Chemistry:Equol

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Short description: Isoflavandiol estrogen metabolized from daidzein
Equol
Equol structure.png
Names
IUPAC name
(3S)-Isoflavan-4,7′-diol
Systematic IUPAC name
(3S)-3-(4-Hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-7-ol
Other names
4',7-Isoflavandiol
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
UNII
Properties
C15H14O3
Molar mass 242.274 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Equol (4',7-isoflavandiol) is an isoflavandiol[1] estrogen metabolized from daidzein, a type of isoflavone found in soybeans and other plant sources, by bacterial flora in the intestines.[2][3] While endogenous estrogenic hormones such as estradiol are steroids, equol is a nonsteroidal estrogen. Only about 30–50% of people have intestinal bacteria that make equol.[4]

History

(S)-Equol was first isolated from horse urine in 1932,[5] and the name was suggested by this equine connection.[6] Since then, equol has been found in the urine or plasma of many other animal species, although these animals have significant differences in their ability to metabolize daidzein into equol.[6] In 1980, scientists reported the discovery of equol in humans.[7] The ability of (S)-equol to play a role in the treatment of estrogen- or androgen-mediated diseases or disorders was first proposed in 1984.[8]

Chemical structure

Equol is a compound that can exist in two mirror-image forms known as enantiomers: (S)-equol and (R)-equol. (S)-equol is produced in humans and animals with the ability to metabolize the soy isoflavone daidzein, while (R)-equol can be chemically synthesized.[9] The molecular and physical structure of (S)-equol is similar to that of the hormone estradiol.[10] (S)-Equol preferentially binds estrogen receptor beta.[2][11]

Pharmacology

Estrogen receptor binding

(S)-equol is a nonsteroidal, selective agonist of ERβ (Ki = 16 nM) with 13-fold selectivity for ERβ over ERα.[3] Relative to (S)-equol, (R)-equol is less potent and binds to ERα (Ki = 50 nM) with 3.5-fold selectivity over ERβ.[3] (S)-Equol has about 2% of estradiol's binding affinity for human estrogen receptor alpha (ERα) and 20% of estradiol's binding affinity for human estrogen receptor beta (ERβ). The preferential binding of (S)-equol to ERβ vs. ERα and in comparison to that of estradiol suggests the molecule may share some of the characteristics of a selective estrogen receptor modulator (SERM).[12] Equol has been found to act as an agonist of the GPER (GPR30).[13]

Pharmacokinetics

(S)-Equol is a very stable molecule that essentially remains unchanged when digested, and this lack of further metabolism explains its very quick absorption and high bioavailability.[14] When (S)-equol is consumed, it is rapidly absorbed and achieves a Tmax (rate of peak plasma concentration) in two to three hours. In comparison, the Tmax of daidzein is 4 to 10 hours because daidzein exists in glycoside (with a glucose side chain) form. The body must convert daidzein to its aglycone form (without the glucose side chain) via removal of the sugar side chain during digestion before it can use daidzein. If consumed directly in aglycone form, daidzein has a Tmax of one to three hours.[15] The percent fractional elimination of (S)-equol in urine after oral administration is high and in some adults can reach close to 100 percent. The percent fractional elimination of daidzein is much lower at 30 to 40 percent.[16]

Production in humans

To produce (S)-equol after soy consumption, humans must have certain strains of bacteria living within their intestines.[8] Twenty-one different strains of intestinal bacteria cultured from humans have been shown to have the ability to transform daidzein into (S)-equol or a related intermediate compound.[6] Several studies indicate that only 25 to 30 percent of the adult populations of Western countries produce (S)-equol after eating soy foods containing isoflavones,[10][17][18][19] while 50 to 60 percent of adults from Japan, Korea, and China are equol-producers.[20][21][22][23] Vegetarians have also been reported to be more capable of transforming daidzein into (S)-equol.[24] Seaweed and dairy consumption can enhance the production of equol.[10][25] The ability of a person to produce (S)-equol is determined by testing people who have not taken any antibiotics for at least a month. For this standardized test, the individual drinks two 240 milliliter glasses of soy milk or eats a soy food equivalent for three days. The (S)-equol concentration in each test subject's urine is determined on day four.[26]

Equol producing bacteria

While many more bacteria are involved in the related intermediate process of equol production, such as conversion of daidzin to daidzein, or genistein to 5-Hydroxy-equol, the bacteria that achieve the complete conversion of daidzein to (S)-equol,[27] include:[28]

Conversion by Bifidobacterium has only been reported once by Tsangalis et al. in 2002[29] and not reproduced since.Bifidobacteria: Genomics and Molecular Aspects Mixed cultures such as Lactobacillus sp. Niu-O16 and Eggerthella sp. Julong 732 can also produce (S)-equol.Bifidobacteria: Genomics and Molecular Aspects Some equol producing bacteria, as implied by their nomenclature, are Adlercreutzia equolifaciens, Slackia equolifaciens and Slackia isoflavoniconvertens.

Health effects

Skin health

The topical effects of equol as an anti-aging substance have been shown in different studies. The effects result from both molecular and structural changes to the skin. Equol can, for instance, lead to an increase in telomere length. As an antioxidant, equol can decrease the aging process by reducing damage caused by reactive oxygen species (ROS). It may also act as a protective anti-photoaging substance by inhibiting acute UVA- induced lipid peroxidation.[30] In addition, equol may have a positive impact on epigenetic regulation.[31] Equol's phytoestrogenic properties may also affect skin health.[32] Reduction of dark circles and eye wrinkles after treatment with equol has been reported.[33] Equol may also protect skin from damage by pollution due to its anti-oxidative and anti-inflammatory properties.[34]

Each of the enantiomers and the racemic mixture of both enantiomers have different characteristics, bioavailabilities and molecular effects.[35] According to one study, (RS)-equol provided the greatest overall improvement in skin health, especially when applied topically.[35]

Hormone-related health effects

Beyond topical effects, medicinal equol has been shown to relieve menopausal symptoms such as hot flashes and muscle and joint pain.[36][37] (RS)-equol was also reported to reduce symptoms associated with menopausal vaginal atrophy, such as vaginal itching, vaginal dryness and pain with intercourse and cause positive shifts in the vaginal bacterial population, cell composition, and pH.[38]

According to animal studies,[39] it has anti-androgenic effects and may lead to inhibited 5-alpha reductase as well as lowered dhydrotestosterone (DHT) levels.

See also

References

  1. ↑ The structures of 7,4’-dihydroxy-isoflavan and its precursors is shown in Structural Elucidation of Hydroxylated Metabolites of the Isoflavan Equol by GC/MS and HPLC/MS by Corinna E. Rüfer, Hansruedi Glatt, and Sabine E. Kulling in Drug Metabolism and Disposition (2005, electronic publication).
  2. ↑ 2.0 2.1 "Enantioselective synthesis of S-equol from dihydrodaidzein by a newly isolated anaerobic human intestinal bacterium". Appl. Environ. Microbiol. 71 (1): 214–9. January 2005. doi:10.1128/AEM.71.1.214-219.2005. PMID 15640190. Bibcode: 2005ApEnM..71..214W. 
  3. ↑ 3.0 3.1 3.2 Muthyala, Rajeev S; Ju, Young H; Sheng, Shubin; Williams, Lee D; Doerge, Daniel R; Katzenellenbogen, Benita S; Helferich, William G; Katzenellenbogen, John A (2004). "Equol, a natural estrogenic metabolite from soy isoflavones". Bioorganic & Medicinal Chemistry 12 (6): 1559–1567. doi:10.1016/j.bmc.2003.11.035. ISSN 0968-0896. PMID 15018930. 
  4. ↑ "High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart". Br. J. Nutr. 94 (6): 873–6. December 2005. doi:10.1079/bjn20051565. PMID 16351761. 
  5. ↑ Marrian, GF; Haslewood, GA (1932). "Equol, a new inactive phenol isolated from the ketohydroxyoestrin fraction of mares' urine". The Biochemical Journal 26 (4): 1227–32. doi:10.1042/bj0261227. PMID 16744928. 
  6. ↑ 6.0 6.1 6.2 Setchell, KD; Clerici, C (July 2010). "Equol: history, chemistry, and formation". The Journal of Nutrition 140 (7): 1355S–62S. doi:10.3945/jn.109.119776. PMID 20519412. 
  7. ↑ Axelson, M; Kirk, DN; Farrant, RD; Cooley, G; Lawson, AM; Setchell, KD (1982-02-01). "The identification of the weak oestrogen equol [7-hydroxy-3-(4'-hydroxyphenyl)chroman in human urine"]. The Biochemical Journal 201 (2): 353–7. doi:10.1042/bj2010353. PMID 7082293. 
  8. ↑ 8.0 8.1 Setchell, KD; Borriello, SP; Hulme, P; Kirk, DN; Axelson, M (September 1984). "Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease". The American Journal of Clinical Nutrition 40 (3): 569–78. doi:10.1093/ajcn/40.3.569. PMID 6383008. 
  9. ↑ Setchell, KD; Brown, NM; Lydeking-Olsen, E (December 2002). "The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones". The Journal of Nutrition 132 (12): 3577–84. doi:10.1093/jn/132.12.3577. PMID 12468591. 
  10. ↑ 10.0 10.1 10.2 Atkinson, C; Frankenfeld, CL; Lampe, JW (March 2005). "Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health". Experimental Biology and Medicine 230 (3): 155–70. doi:10.1177/153537020523000302. PMID 15734719. 
  11. ↑ "Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor {α} (ER{α}) and ERβ in human cells". Toxicol. Sci. 80 (1): 14–25. April 2004. doi:10.1093/toxsci/kfh147. PMID 15084758. http://toxsci.oxfordjournals.org/cgi/content/full/80/1/14. 
  12. ↑ Setchell, KD; Clerici, C; Lephart, ED; Cole, SJ; Heenan, C; Castellani, D; Wolfe, BE; Nechemias-Zimmer, L et al. (May 2005). "S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora". The American Journal of Clinical Nutrition 81 (5): 1072–9. doi:10.1093/ajcn/81.5.1072. PMID 15883431. 
  13. ↑ Prossnitz, Eric R.; Barton, Matthias (2014). "Estrogen biology: New insights into GPER function and clinical opportunities". Molecular and Cellular Endocrinology 389 (1–2): 71–83. doi:10.1016/j.mce.2014.02.002. ISSN 0303-7207. PMID 24530924. 
  14. ↑ Setchell, KD; Zhao, X; Jha, P; Heubi, JE; Brown, NM (Oct 2009). "The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers". The American Journal of Clinical Nutrition 90 (4): 1029–37. doi:10.3945/ajcn.2009.27981. PMID 19710188. 
  15. ↑ Setchell, KD; Zhao, X; Shoaf, SE; Ragland, K (Nov 2009). "The pharmacokinetics of S-(-)equol administered as SE5-OH tablets to healthy postmenopausal women". The Journal of Nutrition 139 (11): 2037–43. doi:10.3945/jn.109.110874. PMID 19776178. 
  16. ↑ Setchell, KD; Clerici, C (Jul 2010). "Equol: pharmacokinetics and biological actions". The Journal of Nutrition 140 (7): 1363S–8S. doi:10.3945/jn.109.119784. PMID 20519411. 
  17. ↑ Lampe, JW; Karr, SC; Hutchins, AM; Slavin, JL (March 1998). "Urinary equol excretion with a soy challenge: influence of habitual diet". Proceedings of the Society for Experimental Biology and Medicine 217 (3): 335–9. doi:10.3181/00379727-217-44241. PMID 9492344. 
  18. ↑ Setchell, KD; Cole, SJ (August 2006). "Method of defining equol-producer status and its frequency among vegetarians". The Journal of Nutrition 136 (8): 2188–93. doi:10.1093/jn/136.8.2188. PMID 16857839. 
  19. ↑ Rowland, IR; Wiseman, H; Sanders, TA; Adlercreutz, H; Bowey, EA (2000). "Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora". Nutrition and Cancer 36 (1): 27–32. doi:10.1207/S15327914NC3601_5. PMID 10798213. 
  20. ↑ Watanabe, S; Yamaguchi, M; Sobue, T; Takahashi, T; Miura, T; Arai, Y; Mazur, W; Wähälä, K et al. (October 1998). "Pharmacokinetics of soybean isoflavones in plasma, urine and feces of men after ingestion of 60 g baked soybean powder (kinako)". The Journal of Nutrition 128 (10): 1710–5. doi:10.1093/jn/128.10.1710. PMID 9772140. 
  21. ↑ Arai, Y; Uehara, M; Sato, Y; Kimira, M; Eboshida, A; Adlercreutz, H; Watanabe, S (March 2000). "Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake". Journal of Epidemiology 10 (2): 127–35. doi:10.2188/jea.10.127. PMID 10778038. 
  22. ↑ Akaza, H; Miyanaga, N; Takashima, N; Naito, S; Hirao, Y; Tsukamoto, T; Fujioka, T; Mori, M et al. (February 2004). "Comparisons of percent equol producers between prostate cancer patients and controls: case-controlled studies of isoflavones in Japanese, Korean and American residents". Japanese Journal of Clinical Oncology 34 (2): 86–9. doi:10.1093/jjco/hyh015. PMID 15067102. 
  23. ↑ Song, KB; Atkinson, C; Frankenfeld, CL; Jokela, T; Wähälä, K; Thomas, WK; Lampe, JW (May 2006). "Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls". The Journal of Nutrition 136 (5): 1347–51. doi:10.1093/jn/136.5.1347. PMID 16614428. 
  24. ↑ Patisaul, HB; Jefferson, W (October 2010). "The pros and cons of phytoestrogens.". Front Neuroendocrinol 31 (4): 400–419. doi:10.1016/j.yfrne.2010.03.003. PMID 20347861. 
  25. ↑ Teas, J.; Hurley, TG (August 2009). "Dietary seaweed modifies estrogen and phytoestrogen metabolism in healthy postmenopausal women". The Journal of Nutrition 139 (9): 939–44. doi:10.3945/jn.108.100834. PMID 19321575. 
  26. ↑ Setchell, KD; Cole, SJ (August 2006). "Method of defining equol-producer status and its frequency among vegetarians". The Journal of Nutrition 136 (8): 2188–93. doi:10.1093/jn/136.8.2188. PMID 16857839. 
  27. ↑ "S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora". Am. J. Clin. Nutr. 81 (5): 1072–9. 2005. doi:10.1093/ajcn/81.5.1072. PMID 15883431. 
  28. ↑ Setchell, K. D.; Clerici, C. (2010). "Equol: History, Chemistry, and Formation". The Journal of Nutrition 140 (7): 1355S–1362S. doi:10.3945/jn.109.119776. PMID 20519412. 
  29. ↑ V, Ravishankar Rai; Bai, Jamuna A. (2014-12-17) (in en). Beneficial Microbes in Fermented and Functional Foods. CRC Press. ISBN 978-1-4822-0663-0. https://books.google.com/books?id=2c_MBQAAQBAJ&dq=Conversion+by+Bifidobacterium+has+only+been+reported+once+by+Tsangalis+et+al.+in+2002&pg=PA295. 
  30. ↑ Reeve V, Widyarini S, Domanski D, Chew K, Barnes K. Protection Against Photoaging in the Hairless Mouse by the Isoflavone Equol. Photochemistry and Photobiology, Volume 81, Issue 6, November 2005, Pages 1548-1553
  31. ↑ Magnet, U.; Urbanek, C.; Gaisberger, D.; Tomeva, E.; Dum, E.; Pointner, A.; Haslberger, A.G. (October 2017). "Topical equol preparation improves structural and molecular skin parameters". International Journal of Cosmetic Science 39 (5): 535–542. doi:10.1111/ics.12408. PMID 28574180. 
  32. ↑ "Skin aging and oxidative stress: Equol's anti-aging effects via biochemical and molecular mechanisms". Ageing Research Reviews 31: 36–54. November 2016. doi:10.1016/j.arr.2016.08.001. PMID 27521253. 
  33. ↑ Urbanek C, Haslberger A, Hippe B, Gessner D, Fiala H, Equol – a Topically Applied Phyto-Oestrogen Improves Skin Characteristics. Global ingredients and Formulations Guide 2016
  34. ↑ Lephart, Edwin (2018-01-29). "Equol's Anti-Aging Effects Protect against Environmental Assaults by Increasing Skin Antioxidant Defense and ECM Proteins While Decreasing Oxidative Stress and Inflammation". Cosmetics 5 (1): 16. doi:10.3390/cosmetics5010016. ISSN 2079-9284. 
  35. ↑ 35.0 35.1 Lephart, Edwin D. (November 2013). "Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin". Pharmaceutical Biology 51 (11): 1393–1400. doi:10.3109/13880209.2013.793720. ISSN 1388-0209. PMID 23862588. 
  36. ↑ Efficacy and safety of natural S-equol supplement in US postmenopausal women. Belinda H. Jenks of Scientific Affairs, Pharmavite LLC, Northridge, CA, et.al.
  37. ↑ Effect of natural S-equol on bone metabolism in equol non-producing postmenopausal Japanese women: a pilot randomized placebo-controlled trial. Tomomi Ueno of Saga Nutraceutricals Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan, et.al
  38. ↑ Mayr, Linda; Georgiev, Dimitar; Toulev, Albena (2019-03-01). "Eine Proof-of-concept-Studie von Isoflavandiol-E55-RS-Vaginalkapseln oder Vaginalgel zur Linderung der menopausalen Vaginalatrophie" (in de). Journal für Gynäkologische Endokrinologie/Österreich 29 (1): 13–22. doi:10.1007/s41974-019-0085-9. ISSN 1996-1553. 
  39. ↑ "Equol Is a Novel Anti-Androgen that Inhibits Prostate Growth and Hormone Feedback, Biology of Reproduction, Volume 70, Issue 4, 1 April 2004, Pages 1188–1195,". https://academic.oup.com/crawlprevention/governor?content=%2fbiolreprod%2farticle%2f70%2f4%2f1188%2f2713057%3flogin%3dfalse. 



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