Pharmacokinetics of Equol, a Soy Isoflavone Metabolite, Changes with the Form of Equol (Dietary versus Intestinal Production) in Ovariectomized Rats

Legette, LeeCole L.; Prasain, Jeevan K.; King, Jennifer L.; Arabshahi, Alireza; Barnes, Stephen; Weaver, Connie M.

doi:10.1021/jf400097m

Cited by 43 publications

(45 citation statements)

References 36 publications

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“…Equol, a metabolite of the soy isoflavone daidzein, is produced by the gut microbiome and metabolized to equol glucuronide by UDP-glucuronosyltransferases, phase II drug-metabolizing enzymes in the liver (52). Circulating equol metabolites are generally present as glucuronidated conjugates; however, monosulfated forms can also be present (53), and here equol sulfate was also increased more than 7-fold in the Oat3KO (Fig. 3).…”

Section: Oat3 Metabolite Ligands and The Gut-liver-kidney Axis Xenobimentioning

confidence: 79%

The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut–liver–kidney axis

Bush

Wu²,

Lun

et al. 2017

Journal of Biological Chemistry

110

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The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) have similar substrate specificity for drugs, but it is far from clear whether this holds for endogenous substrates. By analysis of more than 600 metabolites in the (Oat3 knockout) by LC/MS, we demonstrate OAT3 involvement in the movement of gut microbiome products, key metabolites, and signaling molecules, including those flowing through the gut-liver-kidney axis. Major pathways affected included those involved in metabolism of bile acids, flavonoids, nutrients, amino acids (including tryptophan-derivatives that are uremic toxins), and lipids. OAT3 is also critical in elimination of liver-derived phase II metabolites, particularly those undergoing glucuronidation. Analysis of physicochemical features revealed nine distinct metabolite groups; at least one member of most clusters has been previously validated in transport assays. In contrast to drugs interacting with the OATs, endogenous metabolites accumulating in the (Oat1 knockout) have distinct differences in their physicochemical properties; they are very different in size, number of rings, hydrophobicity, and molecular complexity. Consistent with the Remote Sensing and Signaling Hypothesis, the data support the importance of the OAT transporters in inter-organ and inter-organismal remote communication via transporter-mediated movement of key metabolites and signaling molecules ( gut microbiome-to-intestine-to-blood-to-liver-to-kidney-to-urine). We discuss the possibility of an intimate connection between OATs and metabolite sensing and signaling pathways ( bile acids). Furthermore, the metabolomics and pathway analysis support the view that OAT1 plays a greater role in kidney proximal tubule metabolism and OAT3 appears relatively more important in systemic metabolism, modulating levels of metabolites flowing through intestine, liver, and kidney.

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Section: Oat3 Metabolite Ligands and The Gut-liver-kidney Axis Xenobimentioning

confidence: 79%

The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut–liver–kidney axis

Bush

Wu²,

Lun

et al. 2017

Journal of Biological Chemistry

110

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“…To understand the mechanism of anorectic action of S-equol, it is necessary to determine its distributions in the body. Although little is known about the distribution of S-equol in the body, the second and third peaks of plasma concentration of racemic equol after oral administration may indicate that it undergoes enterohepatic circulation (11). Enterohepatic circulation is often associated with multiple peaks and a longer apparent half-life in a plasma concentration-time profile (14).…”

Section: Methodsmentioning

confidence: 99%

Dietary daidzein induces accumulation of <i>S</i>-equol in enterohepatic circulation to far higher levels than that of daidzein in female rats with and without ovariectomy

et al. 2019

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We previously found that daidzein decreased food intake in female rats. To understand the mechanism of anorectic action of dietary daidzein, it is necessary to determine distributions of daidzein and S-equol, a metabolite of intestinal bacterial conversion from daidzein, in the body. In the present study, we measured the concentrations of daidzein and S-equol in serum and bile in sham-operated and ovariectomized female rats fed a diet containing 150 mg/kg daidzein for 7 days. Dietary daidzein increased serum and bile concentrations of S-equol to far higher levels than those of daidzein. S-equol concentration was more than several hundred fold-higher in bile than in serum, regardless of ovariectomy. Moreover, to investigate whether accumulation of S-equol is facilitated by efficient enterohepatic circulation during continuous intake of daidzein and S-equol, female rats were fed diet containing daidzein or S-equol (both 150 mg/kg), or control diet for 1, 2, 3, or 5 days. Dietary daidzein significantly increased serum and bile concentrations of S-equol in a time-dependent manner, but not those of daidzein. These results indicated that substantial proportion of dietary daidzein was converted to S-equol, which underwent efficient enterohepatic circulation and predominantly accumulated there.

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“…The aglycone of daidzin, daidzein, is further metabolized in the liver and transformed into more water-soluble metabolites by O -glucuronidation and O -sulfation (Legette, Prasain, King et al, 2014). The intestinal microbial transformation of the daidzein entails sequential reduction or hydrogenation reactions and results in the formation of the following metabolites: dihydrodaidzein (DHD, 4′,7-dihydroxyisoflavone), tetrahydrodaidzein (THD, 4′,7-dihydroxyisoflavan-4-ol), and equol (4′,7-dihydroxyisoflavan).…”

Section: Hydrogenations Of Enone and Keto Moietiesmentioning

confidence: 99%

The chemistry of gut microbial metabolism of polyphenols

2016

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Gut microbiota contribute to the metabolism of dietary polyphenols and affect the bioavailability of both the parent polyphenols and their metabolites. Although there is a large number of reports of specific polyphenol metabolites, relatively little is known regarding the chemistry and enzymology of the metabolic pathways utilized by specific microbial species and taxa, which is the focus of this review. Major classes of dietary polyphenols include monomeric and oligomeric catechins (proanthocyanidins), flavonols, flavanones, ellagitannins, and isoflavones. Gut microbial metabolism of representatives of these polyphenol classes can be classified as A- and C-ring cleavage (retro Claisen reactions), C-ring cleavage mediated by dioxygenases, dehydroxylations (decarboxylation or reduction reactions followed by release of H2O molecules), and hydrogenations of alkene moieties in polyphenols, such as resveratrol, curcumin, and isoflavones (mediated by NADPH-dependent reductases). The qualitative and quantitative metabolic output of the gut microbiota depends to a large extent on the metabolic capacity of individual taxa, which emphasizes the need for assessment of functional analysis in conjunction with determinations of gut microbiota compositions.

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Pharmacokinetics of Equol, a Soy Isoflavone Metabolite, Changes with the Form of Equol (Dietary versus Intestinal Production) in Ovariectomized Rats

Cited by 43 publications

References 36 publications

The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut–liver–kidney axis

The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut–liver–kidney axis

Dietary daidzein induces accumulation of <i>S</i>-equol in enterohepatic circulation to far higher levels than that of daidzein in female rats with and without ovariectomy

The chemistry of gut microbial metabolism of polyphenols

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