Genistein

Genistein (C15H10O5) is a naturally occurring compound that belongs to the class of compounds known as isoflavones. It is recognized as an angiogenesis inhibitor and a phytoestrogen.

First isolated in 1899 from the dyer's broom, Genista tinctoria, this is how it got its chemical name. The compound's structure was determined in 1926, revealing its identity with prunetol. It was chemically synthesized in 1928. Genistein is the primary secondary metabolite of Trifolium species and Glycine max.

Natural occurrences

Isoflavones like genistein and daidzein are present in various plants, including lupin, fava beans, soybeans, kudzu, and psoralea, which serve as primary food sources. They are also found in medicinal plants such as Flemingia vestita and F. macrophylla, as well as in coffee. Additionally, they are present in Maackia amurensis cell cultures.

Biological effects

In addition to acting as an antioxidant and anthelmintic, many isoflavones have been demonstrated to interact with animal and human estrogen receptors, producing effects in the body akin to those of the hormone estrogen. Isoflavones also cause non-hormonal effects.

Molecular function

Genistein affects multiple biochemical functions in living cells:

• Full agonist of ERβ (EC50 = 7.62 nM) and, to a significantly lesser degree (~20-fold), a full agonist[11] or partial agonist of ERα

  
  

• Agonist of the G protein-coupled estrogen receptor (affinity of 133 nM)

  
  

• Activates peroxisome proliferator-activated receptors (PPARs)

  
  

• Inhibits several tyrosine kinases

  
  

• Inhibits topoisomerase

  
  

• Inhibits AAAD

  
  

• Exhibits direct antioxidation with some pro-oxidative characteristics

  
  

• Activates the Nrf2 antioxidative response

  
  

• Stimulates autophagy

  
  

• Inhibits the mammalian hexose transporter GLUT1

  
  

• Induces contraction in several types of smooth muscles

  
  

• Modulates the CFTR channel, enhancing its opening at low concentrations and inhibiting it at higher doses.

  
  

• Inhibits cytosine methylation

  
  

• Inhibits DNA methyltransferase

  
  

• Inhibits the glycine receptor

  
  

• Inhibits the nicotinic acetylcholine receptor

Activation of PPARs

The isoflavones genistein and daidzein bind to and activate all three PPAR isoforms: α, δ, and γ. For instance, a membrane-bound PPARγ-binding assay demonstrated that genistein can directly interact with the PPARγ ligand binding domain, with a Ki value of 5.7 mM. Gene reporter assays revealed that genistein, at concentrations ranging from 1 to 100 µM, activated PPARs in a dose-dependent manner in KS483 mesenchymal progenitor cells, breast cancer MCF-7 cells, T47D cells, MDA-MD-231 cells, murine macrophage-like RAW 264.7 cells, endothelial cells, and Hela cells.

Numerous studies indicate that ERs and PPARs influence each other, leading to differential effects in a dose-dependent manner. The overall biological effects of genistein are determined by the balance among these diverse actions.

Tyrosine kinase inhibitor

The primary known activity of genistein is as a tyrosine kinase inhibitor, particularly of the epidermal growth factor receptor (EGFR). Although tyrosine kinases are less common than their ser/thr counterparts, they are involved in nearly all cell growth and proliferation signaling pathways.

Redox-active—not only antioxidant

Genistein may function as a direct antioxidant, like many other isoflavones, potentially reducing the harmful effects of free radicals in tissues.

The same genistein molecule, similar to other isoflavones, can generate free radicals that inhibit topoisomerase II, an enzyme crucial for DNA stability.

In response to genistein exposure, human cells activate the beneficial, detoxifying Nrf2 factor. This pathway may contribute to the health-promoting properties observed with small doses of genistein.

Anthelmintic

The root-tuber peel extract of the leguminous plant Flemingia vestita is traditionally used as an anthelmintic by the Khasi tribes of India. During research into its anthelmintic activity, genistein was identified as the primary isoflavone responsible for its deworming properties. Genistein was later shown to be highly effective against intestinal parasites such as the poultry cestode Raillietina echinobothrida, the pork trematode Fasciolopsis buski, and the sheep liver fluke Fasciola hepatica.

Its anthelmintic effect is achieved by inhibiting the enzymes of glycolysis and glycogenolysis, and by disrupting Ca2+ homeostasis and NO activity in the parasites. Research on human tapeworms such as Echinococcus multilocularis and E. granulosus metacestodes has shown that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.

Atherosclerosis

Genistein helps prevent the dysfunction of the vascular endothelial barrier caused by pro-inflammatory factors and reduces leukocyte-endothelium interaction, thus influencing vascular inflammation, a key process in the pathogenesis of atherosclerosis.

Cancer links

Genistein and other isoflavones are recognized as angiogenesis inhibitors and have been shown to suppress the uncontrolled cell growth of cancer, likely by inhibiting the activity of substances that regulate cell division and cell survival (growth factors). Various studies indicate that moderate doses of genistein can inhibit cancers of the prostate, cervix, brain, breast, and colon. It has also been demonstrated that genistein increases the sensitivity of some cells to radiotherapy; however, the timing of phytoestrogen use is crucial.

Genistein primarily acts as a tyrosine kinase inhibitor. Although tyrosine kinases are less common than their ser/thr counterparts, they are involved in nearly all cell growth and proliferation signal cascades. Inhibition of DNA topoisomerase II is also important for the cytotoxic effects of genistein. The discovery that the transition of normal lymphocytes from quiescence (G0) to the G1 phase of the cell cycle is particularly sensitive to genistein led researchers to propose that this isoflavone could be a potential immunosuppressant. Genistein has been used to selectively target pre B-cells through conjugation with an anti-CD19 antibody.

Research on rodents has shown that genistein is effective in treating leukemia, and it can be combined with certain other antileukemic drugs to enhance their effectiveness.

Estrogen receptor — more cancer links

Due to its structural similarity to 17β-estradiol (estrogen), genistein can compete with it and bind to estrogen receptors. However, genistein has a much higher affinity for estrogen receptor β than for estrogen receptor α.

Data from in vitro and in vivo studies confirm that genistein can accelerate the growth of some ER-expressing breast cancers. Genistein was found to increase the proliferation rate of estrogen-dependent breast cancer when not used alongside an estrogen antagonist. It also reduced the effectiveness of tamoxifen and letrozole—drugs commonly used in breast cancer treatment. Genistein was also found to inhibit the immune response against cancer cells, allowing their survival.

Effects in males

Isoflavones can mimic estrogen, promoting the development and maintenance of female traits, or they can prevent cells from utilizing estrogen-related compounds. In vitro studies have demonstrated that genistein can trigger apoptosis in testicular cells at certain concentrations, raising concerns about its potential impact on male fertility. However, one study concluded that isoflavones had "no observable effect on endocrine measurements, testicular volume, or semen parameters over the study period" in healthy males who took isoflavone supplements daily for two months.

Carcinogenic and toxic potential

Genistein, along with other flavonoids, was identified as a potent topoisomerase inhibitor, similar to certain chemotherapeutic anticancer drugs like etoposide and doxorubicin. At high doses, it was found to be highly toxic to normal cells. This effect might contribute to both the anticarcinogenic and carcinogenic potential of the substance. It was discovered to damage the DNA of cultured blood stem cells, potentially leading to leukemia. Genistein, among other flavonoids, is suspected of increasing the risk of infant leukemia when consumed during pregnancy.

Sanfilippo syndrome treatment

Genistein reduces the pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro animal studies and clinical trials suggest that the symptoms of the disease may be relieved by an appropriate dose of genistein. Genistein was also found to have toxic effects on brain cells. Among the various pathways activated by genistein, autophagy might explain the observed effectiveness of the substance, as autophagy is significantly impaired in the disease.

Cognition

A study of Italians over the age of 50 found that those with the highest genistein intake had the lowest likelihood of cognitive impairment.