Equol

(S)-Equol was first isolated from horse urine in 1932,{{cite journal|last=Marrian|first=GF|author2=Haslewood, GA |title=Equol, a new inactive phenol isolated from the ketohydroxyoestrin fraction of mares' urine |journal=The Biochemical Journal|year=1932|volume=26|issue=4|pages=1227–32|pmid=16744928|pmc=1261026|doi=10.1042/bj0261227}} and the name was suggested by this equine connection.{{cite journal|last=Setchell|first=KD|author2=Clerici, C |title=Equol: history, chemistry, and formation |journal=The Journal of Nutrition|date=July 2010|volume=140|issue=7|pages=1355S–62S|pmid=20519412|doi=10.3945/jn.109.119776|pmc=2884333}} 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. In 1980, scientists reported the discovery of equol in humans.{{cite journal|last=Axelson|first=M |author2=Kirk, DN |author3=Farrant, RD |author4=Cooley, G |author5=Lawson, AM |author6=Setchell, KD|title=The identification of the weak oestrogen equol [7-hydroxy-3-(4'-hydroxyphenyl)chroman] in human urine |journal=The Biochemical Journal|date=1982-02-01|volume=201|issue=2|pages=353–7|pmid=7082293|pmc=1163650 |doi=10.1042/bj2010353}} 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.{{cite journal|last=Setchell|first=KD |author2=Borriello, SP |author3=Hulme, P |author4=Kirk, DN |author5=Axelson, M|s2cid=4467689 |title=Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease |journal=The American Journal of Clinical Nutrition|date=September 1984|volume=40|issue=3|pages=569–78|pmid=6383008|doi=10.1093/ajcn/40.3.569 }}

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.{{cite journal|last=Setchell|first=KD |author2=Brown, NM |author3=Lydeking-Olsen, E|title=The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones |journal=The Journal of Nutrition|date=December 2002|volume=132|issue=12|pages=3577–84|pmid=12468591|doi=10.1093/jn/132.12.3577 |doi-access=free}} The molecular and physical structure of (S)-equol is similar to that of the hormone estradiol.{{cite journal|last=Atkinson|first=C|author2=Frankenfeld, CL|author3=Lampe, JW|date=March 2005|title=Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health|journal=Experimental Biology and Medicine|volume=230|issue=3|pages=155–70|doi=10.1177/153537020523000302|pmid=15734719|s2cid=14112442}} (S)-Equol preferentially binds estrogen receptor beta.{{cite journal |vauthors=Mueller SO, Simon S, Chae K, Metzler M, Korach KS |title=Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor {α} (ER{α}) and ERβ in human cells |journal=Toxicol. Sci. |volume=80 |issue=1 |pages=14–25 |date=April 2004 |pmid=15084758 |doi=10.1093/toxsci/kfh147 |url=http://toxsci.oxfordjournals.org/cgi/content/full/80/1/14|doi-access=free }}

(S)-equol is a nonsteroidal, selective agonist of ERβ (K_i = 16 nM) with 13-fold selectivity for ERβ over ERα. Relative to (S)-equol, (R)-equol is less potent and binds to ERα (K_i = 50 nM) with 3.5-fold selectivity over ERβ. (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).{{cite journal|last=Setchell|first=KD |author2=Clerici, C |author3=Lephart, ED |author4=Cole, SJ |author5=Heenan, C |author6=Castellani, D |author7=Wolfe, BE |author8=Nechemias-Zimmer, L |author9=Brown, NM |author10=Lund, TD |author11=Handa, RJ |author12=Heubi, JE|title=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 |journal=The American Journal of Clinical Nutrition|date=May 2005|volume=81|issue=5|pages=1072–9|pmid=15883431|doi=10.1093/ajcn/81.5.1072 |doi-access=free }} Equol has been found to act as an agonist of the GPER (GPR30).{{cite journal|last1=Prossnitz|first1=Eric R.|last2=Barton|first2=Matthias|title=Estrogen biology: New insights into GPER function and clinical opportunities|journal=Molecular and Cellular Endocrinology|volume=389|issue=1–2|year=2014|pages=71–83|issn=0303-7207|doi=10.1016/j.mce.2014.02.002|pmid=24530924|pmc=4040308}}

(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.{{cite journal|last=Setchell|first=KD|author2=Zhao, X |author3=Jha, P |author4=Heubi, JE |author5=Brown, NM |title=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 |journal=The American Journal of Clinical Nutrition|date=Oct 2009|volume=90|issue=4|pages=1029–37|pmid=19710188|doi=10.3945/ajcn.2009.27981|pmc=2744624}}

When (S)-equol is consumed, it is rapidly absorbed and achieves a T_max (rate of peak plasma concentration) in two to three hours. In comparison, the T_max 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 T_max of one to three hours.{{cite journal|last=Setchell|first=KD|author2=Zhao, X |author3=Shoaf, SE |author4=Ragland, K |title=The pharmacokinetics of S-(-)equol administered as SE5-OH tablets to healthy postmenopausal women |journal=The Journal of Nutrition|date=Nov 2009|volume=139|issue=11|pages=2037–43|pmid=19776178|doi=10.3945/jn.109.110874|doi-access=free}}

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.{{cite journal|last=Setchell|first=KD|author2=Clerici, C |title=Equol: pharmacokinetics and biological actions |journal=The Journal of Nutrition|date=Jul 2010|volume=140|issue=7|pages=1363S–8S|pmid=20519411|doi=10.3945/jn.109.119784|pmc=2884334}}

To produce (S)-equol after soy consumption, humans must have certain strains of bacteria living within their intestines. 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. 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,{{cite journal|last=Lampe|first=JW |author2=Karr, SC |author3=Hutchins, AM |author4=Slavin, JL|title=Urinary equol excretion with a soy challenge: influence of habitual diet |journal=Proceedings of the Society for Experimental Biology and Medicine|date=March 1998|volume=217|issue=3|pages=335–9|pmid=9492344|doi=10.3181/00379727-217-44241|s2cid=23496918 }}{{cite journal|last=Setchell|first=KD|author2=Cole, SJ |title=Method of defining equol-producer status and its frequency among vegetarians|journal=The Journal of Nutrition|date=August 2006|volume=136|issue=8|pages=2188–93|pmid=16857839|doi=10.1093/jn/136.8.2188|doi-access=free}}{{cite journal|last=Rowland|first=IR|author2=Wiseman, H |author3=Sanders, TA |author4=Adlercreutz, H |author5=Bowey, EA |title=Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora |journal=Nutrition and Cancer|year=2000|volume=36|issue=1|pages=27–32|pmid=10798213|doi=10.1207/S15327914NC3601_5|s2cid=10603402}} while 50 to 60 percent of adults from Japan, Korea, and China are equol-producers.{{cite journal|last=Watanabe|first=S|author2=Yamaguchi, M |author3=Sobue, T |author4=Takahashi, T |author5=Miura, T |author6=Arai, Y |author7=Mazur, W |author8=Wähälä, K |author9=Adlercreutz, H |title=Pharmacokinetics of soybean isoflavones in plasma, urine and feces of men after ingestion of 60 g baked soybean powder (kinako) |journal=The Journal of Nutrition|date=October 1998|volume=128|issue=10|pages=1710–5|pmid=9772140|doi=10.1093/jn/128.10.1710|doi-access=free}}{{cite journal|last=Arai|first=Y|author2=Uehara, M |author3=Sato, Y |author4=Kimira, M |author5=Eboshida, A |author6=Adlercreutz, H |author7=Watanabe, S |title=Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake |journal= Journal of Epidemiology|date=March 2000|volume=10|issue=2|pages=127–35|pmid=10778038|doi=10.2188/jea.10.127|doi-access=free}}{{cite journal|last=Akaza|first=H |author2=Miyanaga, N |author3=Takashima, N |author4=Naito, S |author5=Hirao, Y |author6=Tsukamoto, T |author7=Fujioka, T |author8=Mori, M |author9=Kim, WJ |author10=Song, JM |author11=Pantuck, AJ|title=Comparisons of percent equol producers between prostate cancer patients and controls: case-controlled studies of isoflavones in Japanese, Korean and American residents |journal=Japanese Journal of Clinical Oncology|date=February 2004|volume=34|issue=2|pages=86–9|pmid=15067102|doi=10.1093/jjco/hyh015|doi-access=free }}{{cite journal|last=Song|first=KB|author2=Atkinson, C |author3=Frankenfeld, CL |author4=Jokela, T |author5=Wähälä, K |author6=Thomas, WK |author7=Lampe, JW |title=Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls |journal=The Journal of Nutrition|date=May 2006|volume=136|issue=5|pages=1347–51|pmid=16614428|doi=10.1093/jn/136.5.1347|doi-access=free}} Vegetarians have also been reported to be more capable of transforming daidzein into (S)-equol.{{cite journal|last1=Patisaul|first1=HB|last2=Jefferson|first2=W|title=The pros and cons of phytoestrogens.|pmc=3074428|journal=Front Neuroendocrinol|date=October 2010|volume=31|issue=4|pages=400–419|pmid=20347861|doi=10.1016/j.yfrne.2010.03.003}} Seaweed and dairy consumption can enhance the production of equol.{{cite journal|last=Teas|first=J.|author2=Hurley, TG|date=August 2009|title=Dietary seaweed modifies estrogen and phytoestrogen metabolism in healthy postmenopausal women|journal=The Journal of Nutrition|volume=139|issue=9|pages=939–44|doi=10.3945/jn.108.100834|pmid=19321575|doi-access=free}} 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.{{cite journal|last=Setchell|first=KD|author2=Cole, SJ |title=Method of defining equol-producer status and its frequency among vegetarians |journal=The Journal of Nutrition|date=August 2006|volume=136|issue=8|pages=2188–93|pmid=16857839|doi=10.1093/jn/136.8.2188|doi-access=free}}

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,{{cite journal | vauthors = 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 | title = 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 | journal = Am. J. Clin. Nutr. | volume = 81 | issue = 5 | pages = 1072–9 | year = 2005 | pmid = 15883431 | doi = 10.1093/ajcn/81.5.1072| doi-access = free }} include:{{Cite journal |pmc = 2884333|year = 2010|last1 = Setchell|first1 = K. D.|title = Equol: History, Chemistry, and Formation|journal = The Journal of Nutrition|volume = 140|issue = 7|pages = 1355S–1362S|last2 = Clerici|first2 = C.|pmid = 20519412|doi = 10.3945/jn.109.119776}}

• 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

Conversion by Bifidobacterium has only been reported once by Tsangalis et al. in 2002{{Cite book |last1=V |first1=Ravishankar Rai |url=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 |title=Beneficial Microbes in Fermented and Functional Foods |last2=Bai |first2=Jamuna A. |date=2014-12-17 |publisher=CRC Press |isbn=978-1-4822-0663-0 |language=en}} and not reproduced since.[https://books.google.com/books?id=zaJ6teJ1KiYC&pg=PA105 Bifidobacteria: Genomics and Molecular Aspects] Mixed cultures such as Lactobacillus sp. Niu-O16 and Eggerthella sp. Julong 732 can also produce (S)-equol.[https://books.google.com/books?id=zaJ6teJ1KiYC&pg=PA104 Bifidobacteria: Genomics and Molecular Aspects] Some equol producing bacteria, as implied by their nomenclature, are Adlercreutzia equolifaciens, Slackia equolifaciens and Slackia isoflavoniconvertens.

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.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 In addition, equol may have a positive impact on epigenetic regulation.{{Cite journal|last1=Magnet|first1=U.|last2=Urbanek|first2=C.|last3=Gaisberger|first3=D.|last4=Tomeva|first4=E.|last5=Dum|first5=E.|last6=Pointner|first6=A.|last7=Haslberger|first7=A.G.|date=October 2017|title=Topical equol preparation improves structural and molecular skin parameters|journal=International Journal of Cosmetic Science|volume=39|issue=5|pages=535–542|doi=10.1111/ics.12408|pmid=28574180|s2cid=44910993}} Equol's phytoestrogenic properties may also affect skin health.{{cite journal |vauthors=Lephart ED |title=Skin aging and oxidative stress: Equol's anti-aging effects via biochemical and molecular mechanisms |journal=Ageing Research Reviews |volume=31 |issue= |pages=36–54 |date=November 2016 |pmid=27521253 |doi=10.1016/j.arr.2016.08.001 |s2cid=205668316 |url= |issn=}} Reduction of dark circles and eye wrinkles after treatment with equol has been reported.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 Equol may also protect skin from damage by pollution due to its anti-oxidative and anti-inflammatory properties.{{Cite journal|last=Lephart|first=Edwin|date=2018-01-29|title=Equol's Anti-Aging Effects Protect against Environmental Assaults by Increasing Skin Antioxidant Defense and ECM Proteins While Decreasing Oxidative Stress and Inflammation|journal=Cosmetics|volume=5|issue=1|pages=16|doi=10.3390/cosmetics5010016|issn=2079-9284|doi-access=free}}

Each of the enantiomers and the racemic mixture of both enantiomers have different characteristics, bioavailabilities and molecular effects.{{Cite journal|last=Lephart|first=Edwin D.|date=November 2013|title=Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin|journal=Pharmaceutical Biology|volume=51|issue=11|pages=1393–1400|doi=10.3109/13880209.2013.793720|issn=1388-0209|pmid=23862588|doi-access=free}} According to one study, (RS)-equol provided the greatest overall improvement in skin health, especially when applied topically.

Beyond topical effects, medicinal equol has been shown to relieve menopausal symptoms such as hot flashes and muscle and joint pain.Efficacy and safety of natural S-equol supplement in US postmenopausal women. Belinda H. Jenks of Scientific Affairs, Pharmavite LLC, Northridge, CA, et.al.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 (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.{{Cite journal|last1=Mayr|first1=Linda|last2=Georgiev|first2=Dimitar|last3=Toulev|first3=Albena|date=2019-03-01|title=Eine Proof-of-concept-Studie von Isoflavandiol-E55-RS-Vaginalkapseln oder Vaginalgel zur Linderung der menopausalen Vaginalatrophie|journal=Journal für Gynäkologische Endokrinologie/Österreich|language=de|volume=29|issue=1|pages=13–22|doi=10.1007/s41974-019-0085-9|issn=1996-1553|doi-access=free}}

According to animal studies,{{Cite web |title=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 |url=https://academic.oup.com/biolreprod/article/70/4/1188/2713057 |access-date=2023-11-17 }} it has anti-androgenic effects and may lead to inhibited 5-alpha reductase as well as lowered dihydrotestosterone (DHT) levels.

• Daidzein
• Estrogen receptor
• Genistein
• Liquiritigenin
• Menerba
• Prinaberel
• WAY-200070
• Diarylpropionitrile

{{Reflist|2}}

{{Phytoestrogens}}

{{Estrogenics}}

{{Isoflavane}}

{{Soy}}

Category:GPER agonists

Category:Isoflavandiols

Category:Phytoestrogens

Category:Steroid sulfotransferase inhibitors

Category:Selective ERβ agonists