Current Pharmaceutical Design Send Orders for Reprints to reprints@benthamscience.net Current Pharmaceutical Design, 2020, 26, 5837-5843 5837 REVIEW ARTICLE Therapeutic Potential of Equol: A Comprehensive Review Atiya Fatima 1,* , Mohd Shariq Khan 1 and Md. Wasi Ahmad 1,* 1 Department of Chemical Engineering, Dhofar University, Salalah, Sultanate of Oman Abstract: Equol (4',7-isoflavandiol), is a phytoestrogenic compound, which is synthesized from parent mole- cule diadzein by intestinal bacterial flora. It is among one of the most extensively researched molecule due to its high affinity towards estrogen receptors. Its enantiomeric form S-equol has been explored in the treatment of estrogen/androgen mediated diseases. Various therapeutic applications such as anti-cancer, cardioprotective, antidiabetic, antiosteoporosis, anti-ageing, and neuroprotective efficacy are attributed to it. This review ex- plored major studies related to biochemistry and pharmacological applications of equol for human health. A R T I C L E H I S T O R Y Received: May 16, 2020 Accepted: October 12, 2020 DOI: 10.2174/1381612826999201117122915 Keywords: Bioactive molecule, equol, S-equol, isoflavone, nutraceutical, phytoestrogen, selective estrogen receptor modulator (SERM). 1. INTRODUCTION Equol (Fig. 1), an isoflavone, is a bioactive metabolite of dai- dzein that is formed by intestinal bacteria. It is found in high con- centrations in the urine of approximately 40% of the adults con- suming soy containing foods [1] and is produced by the colonic bacterial biotransformation of the soy isoflavone, aglycone daidze- in [2]. It is a chiral molecule, a non-steroidal, estrogenic, non-planar compound with an asymmetric carbon at C3 position giving rise to R and S enantiomers (Fig. 2) [3]. Only a single enantiomer has been found to be detected by bacterial diadzein conversion and its absolute configuration has been assigned to S(-) configuration [4]. Around 21 different species of bacteria are found to have the ability to convert daidzein to S-equol or related compounds [3, 5]. Only a certain percentage of human beings can produce S-equol depending upon their ethnicity and dietary habits [6]. Daidzein is converted into S-equol through a series of reduction and recemiza- tion reactions as depicted in Fig. (3) (modified from Mayo et al. [7]. O HO OH Fig. (1). 3,4-dihydro-3-(4-hydroxyphenyl)-2H-chromen-7-ol. 2. BIOLOGICAL ACTIVITIES AND MODE OF ACTION Equol being a phytoestrogen acts as a selective estrogen recep- tor modulator (SERM), which imparts its special characteristic of having a differential binding affinity towards the two estrogen receptors α and β and is known to conduct estrogenic activity with an affinity for both estrogen receptors [8]. Estrogen receptor bind- ing affinity has a great importance in imparting its biological ac- tions. Estrogen receptors are unequally distributed inside the hu- man body. Since equol has differential binding ability towards the two estrogen receptors; ERα and ERβ, and depending upon the *Address correspondence to these authors at the Department of Chemical Engineering, Dhofar University, Salalah, Sultanate of Oman; Tel: +968- 23237360; Fax: +96823237700; E-mails: atiyaqazi@gmail.com; mwahmad@du.edu.om estradiol concentration, it imparts different effects on different tissue [9-10]. Thus, it can enact a protective effect in the onset and progress of various chronic diseases (Fig. 4). It is thought to have an effect on human health similar to that of the isoflavones genistein and daidzein with higher estrogenic activity than that of daidzein [3]. It has the highest anti-oxidant potential among all isoflavones. The effects of equol are primarily mediated by these two estrogen receptors, ERα and ERβ, which are members of the nuclear receptor superfamily, coded by separate genes. Estrogen receptors use two transactivation functions AF-1 (located in their N-terminal) and AF-2 (C-terminal domains), which after activation by ligand binding, employ co-regulators of gene transcription [11]. R and S-equol induce ER transactivation in an opposite fashion and might produce distinct clinical or experimental effects by dif- ferentially triggering ER transcriptional activities. The natural enantiomer S-equol has a 13-fold higher relative binding affinity for ERβ than ERα. In contrast, the R-enantiomer has a stronger affinity for ERα. S-equol binds to ERβ with a better affinity than its parent compound, daidzein [12]. S-equol has a slower clearance rate and the highest bioavailability in the isoflavone group [3, 13]. 2.1. Anticancer Effects Studies have reported a lower incidence of breast, colon, and prostate cancer in Asian countries than the west. This difference is assumed to be based on a nutritional basis alongside genetic fac- tors, as the Asian population consumes isoflavone as an important component in their diets [14, 15]. Equol anticancer effects are me- diated by activating several cell signaling pathways which cause an alteration in the cellular enzyme expression responsible for coun- teracting oxidative stress [16]. Its physiological effects are also mediated by its action on several epigenetic mechanisms involving DNA methylation, micro RNA regulation and histone modification [17]. There have been several studies reporting the anticancer ef- fects of equol/S-equol on different cancerous cells. S-equol action on microRNA-10a-5p (miR-10a-5p) and phos- phatidylinositol 3-kinase/protein kinase B (PI3K/AKT pathway) lead to inhibited proliferation and promotion of apoptosis in human breast cancer MCF-7 cells [18]. Equol enhances the efficacy of tamoxifen (anti-breast cancer drug) in activating intrinsic apoptotic pathways [19]. When used in combination therapy with genistein, equol increases the Bax/B-cell lymphoma-extra large proteins 1873-4286/20 $65.00+.00 © 2020 Bentham Science Publishers