Submitted Successfully!
Thank you for your contribution! You can also upload a video entry related to this topic through the link below:
https://encyclopedia.pub/user/video_add?id=27457
Check Note
2000/2000
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 2711 2022-09-22 03:48:20 |
2 format change Meta information modification 2711 2022-09-22 05:30:26 |
Biosynthesis Pathway and Metabolism of Isoflavones
Edit
Upload a video

Isoflavones have been widely studied and have attracted extensive attention in fields ranging from chemotaxonomy and plant physiology to human nutrition and medicine. Isoflavones are often divided into three subgroups: simple O-substituted derivatives, prenylated derivatives, and glycosides. Simple O-substituted isoflavones and their glycosides, such as daidzein (daidzin), genistein (genistin), glycitein (glycitin), biochanin A (astroside), and formononetin (ononin), are the most common ingredients in legumes and are considered as phytoestrogens for daily dietary hormone replacement therapy due to their structural similarity to 17-β-estradiol. On the basis of the known estrogen-like potency, these above isoflavones possess multiple pharmacological activities such as antioxidant, anti-inflammatory, anticancer, anti-angiogenetic, hepatoprotective, antidiabetic, antilipidemic, anti-osteoporotic, and neuroprotective activities. 

isoflavones biosynthesis metabolism
Information
Contributors : , , ,
View Times: 100
Revisions: 2 times (View History)
Update Time: 22 Sep 2022

1. Introduction

Plant secondary metabolites (natural products) are produced by the plant cells in plant–environment interactions through some metabolic pathways derived from the primary metabolic pathways. As the products of plant–environment interactions, some plant secondary metabolites function as phytoalexins or phytoantibiotics to protect plants from pathogens. Later on, researchers found that they had antibacterial, antifungal, and antiviral activities in humans. Scientists have continuously pointed out that plant secondary metabolites play important roles in plant physiology, plant pathology, human nutrition, and medicine. Plant secondary metabolites are represented by a variety of low molecular weight organic compounds. According to their structure, plant secondary metabolites are classified into several classes, such as terpenoids, glycosides, phenolics, and alkaloids [1][2]. Flavonoids are the largest and most studied subclass of the phenolics class among many plant secondary metabolites. According to the characteristics of chemical structure, flavonoids can be divided into two main groups: the flavonoids group (mainly including flavanones, flavanonols, flavones, flavonols, flavan-3-ols, flavan-4-ols, and anthocyanidins) and the isoflavonoids group (mainly including isoflavones, isoflavans, pterocarpans, and rotenoids). The structure of flavonoids comprises the 2-phenylchroman skeleton, which is a linear C6-C3-C6 skeleton derived from a phenylpropanoid (C6-C3) starter and three C2 elongation units. However, the structure of the isoflavonoids group comprises the 3-phenylchroman skeleton, which is derived from the 2-phenylchroman skeleton via an aryl migration reaction (Figure 1) [3]. Isoflavonoids have been widely studied and have attracted substantial attention in fields ranging from chemotaxonomy and plant physiology to human nutrition and medicine. In chemotaxonomy, isoflavonoids are recognized as chemosystematic markers due to their presence and distribution in different plants. In general, isoflavonoids are mostly found in legumes (Fabaceae family), such as Astragalus spp., Dalbergia odorifera T. C. Chen, Glycyrrhiza spp. (Licorice), Glycine max (L.) Merr. (soybean), Hedysarum multijugum Maxim, Iris spp., Lupinus spp., Medicago spp. (barrel medic), Pueraria montana var. lobata (Lour.) Merr., Sophora flavescens Aiton, and Trifolium spp. (clover). Occasionally, isoflavonoids can be found in 31 non-leguminous families, such as Asteraceae, Chenopodiaceae, Iridaceae, Moraceae, Myristicaceae, and Nyctaginaceae [4][5][6][7][8]. In plant physiology, isoflavonoids are considered as phytoalexins or phytoantiobiotics due to their antifungal and insecticidal properties. In human nutrition and medicine, isoflavonoids are known as phytoestrogens due to their structural similarity with 17-β-estradiol. So far, approximately 1600 isoflavonoids have been identified, seven subclasses (isoflavones, isoflavans, isoflavanones, isoflavanols, pterocarpans, coumestans, and rotenoids) are mainly mentioned, which are generated through the biosynthetic modification of core (general or central) phenylpropanoid pathways and downstream flavonoid/isoflavonoid branch pathways. In general, isoflavones are the most important and largest subgroup of isoflavonoids, and they often serve as precursors of other isoflavonoid phytoalexins such as isoflavans, pterocarpans, rotenoids, and coumestans due to their core isoflavonoid scaffold. According to the difference in the substitutions and the position of substitutions on the basic structural skeleton, isoflavones are often divided into three subgroups: simple O-substituted derivatives (i.e., hydroxy, methoxy, methylenedioxy, etc.), prenylated derivatives (i.e., prenyl, isoprenyl, etc.), and glycosides [4][5][6][7][8]. Among these three subgroups of isoflavones, simple O-substituted isoflavones such as daidzein, genistein, glycitein, biochanin A, and formononetin are the most common ingredients in the legumes used as daily dietary supplements. The glycosides of simple O-substituted isoflavones (daidzin, genistin, glycitin, ononin, and astroside) are more abundant than these aglycones in the legumes. Due to their structural similarity with 17-β-estradiol, these above isoflavones (simple O-substituted isoflavones, as well as their glycosides and metabolites) are considered to possess estrogen-like properties via binding to estrogen receptors (ERs), leading to the activation of estrogen-related receptor response elements (ERRE) located on the inner side of the nuclear membrane, and, in turn. promoting gene transcription processes. However, simple O-substituted isoflavones usually possess a higher affinity for ERs than their glycosides. As for the affinity of their metabolites for ERs, there is a large degree of variability. For example, the affinity of equol for ERs is greater than that of its parent isoflavone-daidzein, and almost equivalent to that of genistein. However, O-desmethylangolensin (O-DMA) has a weaker affinity for ERs almost equivalent to its parent isoflavone-daidzein. Hence, these simple O-substituted isoflavones and some metabolites are recognized as phytoestrogens for use as dietary estrogen supplements in alternative hormone replacement therapy [9][10][11][12]. Many researchers have studied the various pharmacological activities of these novel simple O-substituted isoflavones (daidzein, genistein, glycitein, formononetin, and biochanin A), their glycosides (including daidzin, genistin, glycitin, ononin, and astroside), and their metabolites (equol and O-DMA). These novel simple O-substituted isoflavones, as well as their glycosides and metabolites, possess many pharmacological activities similar to estrogen, including antioxidant, anti-inflammatory, anticancer, anti-angiogenetic, hepatoprotective, antidiabetic, antilipidemic, anti-osteoporotic, and neuroprotective activities. Some review studies on versatile pharmacological potential, anticancer, antidiabetic, and antilipidemic activities have been presented for individual isoflavones, such as soy isoflavones, genistein, genistin, formononetin, biochanin A, equol, and O-DMA [9][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. However, there are very few review studies on the protective effects of these novel O-substituted isoflavones in cerebral IR (Figure 2).
Figure 1. Core structures of flavonoids and isoflavonoids.
Figure 2. Structures of novel simple O-substituted isoflavones.

2. The Biosynthesis Pathway of Isoflavones

The biosynthesis pathway and related enzymes of isoflavones have been investigated extensively using biochemical and genetic methods. Nearly all enzymes in isoflavone biosynthesis have been isolated, and their structure and functional characterization are understood. Isoflavonoids are synthesized through the core phenylpropanoid pathway and downstream flavonoids/isoflavonoids biosynthetic branch pathway (Figure 3) [32][33].
Figure 3. The core phenylpropanoid pathway and isoflavones biosynthesis pathway. 4CL, 4-coumarate CoA-ligase; C4H, cinnamate 4-hydroxylase; CHI, chalcone isomerase; CHR, chalcone reductase; CHS, chalcone synthase; F6H, flavonoid 6-hydroxylase; HI4′OMT, hydroxyisoflavanone 4′-specific O-methyltransferase; HID, 2-hydroxyisoflavanone dehydratase; HIOMT, hydroxyisoflavanone O-methyltransferase; I2′H, isoflavone 2′hydroxylase; IFS, isoflavone synthase; MT, malonyltransferases; PAL, phenylalanine ammonia-lyase. UGTs. UDP-glycosyltransferases.
The core phenylpropanoid pathway is an important metabolic pathway in plant–environment interactions, which produces secondary metabolites, such as flavonoids and isoflavonoids, from the main substrates, such as phenylalanine or tyrosine. In the initial step of the core phenylpropanoid pathway, phenylalanine (produced from the shikimate pathway) is deaminated by phenylalanine ammonia-lyase (PAL) into cinnamic acid, a precursor of various phenylpropanoids. Then, cinnamic acid is hydroxylated into p-coumarate by cinnamate 4-hydroxylase (C4H). In the final step of the core phenylpropanoid pathway, p-coumarate was converted to p-coumaroyl-CoA by 4-coumarate CoA-ligase (4CL). p-Coumaroyl CoA is at the junction of the downstream biosynthetic branch pathways leading to flavonoid/isoflavonoid/pterocarpan biosynthesis, to flavonoid/anthocyanin/condensed tannin biosynthesis, or to lignin/lignan biosynthesis [34][35].
Chalcone synthase (CHS) is the first committed enzyme of the flavonoid/anthocyanin/condensed tannin and flavonoid/isoflavonoid branch pathway. CHS catalyzes the formation of a tetrahydrochalcone–naringenin chalcone (4,2′,4′,6′-tetrahydroxychalcone) from one molecule of p-coumaroyl-CoA (produced from the core phenylpropanoid pathway) with three malonyl-CoA molecules (produced from acetate pathway) through the stepwise condensation. This naringenin chalcone is catalyzed by chalcone isomerase (CHI) to form one flavanone–naringenin (5,7,4′-trihydroxy-flavanone) through intramolecular cyclization. This step is recognized as one branch of the flavonoid/isoflavonoid/pterocarpan biosynthesis pathway, but it is a common step in most plants. The other branch of the flavonoid/isoflavonoid/pterocarpan biosynthesis pathway is carried out via the co-action of CHS and legume-specific chalcone reductase (CHR) in most legume species. One trihydroxychalcone isoliquiritigenin (4,2′,4′-trihydroxychalcone) is formed from one molecule of p-coumaroyl-CoA and three malonyl-CoA molecules, which are catalyzed by CHS and CHR. Then isoliquiritigenin is also transformed into one flavanone liquiritigenin (4′,7-dihydroxyflavanone) by CHI. The two flavanone intermediates-naringenin and liquiritigenin are successively converted into 2-hydroxyisoflavanones (2-hydroxy-2,3 dihydrogenistein and 2,7,4′-trihydroxyisoflavanone) by isoflavone synthase (IFS, also called 2-hydroxyisoflavanone synthase (2-HIS)) through the aryl migration reaction of the aromatic B-ring from the C-2 to the C-3 position and hydroxylation at the C-2 position. Then the intermediate 2-hydroxyisoflavanones are dehydrated by 2-hydroxyisoflavanone dehydratase (HID) to form the corresponding isoflavones (genistein and daidzein) through the formation of a double bond between the C-2 position and C-3 position of the C-ring. On the other hand, liquiritigenin is first converted into 6-hydroxyflavanone (6,7,4′-trihydroxy flavanone) by flavonoid 6-hydroxylase (F6H). Then, 6,7,4′-trihydroxyflavanone is gradually transformed into 6-hydroxydaidzein by IFS and HID [32][33].
These two isoflavones (genistein and daidzein) are precursors of other isoflavone derivatives because they have a core isoflavone scaffold. They undergo a variety of modification reactions, such as methylation, acetylation, hydroxylation, glycosylation, and malonylation. Among these modification reactions, O-methylation often occurs in the early stage of the flavonoid/isoflavonoid/pterocarpan biosynthesis pathway. This modification increases the lipophilicity of isoflavones and reduces their chemical reactivity, leading to an increase in their antimicrobial activities and their use as phytoalexins for disease resistance in the plants. The most common site of methylation is at the 4′ position of isoflavones. Hydroxyisoflavanone 4′-specific O-methyltransferase (HI4′OMT) catalyzes the transfer of a methyl group to a specific hydroxyl group of these two isoflavones (genistein and daidzein), forming biochanin A and formononetin. Biochanin A and formononetin are also produced from the catalysis of 2-hydroxy isoflavanone (2-hydroxy-2,3 dihydrogenistein and 2,7,4′-trihydroxyisoflavanone) by HI4′OMT and HIS. On the other hand, 6-hydroxydaidzein is also modified by hydroxyisoflavanone O-methyltransferase (HIOMT) to form glycitein. Additionally, glycosylation is the most frequently occurring and most extensive modification of isoflavones. This modification often reflects the interaction between plants and symbiotic or pathogenic microorganisms, and these glycosylated isoflavones are often one of the constitutive storage forms of isoflavones that accumulate in the central vacuole or other compartments. Hence, the content of glycosylated isoflavones (isoflavone glycoside) is higher than that of their aglycone forms in some plants. This modification alters their solubility and chemical properties, leading to different bioavailability, pharmacokinetics, and biological activity toward human health relative to aglycone forms. UDP-glycosyltransferases (UGTs) catalyze the addition of the glycosyl group from a nucleotide sugar (such as UDP sugar donors) to an isoflavone aglycone. Hence, the two core isoflavones (genistein and daidzein) and two 4′-methoxy derivative isoflavones (biochanin A and formononetin) undergo 7-O-glycosylation by UGTs and produce isoflavone 7-O-glycosides, such as genistin, daidzin, astroside, and ononin. Glycitein also undergoes 7-O-glycosylation by UGTs to form isoflavone 7-O-glycoside glycitin. Malonylation follows the process of glycosylation, potentially preventing the enzymatic degradation of the glycosylated isoflavones through altering their lipophilicity. Hence, malonyl isoflavones are also among the constitutively storage forms of isoflavones. Genistin, daidzin, and glycitin are further converted into their respective malonyl derivatives—malonyl genistin, malonyl daidzin, and malonyl glycitin by malonyltransferases (MTs) [32][33][36].
When plants are exposed to some stress factors, such as pathogens, UV radiation and high metal salts, pterocarpans are synthesized from core isoflavones such as daidzein, formononetin, and genistein. These above isoflavones are first converted into 2′-hydroxyisoflavones by isoflavone 2′-hydroxylase (I2′H), and then catalyzed by a series of various enzymes to form various pterocarpans in various plants. For example, daidzein is finally metabolized into glyceollin I, II, and III through the formation of intermediate metabolite 2′-hydroxydaidzein in soybean. Formononetin is finally metabolized into medicarpin, glycinol, and pisatin through the formation of intermediate metabolite 2′-hydroxyformononetin in Medicago truncatula Gaertn. [37].

3. The Metabolism of Isoflavones

These simple O-substituted isoflavones are widely present in leguminous plants (such as soybean and clover), and these plants are used in large quantities as feed for farm animals; accordingly, the metabolic processes of isoflavones have been extensively studied in sheep, cattle, goats, poultry, and humans [38][39]. The previous section described that simple O-substituted isoflavones mostly exist in plants in their glycoside form. However, isoflavone glycosides usually have higher hydrophilicity, resulting in low absorbance and low bioavailability because of the additional sugar group in the structure. Numerous studies have pointed out that deglycosylation via intestinal β-glycosidase is an important first step in the processes of metabolism, excretion, and biological activities of the isoflavone glycosides (genistin, daidzin, astroside, ononin, and glycitin) of these simple O-substituted isoflavones (genistein, daidzein, biochanin A, formononetin, and glyceitin). When these isoflavone glycosides are ingested from the dietary supplements, they are converted to the free O-substituted isoflavone aglycones through the hydrolysis of glycosidic bonds (deglycosylation or hydrolysis reaction) by intestinal β-glycosidase of the small intestinal microbiota and gastrointestinal mucosal cells. Then, the released aglycones are either absorbed intact through the epithelium of the small intestine (jejunum) or subjected to further metabolic processes (such as glucuronidation and sulfanation) by the intestinal microbiota [40][41]. For example, daidzin, genistin, glycitin, astroside, ononin, and glycitin are decomposed into daidzein, genistein, glycitein, biochanin A, formononetin, and glyceitin by intestinal β-glycosidase, respectively (Figure 4A,B). These free aglycones are derived from the original dietary supplements and from glycoside hydrolysis, thus, they are absorbed at different times (two stages) after ingestion. In pharmacokinetic investigation, the time of peak plasma concentrations of aglycones after ingesting aglycones is from 4–7 h, but the time after ingesting the glycosides is shifted to between 8 and 11 h [41][42][43]. After the ingestion of the dietary supplements containing O-substituted isoflavones, the plasma concentration curve of aglycones shows a double-peak pattern. There is an early increase in aglycone plasma concentrations within 30 min and 2 h after ingestion and then a second peak appears after between 4a and 8 h [44]. Hence, O-substituted isoflavone aglycones, which are less abundant, are first absorbed in the stomach, duodenum, and proximal jejunum. Then, the initial hydrolysis (deglycosylation) of O-substituted isoflavone glycosides is the rate-limiting step for absorption of these glycosides. Once absorbed, the free aglycones are transported to the liver, and then the hepatic microsomes catalyze the conjugation of O-substituted isoflavone glycosides with glucuronate and sulfate, such as daidzein, genistein, and glycitein at the 7- or 4′-position, and biochanin A and formononetin at the 7-position. These glucuronides are excreted in the bile and undergo enterohepatic circulation [45]. Immediately after, a small amount of unhydrolyzed and unabsorbed isoflavone glycosides in the small intestine is decomposed by enterobacterial enzymes in the colon along with the sulfated and glucuronidated forms of isoflavones, which are excreted into the small intestine through enterohepatic circulation. In fact, isoflavone glucuronides (~75%) are the main metabolites of O-substituted isoflavones in the plasma, followed by isoflavone sulfates (~24%), while aglycones only account for less than 1% [42]. Finally, these isoflavone glucuronides and sulfates are excreted in the urine due to their higher water solubility.
Figure 4. Proposed metabolic pathway of novel simple O-substituted isoflavones ((A) daidzin, daidzein, genistin, genistein, biochanin A, and formononetin; (B) glycitin and glycitein). O-DMA, O-desmethylangolensin.
In addition, 7-hydroxyisoflavones (genistein and daidzein) are converted by other metabolic processes (such as reduction and hydroxylation) by the intestinal microbiota and liver microsomes. Genistein is first reduced to dihydrogenistein, and then metabolized to 6′-hydroxy-O-DMA, 4-hydroxyphenyl-2-propionic acid (HPPA), and p-ethyl-phenol through hydroxylation (Figure 4A). Daidzein is also first reduced to dihydrodaidzein and then metabolized to O-DMA, S-equol, 3-hydroxy-equol, and 6-hydroxy-equol through hydroxylation at the 3′- or 6-position (Figure 4A). HPPA and 6′-hydroxy-O-DMA are the two main end metabolites of genistein in humans. O-DMA and S-equol are the two main end metabolites of daidzein in humans [46][47]. Then, S-equol is also conjugated with glucuronate and sulfate at the 7- or 4′-position. Simple 7-hydroxyisoflavones (genistin, genistein, daidzin, daidzein, S-equol, and O-DMA) are mainly excreted with isoflavone glucuronides and sulfates in the urine, whereas a small amount of 7-hydroxyisoflavones is eliminated in the feces.
However, 4′-methoxyisoflavones (biochanin A and formononetin) are firstly converted to daidzein and genistein through O-demethylation. After demethylation, biochanin A (formononetin) and its metabolite genistein (daidzein) undergo glucuronidation and sulfanation. Furthermore, its metabolite genistein (daidzein) is further reduced and hydroxylated to HPPA and 6′-hydroxy-O-DMA (O-DMA and equol) by liver cytochrome P450 isoforms. On the other hand, biochanin A (formononetin) is hydroxylated to 3′,5,7-trihydroxy-4′-methoxyisoflavone (3′,7-dihydroxy-4′-methoxyisoflavone), 5,6,7-trihydroxy-4′-methoxyisoflavone (6,7-dihydroxy-4′-methoxyisoflavone), and 5,7,8-trihydroxy-4′-methoxyisoflavone (7,8-dihydroxy-4′-methoxyisoflavone) at the 3′-,6-, or 8-position by hepatic microsomes. Then, these hydroxylate metabolites are demethylated to additional metabolites [48][49][50] (Figure 4A).
As for glycitein, only a small amount is converted to daidzein through demethoxylation because the proximity of the 6-methoxyl and the 7-hydroxyl groups blocks the demethoxylation. It is predominately reduced to dihydroglycitein, and then metabolized to 6-methoxy equol, 5′-methoxyl-O-DMA, and dihydro-6,7,4′-trihydroxyisoflavone by liver cytochrome P450 isoforms [51] (Figure 4B).

References

  1. Yang, L.; Wen, K.S.; Ruan, X.; Zhao, Y.X.; Wei, F.; Wang, Q. Response of Plant Secondary Metabolites to Environmental Factors. Molecules 2018, 23, 762.
  2. Wink, M. Modes of Action of Herbal Medicines and Plant Secondary Metabolites. Medicines 2015, 2, 251–286.
  3. Nakayama, T.; Takahashi, S.; Waki, T. Formation of Flavonoid Metabolons: Functional Significance of Protein-Protein Interactions and Impact on Flavonoid Chemodiversity. Front. Plant Sci. 2019, 10, 821.
  4. Veitch, N.C. Isoflavonoids of the leguminosae. Nat. Prod. Rep. 2013, 30, 988–1027.
  5. Veitch, N.C. Isoflavonoids of the leguminosae. Nat. Prod. Rep. 2007, 24, 417–464.
  6. Lapcik, O. Isoflavonoids in non-leguminous taxa: A rarity or a rule? Phytochemistry 2007, 68, 2909–2916.
  7. Mackova, Z.; Koblovska, R.; Lapcik, O. Distribution of isoflavonoids in non-leguminous taxa—An update. Phytochemistry 2006, 67, 849–855.
  8. Reynaud, J.; Guilet, D.; Terreux, R.; Lussignol, M.; Walchshofer, N. Isoflavonoids in non-leguminous families: An update. Nat. Prod. Rep. 2005, 22, 504–515.
  9. Mayo, B.; Vazquez, L.; Florez, A.B. Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed Beneficial Health Effects. Nutrients 2019, 11, 2231.
  10. Rafii, F. The role of colonic bacteria in the metabolism of the natural isoflavone daidzin to equol. Metabolites 2015, 5, 56–73.
  11. Pilsakova, L.; Riecansky, I.; Jagla, F. The physiological actions of isoflavone phytoestrogens. Physiol. Res. 2010, 59, 651–664.
  12. Frankenfeld, C.L. O-desmethylangolensin: The importance of equol’s lesser known cousin to human health. Adv. Nutr. 2011, 2, 317–324.
  13. Luo, M.; Yang, Z.Q.; Huang, J.C.; Wang, Y.S.; Guo, B.; Yue, Z.P. Genistein protects ovarian granulosa cells from oxidative stress via cAMP-PKA signaling. Cell Biol. Int. 2020, 44, 433–445.
  14. Weng, L.; Zhang, F.; Wang, R.; Ma, W.; Song, Y. A review on protective role of genistein against oxidative stress in diabetes and related complications. Chem. Biol. Interact. 2019, 310, 108665.
  15. Uddin, M.S.; Kabir, M.T. Emerging Signal Regulating Potential of Genistein Against Alzheimer’s Disease: A Promising Molecule of Interest. Front. Cell Dev. Biol. 2019, 7, 197.
  16. Tuli, H.S.; Tuorkey, M.J.; Thakral, F.; Sak, K.; Kumar, M.; Sharma, A.K.; Sharma, U.; Jain, A.; Aggarwal, V.; Bishayee, A. Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances. Front. Pharmacol. 2019, 10, 1336.
  17. Thangavel, P.; Puga-Olguin, A.; Rodriguez-Landa, J.F.; Zepeda, R.C. Genistein as Potential Therapeutic Candidate for Menopausal Symptoms and Other Related Diseases. Molecules 2019, 24, 3892.
  18. Schreihofer, D.A.; Oppong-Gyebi, A. Genistein: Mechanisms of action for a pleiotropic neuroprotective agent in stroke. Nutr. Neurosci. 2019, 22, 375–391.
  19. Sureda, A.; Sanches Silva, A.; Sanchez-Machado, D.I.; Lopez-Cervantes, J.; Daglia, M.; Nabavi, S.F.; Nabavi, S.M. Hypotensive effects of genistein: From chemistry to medicine. Chem. Biol. Interact. 2017, 268, 37–46.
  20. Mukund, V.; Mukund, D.; Sharma, V.; Mannarapu, M.; Alam, A. Genistein: Its role in metabolic diseases and cancer. Crit. Rev. Oncol. Hematol. 2017, 119, 13–22.
  21. Devi, K.P.; Shanmuganathan, B.; Manayi, A.; Nabavi, S.F.; Nabavi, S.M. Molecular and Therapeutic Targets of Genistein in Alzheimer’s Disease. Mol. Neurobiol. 2017, 54, 7028–7041.
  22. de Oliveira, M.R. Evidence for genistein as a mitochondriotropic molecule. Mitochondrion 2016, 29, 35–44.
  23. Nabavi, S.F.; Daglia, M.; Tundis, R.; Loizzo, M.R.; Sobarzo-Sanchez, E.; Orhan, I.E.; Nabavi, S.M. Genistein: A Boon for Mitigating Ischemic Stroke. Curr. Top. Med. Chem. 2015, 15, 1714–1721.
  24. Islam, A.; Islam, M.S.; Uddin, M.N.; Hasan, M.M.I.; Akanda, M.R. The potential health benefits of the isoflavone glycoside genistin. Arch. Pharmacal Res. 2020, 43, 395–408.
  25. Ahmed, T.; Javed, S.; Tariq, A.; Budzynska, B.; D’Onofrio, G.; Daglia, M.; Nabavi, S.F.; Nabavi, S.M. Daidzein and its Effects on Brain. Curr. Med. Chem. 2017, 24, 365–375.
  26. Ganai, A.A.; Farooqi, H. Bioactivity of genistein: A review of in vitro and in vivo studies. Biomed. Pharmacother. 2015, 76, 30–38.
  27. Sarfraz, A.; Javeed, M.; Shah, M.A.; Hussain, G.; Shafiq, N.; Sarfraz, I.; Riaz, A.; Sadiqa, A.; Zara, R.; Zafar, S.; et al. Biochanin A: A novel bioactive multifunctional compound from nature. Sci. Total Environ. 2020, 722, 137907.
  28. Yu, C.; Zhang, P.; Lou, L.; Wang, Y. Perspectives Regarding the Role of Biochanin A in Humans. Front. Pharmacol. 2019, 10, 793.
  29. Sekikawa, A.; Ihara, M.; Lopez, O.; Kakuta, C.; Lopresti, B.; Higashiyama, A.; Aizenstein, H.; Chang, Y.F.; Mathis, C.; Miyamoto, Y.; et al. Effect of S-equol and Soy Isoflavones on Heart and Brain. Curr. Cardiol. Rev. 2019, 15, 114–135.
  30. Ong, S.K.L.; Shanmugam, M.K.; Fan, L.; Fraser, S.E.; Arfuso, F.; Ahn, K.S.; Sethi, G.; Bishayee, A. Focus on Formononetin: Anticancer Potential and Molecular Targets. Cancers 2019, 11, 611.
  31. Jiang, D.; Rasul, A.; Batool, R.; Sarfraz, I.; Hussain, G.; Mateen Tahir, M.; Qin, T.; Selamoglu, Z.; Ali, M.; Li, J.; et al. Potential Anticancer Properties and Mechanisms of Action of Formononetin. BioMed Res. Int. 2019, 2019, 5854315.
  32. Wang, X. Structure, function, and engineering of enzymes in isoflavonoid biosynthesis. Funct. Integr. Genom. 2011, 11, 13–22.
  33. Du, H.; Huang, Y.; Tang, Y. Genetic and metabolic engineering of isoflavonoid biosynthesis. Appl. Microbiol. Biotechnol. 2010, 86, 1293–1312.
  34. Biala, W.; Jasinski, M. The Phenylpropanoid Case—It Is Transport That Matters. Front. Plant Sci. 2018, 9, 1610.
  35. Zabala, G.; Zou, J.; Tuteja, J.; Gonzalez, D.O.; Clough, S.J.; Vodkin, L.O. Transcriptome changes in the phenylpropanoid pathway of Glycine max in response to Pseudomonas syringae infection. BMC Plant Biol. 2006, 6, 26.
  36. Anguraj Vadivel, A.K.; Renaud, J.; Kagale, S.; Dhaubhadel, S. GmMYB176 Regulates Multiple Steps in Isoflavonoid Biosynthesis in Soybean. Front. Plant Sci. 2019, 10, 562.
  37. Goel, A.; Kumar, A.; Raghuvanshi, A. Synthesis, stereochemistry, structural classification, and chemical reactivity of natural pterocarpans. Chem. Rev. 2013, 113, 1614–1640.
  38. Lundh, T. Metabolism of estrogenic isoflavones in domestic animals. Proc. Soc. Exp. Biol. Med. 1995, 208, 33–39.
  39. Batterham, T.J.; Hart, N.K.; Lamberton, J.A. Metabolism of oestrogenic isoflavones in sheep. Nature 1965, 206, 509.
  40. Walsh, K.R.; Haak, S.J.; Bohn, T.; Tian, Q.; Schwartz, S.J.; Failla, M.L. Isoflavonoid glucosides are deconjugated and absorbed in the small intestine of human subjects with ileostomies. Am. J. Clin. Nutr. 2007, 85, 1050–1056.
  41. Zubik, L.; Meydani, M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am. J. Clin. Nutr. 2003, 77, 1459–1465.
  42. Gu, L.; House, S.E.; Prior, R.L.; Fang, N.; Ronis, M.J.; Clarkson, T.B.; Wilson, M.E.; Badger, T.M. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J. Nutr. 2006, 136, 1215–1221.
  43. Setchell, K.D.; Brown, N.M.; Desai, P.; Zimmer-Nechemias, L.; Wolfe, B.E.; Brashear, W.T.; Kirschner, A.S.; Cassidy, A.; Heubi, J.E. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J. Nutr. 2001, 131, 1362S–1375S.
  44. Yang, Z.; Kulkarni, K.; Zhu, W.; Hu, M. Bioavailability and pharmacokinetics of genistein: Mechanistic studies on its ADME. Anti-Cancer Agents Med. Chem. 2012, 12, 1264–1280.
  45. Sfakianos, J.; Coward, L.; Kirk, M.; Barnes, S. Intestinal uptake and biliary excretion of the isoflavone genistein in rats. J. Nutr. 1997, 127, 1260–1268.
  46. Lopes, D.B.; de Avila, A.R.A.; de Queiros, L.D.; Macedo, J.A.; Macedo, G.A. Bioconversion of Isoflavones into Bioactive Equol: State of the Art. Recent Pat. Food Nutr. Agric. 2016, 8, 91–98.
  47. Gaya, P.; Medina, M.; Sanchez-Jimenez, A.; Landete, J.M. Phytoestrogen Metabolism by Adult Human Gut Microbiota. Molecules 2016, 21, 1034.
  48. Yin, J.; Zhang, X.; Zhang, Y.; Ma, Y.; Li, L.; Li, D.; Zhang, L.; Zhang, Z. Comprehensive Study of the in Vivo and in Vitro Metabolism of Dietary Isoflavone Biochanin A Based on UHPLC-Q-TOF-MS/MS. J. Agric. Food Chem. 2019, 67, 12481–12495.
  49. Luo, L.Y.; Fan, M.X.; Zhao, H.Y.; Li, M.X.; Wu, X.; Gao, W.Y. Pharmacokinetics and Bioavailability of the Isoflavones Formononetin and Ononin and Their in Vitro Absorption in Ussing Chamber and Caco-2 Cell Models. J. Agric. Food Chem. 2018, 66, 2917–2924.
  50. Tolleson, W.H.; Doerge, D.R.; Churchwell, M.I.; Marques, M.M.; Roberts, D.W. Metabolism of biochanin A and formononetin by human liver microsomes in vitro. J. Agric. Food Chem. 2002, 50, 4783–4790.
  51. Simons, A.L.; Renouf, M.; Hendrich, S.; Murphy, P.A. Metabolism of glycitein (7,4′-dihydroxy-6-methoxy-isoflavone) by human gut microflora. J. Agric. Food Chem. 2005, 53, 8519–8525.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , ,
View Times: 100
Revisions: 2 times (View History)
Update Time: 22 Sep 2022
Table of Contents
    1000/1000

    Confirm

    Are you sure to Delete?

    Video Upload Options

    Do you have a full video?
    Cite
    If you have any further questions, please contact Encyclopedia Editorial Office.
    Yang, S.; Lien, J.; Tsai, C.; Wu, C. Biosynthesis Pathway and Metabolism of Isoflavones. Encyclopedia. Available online: https://encyclopedia.pub/entry/27457 (accessed on 07 October 2022).
    Yang S, Lien J, Tsai C, Wu C. Biosynthesis Pathway and Metabolism of Isoflavones. Encyclopedia. Available at: https://encyclopedia.pub/entry/27457. Accessed October 07, 2022.
    Yang, Shu-Er, Jin-Cherng Lien, Chia-Wen Tsai, Chi-Rei Wu. "Biosynthesis Pathway and Metabolism of Isoflavones," Encyclopedia, https://encyclopedia.pub/entry/27457 (accessed October 07, 2022).
    Yang, S., Lien, J., Tsai, C., & Wu, C. (2022, September 22). Biosynthesis Pathway and Metabolism of Isoflavones. In Encyclopedia. https://encyclopedia.pub/entry/27457
    Yang, Shu-Er, et al. ''Biosynthesis Pathway and Metabolism of Isoflavones.'' Encyclopedia. Web. 22 September, 2022.
    Top
    Feedback