Vicia faba'', commonly known as the broad bean, fava bean, or faba bean, is a species of vetch, a flowering plant in the pea and bean family Fabaceae. It is widely cultivated as a crop for human consumption, and also as a cover crop. Var ...

soybean The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses. Traditional unfermented food uses of soybeans include soy milk, from which tofu ...

kudzu Kudzu (; also called Japanese arrowroot or Chinese arrowroot) is a group of climbing, coiling, and trailing deciduous perennial vines native to much of East Asia, Southeast Asia, and some Pacific islands, but invasive in many parts of the wor ...

, and psoralea being the primary food source, also in the

medicinal plant Medicinal plants, also called medicinal herbs, have been discovered and used in traditional medicine practices since prehistoric times. Plants synthesize hundreds of chemical compounds for various functions, including defense and protection a ...

s, ''

Flemingia vestita ''Flemingia vestita'' (synonyms ''Flemingia procumbens'' Roxb.; ''Moghania vestita'' (Benth.) ex Baker Kuntze; ''Moghania procumbens'' (Roxb.) Mukerjee) famously known as ''Sohphlang'' is a nitrogen fixing herb with characteristic tuberous ro ...

'' and '' F. macrophylla'', and

coffee Coffee is a drink prepared from roasted coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulating effect on humans, primarily due to its caffeine content. It is the most popular hot drink in the world. Seeds of ...

. It can also be found in ''

Maackia amurensis ''Maackia amurensis'', commonly known as the Amur maackia, is a species of tree in the family Fabaceae that can grow 15 metres (49 ft) tall. The species epithet and common names are from the Amur River region, where the tree originated; it ...

'' cell cultures.

Biological effects

Besides functioning as an

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants ...

and

anthelmintic Anthelmintics or antihelminthics are a group of antiparasitic, antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the h ...

, many

isoflavone Isoflavones are substituted derivatives of isoflavone, a type of naturally occurring isoflavonoids, many of which act as phytoestrogens in mammals. Isoflavones are produced almost exclusively by the members of the bean family, Fabaceae (Leguminos ...

s have been shown to interact with

animal Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...

and

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of th ...

s, causing effects in the body similar to those caused by the hormone estrogen.

Isoflavone Isoflavones are substituted derivatives of isoflavone, a type of naturally occurring isoflavonoids, many of which act as phytoestrogens in mammals. Isoflavones are produced almost exclusively by the members of the bean family, Fabaceae (Leguminos ...

s also produce non-hormonal effects.

Molecular function

Genistein influences multiple

biochemical Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology ...

functions in living cells: *

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

( EC₅₀ = 7.62 nM) and, to a much lesser extent (~20-fold),

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonist ...

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex h ...

* agonist of G protein-coupled estrogen receptor (affinity of 133 nM) * activation of peroxisome proliferator-activated receptors (

PPAR In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the ...

s) * inhibition of several

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cl ...

s * inhibition of

topoisomerase DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues i ...

* inhibition of AAAD * direct antioxidation with some pro oxidative features * activation of Nrf2 antioxidative response * stimulation of

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

* inhibition of the mammalian

hexose In chemistry, a hexose is a monosaccharide (simple sugar) with six carbon atoms. The chemical formula for all hexoses is C6H12O6, and their molecular weight is 180.156 g/mol. Hexoses exist in two forms, open-chain or cyclic, that easily conver ...

transporter

GLUT1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose acros ...

* contraction of several types of

smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...

s * modulation of CFTR channel, potentiating its opening at low concentration and inhibiting it a higher doses. * inhibition of cytosine methylation * inhibition of

DNA methyltransferase In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosy ...

* inhibition of the

glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory ...

* inhibition of the

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral n ...

Activation of PPARs

Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms, α, δ, and γ. 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. 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.

Tyrosine kinase inhibitor

The main known activity of genistein is

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosp ...

, mostly of

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor rec ...

(EGFR). Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades.

Redox-active—not only antioxidant

Genistein may act as direct

, similar to many other

s, and thus may alleviate damaging effects of

free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spon ...

in tissues. The same molecule of genistein, similar to many other

s, by generation of free radicals poison

II, an enzyme important for maintaining DNA stability. 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.

Anthelmintic

The root-tuber peel extract of the leguminous plant '' Felmingia vestita'' is the traditional

of the Khasi tribes of India. While investigating its anthelmintic activity, genistein was found to be the major

responsible for the

deworming Deworming (sometimes known as worming, drenching or dehelmintization) is the giving of an anthelmintic drug (a wormer, dewormer, or drench) to a human or animals to rid them of helminths parasites, such as roundworm, flukes and tapeworm. Pur ...

property. Genistein was subsequently demonstrated to be highly effective against

intestinal parasite An intestinal parasite infection is a condition in which a parasite infects the gastro-intestinal tract of humans and other animals. Such parasites can live anywhere in the body, but most prefer the intestinal wall. Routes of exposure and inf ...

s such as the

poultry Poultry () are domesticated birds kept by humans for their eggs, their meat or their feathers. These birds are most typically members of the superorder Galloanserae (fowl), especially the order Galliformes (which includes chickens, quail ...

cestode Cestoda is a Class (biology), class of parasitic worms in the flatworm phylum (Platyhelminthes). Most of the species—and the best-known—are those in the subclass Eucestoda; they are ribbon-like worms as adults, known as tapeworms. Their bodi ...

Raillietina echinobothrida ''Raillietina echinobothrida'' is a parasitic tapeworm belonging to the class Cestoda. It is the most prevalent and pathogenic helminth parasite in birds, particularly in domestic fowl, '' Gallus domesticus'' Linnaeus, 1758. It requires two ...

'', the

pork Pork is the culinary name for the meat of the domestic pig (''Sus domesticus''). It is the most commonly consumed meat worldwide, with evidence of pig husbandry dating back to 5000 BCE. Pork is eaten both freshly cooked and preserved ...

trematode Trematoda is a Class (biology), class of flatworms known as flukes. They are obligate parasite, obligate internal Parasitism, parasites with a complex biological life cycle, life cycle requiring at least two Host_(biology), hosts. The intermedia ...

'' Fasciolopsis buski'', and the sheep liver fluke ''Fasciola hepatica''. It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and

glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase. Mechanism ...

, and disturbing the Ca2+ homeostasis and NO activity in the

parasites Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...

. It has also been investigated in human tapeworms such as ''

Echinococcus multilocularis ''Echinococcus multilocularis'' is a small cyclophyllid tapeworm found extensively in the northern hemisphere. ''E. multilocularis,'' along with other members of the ''Echinococcus'' genus (especially '' E. granulosus''), produce diseases known ...

'' and '' E. granulosus'' metacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.

Atherosclerosis

Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits

leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...

interaction, thereby modulating vascular inflammation, a major event in the

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually ...

Cancer links

Genistein and other

s have been identified as

angiogenesis inhibitors An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels ( angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical d ...

, and found to inhibit the uncontrolled cell growth of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

, most likely by inhibiting the activity of substances in the body that regulate

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...

and cell survival (

growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for re ...

). Various studies have found that moderate doses of genistein have inhibitory effects on

s of the

prostate The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...

cervix The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes durin ...

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and s ...

and colon. It has also been shown that genistein makes some cells more sensitive to radio-therapy.; although, timing of

use is also important. Genistein's chief method of activity is as a

. 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. 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

may be potential

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified into ...

. Genistein has been used to selectively target pre B-cells via conjugation with an anti-CD19 antibody. Studies on rodents have found genistein to be useful in the treatment of

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

, and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.

Estrogen receptor — more cancer links

Due to its structure similarity to 17β-estradiol (

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...

), genistein can compete with it and bind to

s. However, genistein shows much higher affinity toward

estrogen receptor β Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

than toward estrogen receptor α. Data from ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' 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. It was also found to decrease efficiency of

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

and

letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most commo ...

- drugs commonly used in breast cancer therapy. Genistein was found to inhibit immune response towards cancer cells allowing their survival.

Effects in males

Isoflavones can act like

, 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; 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.

Carcinogenic and toxic potential

Genistein was, among other

flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

s, found to be a strong

topoisomerase inhibitor Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular r ...

, similarly to some chemotherapeutic anticancer drugs ex.

etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...

and

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used tog ...

. In high doses it was found to be strongly toxic to normal cells. This effect may be responsible for both anticarcinogenic and carcinogenic potential of the substance. It was found to deteriorate DNA of cultured blood stem cells, which may lead to leukemia. Genistein among other

s is suspected to increase risk of infant leukemia when consumed during pregnancy.

Sanfilippo syndrome treatment

Genistein decreases pathological accumulation of

glycosaminoglycan Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...

s in

Sanfilippo syndrome Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare autosomal recessive lysosomal storage disease that primarily affects the brain and spinal cord. It is caused by a buildup of large sugar molecules called glyc ...

. ''In vitro'' animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by adequate dose of genistein. Genistein was found to also possess toxic properties toward brain cells. Among many pathways stimulated by genistein,

may explain the observed efficiency of the substance as

is significantly impaired in the disease.

Cognition

A study looking at Italians older than 50 found that those with the highest genistein intake had the lowest odds of cognitive impairment.

Related compounds

Genistin Genistin is an isoflavone found in a number of dietary plants like soy and kudzu. It was first isolated in 1931 from the 90% methanol extract of a soybean meal, when it was found that hydrolysis with hydrochloric acid produced 1 mole each of ...

is the 7-O-beta-D- glucoside of genistein. * Wighteone can be described as 6-

isopentenyl Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...

genistein * KBU2046 under investigation for

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

. * B43-genistein, an anti-

CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...

antibody linked to genistein e.g. for

References

External links

Compound Summary at NCBI PubChem

Fact Sheet at Zerobreastcancer

Information at Phytochemicals

Description at NCI Drug Dictionary
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Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ( ...

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