Identification

Name
Isoflavone
Accession Number
DB12007
Type
Small Molecule
Groups
Experimental
Description

Isoflavone is a soy phytoestrogen and a biologically active component of several agriculturally important legumes such as soy, peanut, green peas, chick peas and alfalfa [4]. Soybean is an exceptionally rich source of dietary isoflavones, where the average isoflavone content is 1-2 mg/gram [4]. The main soy isoflavones are mostly present in glycosylated forms and include Genistein, Daidzein, and glycitein, which accounts for approximately 50%, 40%, and 10%, respectively, of the total soybean isoflavone content [1]. The clinical benefits of soy proteins have been studied and demonstrated for many years, with some evidence of soy products associated with a reduced incidences of coronary heart disease, atherosclerosis, type II diabetes mellitus, and breast and prostate cancer [2]. While existing data are consistent or inadequate in supporting most of the suggested health benefits of consuming soy proteins and isoflavones [2], the trials investigating isoflavone as a potential treatment for atrophy, menopause, and postmenopausal symptoms are ongoing. Isoflavone is found as one of constituents in oral over-the-counter dietary supplements indicated for improved bone mass density and body fat regulation.

Structure
Thumb
Synonyms
  • 3-phenyl-4H-1-benzopyran-4-one
  • 3-Phenylchromone
  • Isoflavon
External IDs
NSC-135405
Categories
Not Available
UNII
OVO2KUW8H8
CAS number
574-12-9
Weight
Average: 222.243
Monoisotopic: 222.068079562
Chemical Formula
C15H10O2
InChI Key
GOMNOOKGLZYEJT-UHFFFAOYSA-N
InChI
InChI=1S/C15H10O2/c16-15-12-8-4-5-9-14(12)17-10-13(15)11-6-2-1-3-7-11/h1-10H
IUPAC Name
3-phenyl-4H-chromen-4-one
SMILES
O=C1C(=COC2=CC=CC=C12)C1=CC=CC=C1

Pharmacology

Indication

Indicated for over-the-counter use as a dietary supplement for increasing bone density and regulating blood fat.

Associated Therapies
Pharmacodynamics

Isolated soy protein with isoflavones was shown to decrease LDL cholesterol levels in randomized trials assessed by the American Heart Association [2]. In a study of postmenopausal women, daily dietary intake of 101 mg of aglycone isoflavones (indicating Genistein and Daidzein) was associated with lowered LDL cholesterol and apolipoprotein B levels by 8% and reduced systolic and diastolic blood pressure by 6.8% in hypertensive women [2]. In a meta-analysis of randomized controlled trials of menopausal women, soy isoflavones attenuated bone loss of the spine and decreased the levels of deoxypyridinoline, a bone resorption marker, while increasing serum bone-specific alkaline phosphatase, a bone formation marker [2]. The findings from studies investigating the effects of soy consumption on menopausal symptoms, breast cancer, and prostate cancer remain somewhat controversial and inconclusive. Consumption of soy isoflavones may decrease the markers of cancer development and progression in prostate cells, including prostate-specific antigen (PSA), testosterone, and androgen receptor in patients with prostate cancer but not in normal subjects [2]. Although epidemiologic data in Asian women demonstrate that high soy food intake is associated with protection against breast cancer, soy foods have little effect on intermediary markers of breast cancer risk and postmenopausal soy intake may not reduce the risk of developing breast cancer [1]. However, preliminary studies show that soy food intake reduces tumor recurrence in breast cancer patients [1]. Soy isoflavones reported to interfere with thyroid peroxidase, which are involved in the production of thyroid hormones [4].

Mechanism of action

Isoflavones are selective estrogen receptor modulators that exert estrogenic-like effects under certain experimental conditions [1], as they are structurally similar to mammalian 17β-estradiol. They may bind to both α and β isoforms of estrogen receptor (ER), but with binding affinities to ERβ approximately 20 times higher than that to ERα [2]. The role of isoflavones on estrogen-dependent cancer has been studied, since they may mediate antiestrogenic actions by blocking the binding of endogenous estrogens and their receptor signalling [3]. In cell culture, Genistein inhibited the proliferation of MDA-MB-231 human breast cancer cells, probably by arresting the cell cycle progression at the G2–M transition [3]. In addition, genistein was shown to induce apoptosis, modify eicosanoid metabolism, and inhibit angiogenesis [3]. There is an evidence that soy isoflavones may act on androgen receptors to inhibit tyrosine kinase activity, thereby blocking the growth and proliferation of cancer cells [3].

Isoflavones may not significantly contribute to the hypolipidemic effects of soy protein, but may exert coronary benefits by improving endothelial function; in clinical trials of postmenopausal women, isoflavones improved flow-mediated dilation in women with impaired endothelial function [1]. Some observational data suggests that isoflavones improve endothelial function by increasing the number of circulating endothelial progenitor cells, which replace damaged endothelial cells [1]. Isoflavone may modulate the key transcription factors involved in the regulation of lipid metabolism by acting on the peroxisome proliferator-activated receptors (PPAR) alpha and gamma, which are receptors that regulate the transcription of genes involved in lipid and glucose homeostasis and lipid metabolism [3]. Multiple biological actions of isoflavones, such as favorable effect on the blood lipid profile and inhibition of LDL cholesterol oxidation, may lead to cardio protective effects [3].

Genistein has been shown to have antioxidant properties on hydrogen peroxide production in vitro and blocks the formation of oxygen free radicals [3]. Studies also suggest that at micromolar concentrations, genistein increases glucose-stimulated insulin secretion in cell lines and mouse pancreatic islets via a cAMP-dependent protein kinase mechanism [3]. Based on the findings of experimental studies, genistein may exert a positive effect on bone formation by decreasing osteoclastic resorption factor, such as collagen C-telopeptide, and increasing osteoblastic formation markers, such as bone-alkaline phosphatase [3]. In vitro, it antagonized the catabolic effects of parathyroid hormone (PTH) in osteoblasts by reversing the PTH-induced increase in soluble receptor activator of nuclear factor-xB ligand and decrease in osteoprotegerin expression [3].

TargetActionsOrganism
UPeroxisome proliferator-activated receptor alpha
agonist
Human
UPeroxisome proliferator-activated receptor gamma
agonist
Human
Absorption

Following oral ingestion, serum isoflavone concentrations increase in a dose-dependent manner [1]. Isoflavones are metabolized by gut microflora, where they need to undergo deglycosylation in order to be absorbed in the intestine [4]. After oral ingestion, glycosylated isoflavones are rapidly deglycosylated, absorbed and metabolized in intestinal enterocytes and liver, entering the systemic circulation predominantly as conjugates with limited bioavailability [4]. In humans, the mean time to reach peak plasma concentrations (Tmax) for conjugated and unconjugated genistein and daidzein are approximately 5-6 and 6-8 hours, respectively [4].

Volume of distribution

Isoflavones are readily distributed to all tissues, and they are known to cross the placental barrier and blood brain barrier [4]. They are also distributed to the extra-vascular compartments. In a human study, the volume of distribution of daidzein and genistein were 336.25 L and 258.76 L, respectively [4].

Protein binding

No pharmacokinetic data available.

Metabolism

The conversion of glycosylated isoflavones to de glycosylated isoflavones begins in the oral cavity, wherein oral microflora and oral epithelium exhibit β-glucosidase activity [4]. Further conversion is mediated by intestinal lactase phlorizin hydrolase on the luminal side of the intestinal brush border to form aglycones that diffuses into the enterocytes [4]. The glycosylated isoflavones may also be converted to aglycone in the large intestines by the resident intestinal microflora. Isoflavone aglycones that enter the intestinal cell via passive diffusion are rapidly conjugated into sulfate or glucuronide conjugates [4].

Under the anaerobic, reductive conditions of the colon, genistein undergoes reduction to form dihydrogenistein and further to 5-hydroxyequol, while daidzein is reduced to dihydrodaidzein and equol [4]. Microbial cleavage of the Ring-C of isoflavones produces deoxybenzoin metabolites (DOBs), which retains similar biological activity as unchanged isoflavones and are passively absorbed [4]. There is a large interindividual variation in isoflavone metabolism, leading to circulating concentrations of isoflavone metabolites and parent isoflavones varying up to hundreds-fold [1]. About 25% of the non-Asian and 50% of the Asian population host the intestinal bacteria that convert the daidzein into the isoflavonoid equol, which is a beneficial isoflavonoid [1].

Route of elimination

Renal excretion is the predominant route of elimination for dietary isoflavones, where approximately 10-60% of total administered dose is excreted in urine [4]. Glucuronide conjugates account for the majority (70-90%) of the isoflavone content in urine, followed by sulphate conjugates (10-25%) and aglycone forms (1-10%) [4]. Fecal excretion is minimal, which accounts for 1-4% of the dietary isoflavone ingested [4].

Half life

The half-life of isoflavones is between 4 and 8 h [1]. Daidzein has a longer intestinal half-life than genistein due to more rapid degradation of genistein [3]. Individual half-life of daidzein and genistein in a human pharmacokinetic study were 7.75 h and 7.77 h, respectively [4].

Clearance

In a human study, the clearance rate for daidzein and genistein were 30.09 L/h and 21.85 L/h, respectively [4].

Toxicity

No toxicokinetic data available.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Isoflavone which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Isoflavone which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Isoflavone which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Messina M: Soy foods, isoflavones, and the health of postmenopausal women. Am J Clin Nutr. 2014 Jul;100 Suppl 1:423S-30S. doi: 10.3945/ajcn.113.071464. Epub 2014 Jun 4. [PubMed:24898224]
  2. Xiao CW: Health effects of soy protein and isoflavones in humans. J Nutr. 2008 Jun;138(6):1244S-9S. doi: 10.1093/jn/138.6.1244S. [PubMed:18492864]
  3. Kalaiselvan V, Kalaivani M, Vijayakumar A, Sureshkumar K, Venkateskumar K: Current knowledge and future direction of research on soy isoflavones as a therapeutic agents. Pharmacogn Rev. 2010 Jul;4(8):111-7. doi: 10.4103/0973-7847.70900. [PubMed:22228950]
  4. Chandrasekharan S: Pharmacokinetics of Dietary Isoflavones Journal of Steroids & Hormonal Science.
External Links
KEGG Compound
C00799
PubChem Compound
72304
PubChem Substance
347828325
ChemSpider
65255
ChEBI
18220
ChEMBL
CHEMBL366460
Wikipedia
Isoflavones
MSDS
Download (46.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAtrophy1
3Unknown StatusTreatmentMenopause1
3Unknown StatusTreatmentPostmenopausal Syndrome1
4CompletedTreatmentMenopausal Hot Flushes1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00843 mg/mLALOGPS
logP3.51ALOGPS
logP3.34ChemAxon
logS-4.4ALOGPS
pKa (Strongest Basic)-5.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area26.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity65.74 m3·mol-1ChemAxon
Polarizability23.64 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - EI-BGC-MSsplash10-00di-4390000000-b4cbfa0f201f2f6fa3db
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as isoflavones. These are polycyclic compounds containing a 2-isoflavene skeleton which bears a ketone group at the C4 carbon atom.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Isoflavonoids
Sub Class
Isoflav-2-enes
Direct Parent
Isoflavones
Alternative Parents
Chromones / Pyranones and derivatives / Benzene and substituted derivatives / Heteroaromatic compounds / Oxacyclic compounds / Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Isoflavone / Chromone / Benzopyran / 1-benzopyran / Pyranone / Benzenoid / Monocyclic benzene moiety / Pyran / Heteroaromatic compound / Oxacycle
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
isoflavones (CHEBI:18220) / Isoflavonoids (LMPK12050000) / a small molecule (ISOFLAVONE)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleyleth...
Gene Name
PPARA
Uniprot ID
Q07869
Uniprot Name
Peroxisome proliferator-activated receptor alpha
Molecular Weight
52224.595 Da
References
  1. Mezei O, Banz WJ, Steger RW, Peluso MR, Winters TA, Shay N: Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells. J Nutr. 2003 May;133(5):1238-43. doi: 10.1093/jn/133.5.1238. [PubMed:12730403]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE...
Gene Name
PPARG
Uniprot ID
P37231
Uniprot Name
Peroxisome proliferator-activated receptor gamma
Molecular Weight
57619.58 Da
References
  1. Mezei O, Banz WJ, Steger RW, Peluso MR, Winters TA, Shay N: Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells. J Nutr. 2003 May;133(5):1238-43. doi: 10.1093/jn/133.5.1238. [PubMed:12730403]

Drug created on October 20, 2016 15:10 / Updated on November 02, 2018 07:18