Equol

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Equol
Equol structure.png
Names
IUPAC name
(3S)-Isoflavan-4,7′-diol
Preferred IUPAC name
(3S)-3-(4-Hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-7-ol
Other names
4',7-Isoflavandiol
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.007.749 Edit this at Wikidata
KEGG
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C15H14O3/c16-13-4-1-10(2-5-13)12-7-11-3-6-14(17)8-15(11)18-9-12/h1-6,8,12,16-17H,7,9H2/t12-/m1/s1 checkY
    Key: ADFCQWZHKCXPAJ-GFCCVEGCSA-N checkY
  • InChI=1/C15H14O3/c16-13-4-1-10(2-5-13)12-7-11-3-6-14(17)8-15(11)18-9-12/h1-6,8,12,16-17H,7,9H2/t12-/m1/s1
    Key: ADFCQWZHKCXPAJ-GFCCVEGCBP
SMILES
  • C1C(COC2=C1C=CC(=C2)O)C3=CC=C(C=C3)O
  • Oc1ccc(cc1)[C@@H]2Cc3c(OC2)cc(O)cc3
Properties
Chemical formula
 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).
checkY  (what is checkY☒N ?)
Infobox references

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. However, 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 effectiveness in metabolizing the soy isoflavone 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 the enantiomers, (S)-equol and (R)-equol. However, only (S)-equol is produced in humans and animals with the ability to produce equol after soy isoflavone consumption. (S)-Equol is not of plant origin. It is a metabolite of the soy isoflavone daidzein. (S)-equol thus is characterized as an isoflavan.[6] In contrast, R-equol is not made in humans, but can be chemically synthesized, such as in the laboratory.[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, in contrast, binds to ERα (Ki = 50 nM) with 3.5-fold selectivity over ERβ.[3] (S)-Equol has about 2% of the affinity for the human estrogen receptor alpha (ERα) estrogen compared to estradiol. (S)-Equol has a stronger affinity for the human estrogen receptor beta (ERβ), yet this affinity is still just 20% that of estradiol. The preferential binding of (S)-equol to ERβ, compared to ERα and to that of estradiol, indicates 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 the daidzein is 4 to 10 hours because it occurs in a glycoside (with a glucose side chain) form, and the body must, in order to use daidzein, convert daidzein to its aglycone form (without the glucose side chain), achieved through removal of the sugar during digestion. If consumed directly in aglycone form, daidzein has a Tmax of one to three hours.[15] Also, the percent fractional elimination of (S)-equol in urine after oral administration is extremely high and, in some adults, can be close to 100 percent, which is far higher than the percent fractional eliminations of either daidzein (30 to 40 percent) or genistein (7 to 15 percent).[16]

Production in humans[]

Not all humans can produce (S)-equol after soy consumption.[8] The ability to do so depends on having certain strains of bacteria living within the intestine. Twenty-one different strains of intestinal bacteria cultured from humans 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 population of Western countries produces (S)-equol after eating soy foods containing isoflavones,[10][17][18][19] significantly lower than the reported 50 to 60 percent frequency of equol-producers in adults from Japan, Korea, or China.[20][21][22][23] Vegetarians are more capable of transforming daidzein in this substance too.[24] In research studies, the ability of a person to produce (S)-equol is determined with a standardized test in which the person, who has not had antibiotics for at least a month prior to testing, drinks two 240 milliliter glasses of soy milk or eats a soy food equivalent for three days followed by measurement of (S)-equol concentrations in their urine on the test's fourth day.[25] Seaweed and dairy consumption enhances the production of equol.[10][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 can produce a complete conversion of daidzein to (S)-equol,[27] are the following:[28]

  • Adlercreutzia equolifaciens
  • Asaccharobacter celatus AHU1763
  • Bacteroides ovatus
  • Bifidobacterium
  • Bifidobacterium animalis
  • Coriobacteriaceae sp MT1B9
  • Eggerthella sp YY7918
  • Enterococcus faecium
  • Eubacterium sp D1 and D2
  • Finegoldia magna
  • Lactobacillus mucosae
  • Lactobacillus sp Niu-O16
  • Lactococcus garvieae (Lc 20-92)
  • Ruminococcus productus
  • Slackia sp HE8
  • Slackia equolifaciens (Strain DZE)
  • Streptococcus intermedius
  • Veillonella sp

However, the Bifidobacterium conversion has only been claimed once by Tsangalis et al. 2002, 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 effect of Equol as anti-aging and skin health improving substance was shown in different studies. Equol can occur as different isomeres: R-equol, S-equol and RS-equol. Each of these forms has different characters, bioavailabilities and molecular effects.[29] As an antioxidative operating substance, equol can decrease the aging process by reducing ROS events. Additionally, the phytoestrogenic properties influence the skin health positively.[30]

According to a study, the isomer RS-equol, has the best positive impact, especially when applied topically.[29]

Equol was shown to have beneficial effects on different skin parameters, such as molecular und structural ones. Additionally, the topical treatment with equol can lead to an increase of telomere length. It may also have a positive impact on epigenetic regulation leading to a reduced aging process in skin.[31] Moreover, a reduction of dark circles and also of eye wrinkles after the treatment with equol was shown.[32]

Furthermore, there is evidence for the potential role of equol as protective antiphotoaging substance, through its antioxidant action against acute UVA- induced lipid peroxidation.[33]

Another health benefit of treatment with equol as antioxidative and anti-inflammatory substance may be its protecting property against pollution.[34]

Other health effects[]

Furthermore, equol has also a proven effect on other different conditions, as for example in the treatment of menopausal symptoms. The treatment with equol could relieve hot flashes, and muscle and joint pain.[35][36] Other studies were able to point out the positive effect of RS-equol on symptoms of menopausal vaginal atrophy, such as vaginal itching, vaginal dryness, or pain with intercourse. Another consequence was a positive shift of vaginal bacteria, composition of vaginal cells, and ph-value.[37]

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. ^ a b Wang XL, Hur HG, Lee JH, Kim KT, Kim SI (January 2005). "Enantioselective synthesis of S-equol from dihydrodaidzein by a newly isolated anaerobic human intestinal bacterium". Appl. Environ. Microbiol. 71 (1): 214–9. doi:10.1128/AEM.71.1.214-219.2005. PMC 544246. PMID 15640190.
  3. ^ a b c 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. ^ Frankenfeld CL, Atkinson C, Thomas WK, et al. (December 2005). "High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart". Br. J. Nutr. 94 (6): 873–6. 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. PMC 1261026. PMID 16744928.
  6. ^ a b c d 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. PMC 2884333. 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. PMC 1163650. PMID 7082293.
  8. ^ a b 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. S2CID 4467689.
  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. ^ a b c 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 (Maywood, N.J.). 230 (3): 155–70. doi:10.1177/153537020523000302. PMID 15734719. S2CID 14112442.
  11. ^ Mueller SO, Simon S, Chae K, Metzler M, Korach KS (April 2004). "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. doi:10.1093/toxsci/kfh147. PMID 15084758.
  12. ^ Setchell, KD; Clerici, C; Lephart, ED; Cole, SJ; Heenan, C; Castellani, D; Wolfe, BE; Nechemias-Zimmer, L; Brown, NM; Lund, TD; Handa, RJ; Heubi, JE (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. PMC 4040308. 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. PMC 2744624. 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. PMC 2884334. 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. S2CID 23496918.
  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. S2CID 10603402.
  20. ^ Watanabe, S; Yamaguchi, M; Sobue, T; Takahashi, T; Miura, T; Arai, Y; Mazur, W; Wähälä, K; Adlercreutz, H (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; Kim, WJ; Song, JM; Pantuck, AJ (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. PMC 3074428. PMID 20347861.
  25. ^ 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.
  26. ^ 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.
  27. ^ Setchell KD, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, Wolfe BE, Nechemias-Zimmer L, Brown NM, Lund TD, Handa RJ, Heubi JE (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". Am. J. Clin. Nutr. 81 (5): 1072–9. 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. PMC 2884333. PMID 20519412.
  29. ^ a b 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.
  30. ^ Lephart ED (November 2016). "Skin aging and oxidative stress: Equol's anti-aging effects via biochemical and molecular mechanisms". Ageing Research Reviews. 31: 36–54. doi:10.1016/j.arr.2016.08.001. PMID 27521253.
  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. S2CID 44910993.
  32. ^ 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
  33. ^ 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
  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. ^ Efficacy and safety of natural S-equol supplement in US postmenopausal women. Belinda H. Jenks of Scientific Affairs, Pharmavite LLC, Northridge, CA, et.al.
  36. ^ 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
  37. ^ 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". Journal für Gynäkologische Endokrinologie/Österreich (in German). 29 (1): 13–22. doi:10.1007/s41974-019-0085-9. ISSN 1996-1553.
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