Equol (4',7-isoflavandiol) is an

isoflavandiol Isoflavanes are a class of isoflavonoids, which are themselves types of polyphenolic compounds. They have the 3-phenylchroman (isoflavan, CAS number: 4737-26-2, molecular formula: C15H14O, exact mass: 210.1044646 u) backbone. Examples * Equol S ...

The 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 acti ...

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 a ...

, 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 The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses. Traditional unfermented food uses of soybeans include soy milk, from which tofu and ...

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 ...

. 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 of f ...

are

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

s, 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 mod ...

. 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

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

s: (''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 An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

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 ...

. 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 Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists a ...

(SERM). Equol has been found to act as an

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 Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...

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%. H ...

. When (''S'')-equol is consumed, it is rapidly absorbed and achieves a T_max (rate of

peak plasma concentration Cmax is the maximum (or peak) Serum (blood), serum concentration (chemistry), concentration that a drug achieves in a specified compartment (pharmacokinetics), compartment or test area of the body after the drug has been administered and before th ...

) 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 glycosides. ...

(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 Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mic ...

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 Seaweed, or macroalgae, refers to thousands of species of macroscopic, multicellular, marine algae. The term includes some types of '' Rhodophyta'' (red), ''Phaeophyta'' (brown) and ''Chlorophyta'' (green) macroalgae. Seaweed species such as ...

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

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

s 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 th ...

* 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. Unusua ...

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 ''Bifidobacterium animalis'' is a gram-positive, anaerobic, rod-shaped bacterium of the ''Bifidobacterium'' genus which can be found in the large intestines of most mammals, including humans. ''Bifidobacterium animalis'' and ''Bifidobacterium la ...

* Coriobacteriaceae sp MT1B9 * Eggerthella sp YY7918 *

Enterococcus faecium ''Enterococcus faecium'' is a Gram-positive, gamma-hemolytic or non- hemolytic bacterium in the genus ''Enterococcus''. It can be commensal (innocuous, coexisting organism) in the gastrointestinal tract of humans and animals, but it may also be ...

* 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 ''Streptococcus intermedius'' is an aerotolerant anaerobic commensal bacterium and a member of the ''Streptococcus anginosus'' group. The ''S. anginosus'' group, occasionally termed “''Streptococcus milleri'' group” (SMG) display hemolytic a ...

* 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 diver ...

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 ''Slackia equolifaciens'' is an equol-producing bacterium from the genus of ''Slackia'' which has been isolated from human faeces from Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It ...

and

Slackia isoflavoniconvertens ''Slackia isoflavoniconvertens'' is a bacterium from the genus of ''Slackia'' which has been isolated from faeces of a human from Nuthetal in Germany. ''Slackia isoflavoniconvertens'' can metabolize daidzein and genistein, two compounds in the ...

Health effects

Skin health

The topical effects of equol as an

anti-aging The anti-aging movement is a social movement devoted to eliminating or reversing aging, or reducing the effects of it. A substantial portion of the attention of the movement is on the possibilities for life extension, but there is also interest in ...

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 Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chai ...

. In addition, equol may have a positive impact on

epigenetic regulation In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...

. 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 In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

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 Menstruation, menstrual periods stop permanently, and they are no longer fertility, able to bear children. Menopause usually occurs between the age of 47 and 54. Medic ...

symptoms such as hot flashes and muscle and joint pain. (RS)-equol was also reported to reduce symptoms associated with menopausal

vaginal atrophy Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to not enough estrogen. Symptoms may include pain with sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination. It generally does no ...

, 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