Equol (4',7-isoflavandiol) is an isoflavandiolThe structures of 7,4’-dihydroxy-isoflavan and its precursors is shown i
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).

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

metabolized from

daidzein Daidzein (7-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one) is a naturally occurring compound found exclusively in soybeans and other legumes and structurally belongs to a class of compounds known as isoflavones. Daidzein and other isoflavones ar ...

, a type of

isoflavone Isoflavones are substituted derivatives of isoflavone, a type of naturally occurring isoflavonoids, many of which act as phytoestrogens in mammals. Isoflavones are produced almost exclusively by the members of the bean family, Fabaceae (Leguminosae) ...

found in soybeans and other plant sources, by bacterial flora in the

intestines The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

. While endogenous estrogenic hormones such as

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

are steroids, equol is a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

. Only about 30–50% of people have intestinal bacteria that make equol.

History

(''S'')-Equol was first isolated from horse urine in 1932, and the name was suggested by this equine connection. 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. The ability of (''S'')-equol to play a role in the treatment of

- or androgen-mediated diseases or disorders was first proposed in 1984.

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. The molecular and physical structure of (''S'')-equol is similar to that of the hormone

. (''S'')-Equol preferentially binds

estrogen receptor beta Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

Pharmacology

Estrogen receptor binding

(''S'')-equol is a

, selective agonist of

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

(K_i = 16 nM) with 13-fold selectivity for ERβ over

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex h ...

. 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

's binding affinity for human

estrogen receptor alpha Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...

(ERα) and 20% of estradiol's binding affinity for human

(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). Equol has been found to act as an agonist of the

GPER G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the ''GPER'' gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible ...

(GPR30).

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 In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

. 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 In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycoside ...

(with a glucose side chain) form. The body must convert daidzein to its

aglycone An aglycone (aglycon or genin) is the compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid molecule. Detection A way to identify 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. 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.

Production in humans

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, while 50 to 60 percent of adults from Japan, Korea, and China are equol-producers. Vegetarians have also been reported to be more capable of transforming

ito (S)-equol. Seaweed and dairy consumption can enhance the production of equol. 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.

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 Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen. It was first isolated in 1899 from the dyer's bro ...

to 5-Hydroxy-equol, the bacteria that achieve the ''complete conversion'' of daidzein to (S)-equol, include: *

Adlercreutzia equolifaciens ''Adlercreutzia equolifaciens'' is a equol-producing bacterium from the genus of ''Adlercreutzia ''Adlercreutzia'' is a genus in the phylum Actinomycetota (Bacteria). Etymology The generic name derives from H. Adlercreutz, a professor at t ...

* Asaccharobacter celatus AHU1763 *

Bacteroides ovatus ''Bacteroides'' is a genus of Gram-negative, obligate anaerobic bacteria. ''Bacteroides'' species are non endospore-forming bacilli, and may be either motile or nonmotile, depending on the species. The DNA base composition is 40–48% GC. Unus ...

Bifidobacterium ''Bifidobacterium'' is a genus of gram-positive, nonmotile, often branched anaerobic bacteria. They are ubiquitous inhabitants of the gastrointestinal tract though strains have been isolated from the vagina and mouth ('' B. dentium'') of mammal ...

* 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 and not reproduced sinc
Bifidobacteria: Genomics and Molecular Aspects
Mixed cultures such as

Lactobacillus ''Lactobacillus'' is a genus of Gram-positive, aerotolerant anaerobes or microaerophilic, rod-shaped, non-spore-forming bacteria. Until 2020, the genus ''Lactobacillus'' comprised over 260 phylogenetically, ecologically, and metabolically div ...

sp. Niu-O16 and

Eggerthella ''Eggerthella'' is a bacterial genus of Actinomycetota, in the family Coriobacteriaceae. Members of this genus are anaerobic, non-sporulating, non-motile, Gram-positive bacilli that grow singly, as pairs, or in short chains. They are found in t ...

sp. Julong 732 can also produce (''S'')-equo
Bifidobacteria: Genomics and Molecular Aspects
Some equol producing bacteria, as implied by their nomenclature, are

Adlercreutzia ''Adlercreutzia'' is a genus in the phylum Actinomycetota (Bacteria). Etymology The generic name derives from H. Adlercreutz, a professor at the University of Helsinki in Finland, for his contributions to research on the effects of phytoestrog ...

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 A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...

length. As an antioxidant, equol can decrease the aging process by reducing damage caused by

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

(ROS). It may also act as a protective anti-photoaging substance by inhibiting acute UVA- induced lipid peroxidation. In addition, equol may have a positive impact on epigenetic regulation. Equol's phytoestrogenic properties may also affect skin health. Reduction of dark circles and eye wrinkles after treatment with equol has been reported. Equol may also protect skin from damage by pollution due to its anti-oxidative and

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

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

Other health effects

Beyond topical effects, equol has been shown to relieve

menopausal Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...

symptoms such as hot flashes and muscle and joint pain. (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.

References

{{Soy GPER agonists Isoflavandiols Phytoestrogens Steroid sulfotransferase inhibitors Selective ERβ agonists