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© 2006 American Society for Nutrition J. Nutr. 136:2291-2296, September 2006

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Bioavailability of Isoflavones after Ingestion of Soy Beverages in Healthy Adults1

Mitsuyoshi Kano*, Tomomi Takayanagi, Katsuhisa Harada, Seigo Sawada and Fumiyasu Ishikawa

Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo 186–8650, Japan

* To whom correspondence should be addressed. E-mail: mitsuyoshi-kano{at}yakult.co.jp.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
It is unknown whether the bioavailability of isoflavones is affected by the concomitant ingestion of glucosides or aglycones. This study was designed to investigate the effects of soymilk-based beverages containing different types of isoflavones on their absorption, excretion, and metabolism. Twelve healthy volunteers consumed 3 kinds of soymilk: untreated soymilk, ß-glucosidase–treated soymilk, and fermented soymilk. Blood samples were collected after 0, 1, 2, 3, 4, 5, 6, 7, 8, and 24 h. Urine samples were collected from 0 to 48 h. Concentrations of isoflavones and daidzein metabolites in serum and urine were measured by liquid chromatography-mass spectrometry. After the ingestion of soymilk, the total concentration of isoflavones in serum rose slowly and reached a maximum of 0.94 ± 0.39 µmol/L at 6.0 ± 1.2 h. However, ß-glucosidase–treated soymilk and fermented soymilk increased the serum isoflavone concentration significantly more quickly with maximum concentrations at 1.0 h of 1.75 ± 0.33 µmol/L and 2.05 ± 0.32 µmol/L, respectively. The urinary excretion of isoflavones after ingesting of these aglycone-enriched preparations was significantly greater than after consumption of untreated soymilk up to 8 h after injection, but not thereafter. The total and individual concentrations of isoflavones in serum and urine did not differ when subjects consumed the 2 aglycone-enriched soymilks. However, in equol producers (n = 5), the ingestion of ESM tended to increase urinary excretion of equol compared with the consumption of FSM (P = 0.08). These results demonstrated that the isoflavone aglycones of soymilk were absorbed faster and in greater amounts than their glucosides in healthy adults and that the metabolism of isoflavones might be affected by the type of soymilk consumed.


   Introduction
TOP
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 
Soybean is rich in protein, fat, and carbohydrate, and has attracted much attention because of its potential health benefits (1–3). Many of these benefits derive from isoflavones. Isoflavones are nonsteroidal phytoestrogenic and antioxidative polyphenolic molecules with the potential to protect against hormone-dependent diseases, such as breast cancer, prostate cancer, menopausal symptoms, cardiovascular disease, and osteoporosis (4–9).

The natural isoflavones in soybeans and unfermented soyfoods occur as glucose-conjugated forms (10,11). Once ingested, isoflavone glucosides are hydrolyzed to absorbable aglycones (12). Intestinal microflora affect the metabolism or absorption of isoflavones as, for example, when they are hydrolyzed to aglycones or transformed into metabolites such as equol or O-desmethylangolensin (O-DMA)2 from daidzein, and so on (13–16). Therefore, it is commonly assumed that isoflavone aglycones are absorbed quickly compared with glucoside forms. However, the bioavailability of aglycones and glucosides of soy isoflavones is controversial (17–21). Izumi et al. (17) found a greater bioavailability of aglycones, whereas Setchell et al. (18) reported a more efficient use of glucosides. Other studies showed that absorption between aglycones and glucosides did not differ significantly (19–22). It makes sense that isoflavone aglycones are absorbed faster than glucosides, because aglycones have greater hydrophobicity and a smaller molecular weight, whereas glucosides have lower absorbability and must be converted to aglycones.

The present study indicates that isoflavones in fermented soymilk (aglycone-enriched) are absorbed more efficiently by rats than those in unfermented soymilk (glucoside-enriched) (23). Additionally, we found that the physiological effects of fermented soymilks are greater than those of unfermented ones (23–28) because of the greater bioavailability of aglycones themselves. However, fermentation products (lactic acid and acetic acid) and probiotics (Bifidobacterium breve) can influence the absorption or metabolism of isoflavones. According to previous reports, organic acids enhance the absorption of calcium (29), and intestinal flora affect the absorption or metabolism of flavonoids (30).

We investigated the influence of the molecular form of isoflavones (aglycones and glucosides) and the methods of converting isoflavones to aglycones on their bioavailability in soymilk. To standardize the conditions (isoflavone ratios, other isoflavone components, and so on) we used soymilk, enzyme-treated soymilk (ESM; i.e., hydrolysis with ß-glucosidases), and fermented soymilk (FSM; i.e., fermentation by B. breve and Lactobacillus mali).


   Subjects and Methods
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 Discussion
 LITERATURE CITED
 
    Chemicals. Isoflavones (daidzein, genistein, and glycitein) were purchased from Fujikko. ß-glucuronidase/sulfatase was obtained from Sigma-Aldrich. Equol was purchased from Extrasynthèse. O-DMA was synthesized from 1,3-dimethoxybenzene and 4-methoxyphenyl chloride (see Supplemental Data). All other reagents and chemicals used were commercially available products of extra-pure grade.

    Soymilk, fermented soymilk, and enzyme-treated soymilk. Soymilk (4.48% protein and 2.93% lipid) was purchased from Shikokukakouki (Tokushima). ESM was made as follows: isoflavones were hydrolyzed in the soymilk by incubating with ß -glycosidase (obtained from Amano Enzyme) for 2 h at 40°C. For the FSM preparation, B. breve strain Yakult and L. mali YIT 0243 were obtained from the Culture Collection Research Laboratory of Yakult Central Institute for Microbiological Research. A seed preculture, prepared anaerobically in the soymilk, was freshly added to ultra high temperature–sterilized (146°C, 8.6 s) soymilk at an inoculation ratio of 1:100 and fermented statically at 37°C for 21 h. The titratable acidity, pH, organic acids, and viable cell count of the fermented soymilk were 0.645%, 4.8, 29.2 mmol/L (lactic acid) and 20.4 mmol/L (acetic acid) and 1.53 x 1012 (B. breve) and 1.26 x 1012 (L. mali) colony-forming units/L, respectively. The composition was unaffected by the fermentation process as described previously (23). The isoflavones present in soymilk, FSM, and ESM are listed in Table 1. The proportion of aglycones in each sample (ESM and FSM) was >90%.


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  		TABLE 1 Isoflavone concentrations in soymilk, ß-glucosidase–treated soymilk, and fermented soymilk beverages

 
    Subjects. Twelve healthy volunteers (9 men and 3 women) aged 25–51 (33.9 ± 7.0) y, with a body mass index of 19–26 (21.3 ± 2.3) kg/m2, participated in the study. These same subjects consumed each of the 3 beverages. The protocol was approved by the Human Studies Committee of the Yakult Central Institute for Microbiological Research, in accordance with the Helsinki Declaration and the Committee's own guidelines.

    Study design. The study consisted of 3 periods of 7 d. Subjects refrained from consuming soy-containing foods for 1 wk before the test until the completion of the study. The first period was used to evaluate the absorption of isoflavones in soymilk. On d 1, subjects were served 3 isoflavone-free meals (breakfast, lunch, and dinner). After an overnight fast, they ingested 100 mL of soymilk at 0900 on d 2. Four hours later, at 1300, the subjects were served rice balls. Ten, 24, 28, and 34 h after consuming the soymilk, they were served isoflavone-free food. The subjects were allowed to consume only water, except for the meals served, from 24 h before to 48 h after ingestion of the soymilk. Blood samples were collected at fixed time points (0 to 8 h periodically, and then at 24 h). Urine samples were collected at fixed time points (0, 2, 4, 6, 8, 12, 24, 36, and 48 h) and arbitrary micturition time points after ingestion. Serum was obtained by centrifugation at 2000 x g for 20 min at 4°C. Serum and urine were stored at –70°C until the analysis. The second and third periods were used to evaluate the absorption of isoflavones in ESM and FSM, respectively. Conditions were the same as in the first period. One subject took Chinese medicine with small amounts of isoflavones at 34 h after consuming the soymilk, so her urinary data were excluded from the statistical analysis.

    Measurement of isoflavone concentrations in serum and urine. Fifty µL of serum or urine was added to 50 µL of acetate buffer (0.2 mol/L, pH 5.0) containing 100 units of ß-glucuronidase and incubated for 15 h at 37°C to release the aglycone forms of isoflavones from the glucuronide and sulfate conjugates. Methanol (400 µL) was added to these mixtures and mixed by vortex and sonication, and centrifuged at 5000 x g for 5 min at 4°C. The supernatant fluid was filtered through an Ultrafree-MC 0.45-µm filter unit (Millipore). A portion was subjected to HPLC.

Liquid chromatography-mass spectrometry analyses were conducted using a Micromass ZQ4000 LC-MS system (Waters) equipped with a 2695 HPLC system and 996 photodiode array (PDA) detector (Waters), and Empower Software, version 5.00 (Waters). The column for HPLC was an Imtakt Cadenza CD-C18, 75 x 3.0 mm and 3 µm in particle size (Imtakt). The mobile phase was a 0.1% formic acid aqueous solution and acetonitrile (70:30 v:v). The run time was 12 min and was followed by a 5-min delay prior to the next injection. The other conditions were as follows: PDA range of 210–400 nm, detection wavelength of 276 nm, flow rate of 0.4 mL/min, column temperature of 30°C, sample temperature of 10°C, and injection volume of 10 µL. Electrospray ionization was performed in the positive ion mode. MS conditions were as follows: nebulizer gas flow of 200 L/h, capillary voltage of 3.4 kV, desolvation gas flow of 450 L/h, desolvation temperature of 450°C, cone gas flow of 50 L/h, cone voltage of 10–40 V, source temperature of 50°C, and multiplier voltage of 650 V. MS was performed in the scanning mode with multiple selected–ion recording (SIR).

HPLC was carried out with a 2690 HPLC system and 996 PDA detector (Waters) and Millennium32 Software, version 3.06 (Waters). The column was a Cadenza CD-C18, 100 x 4.6 mm, 3 µm particle size (Imtakt). The mobile phase was a 0.1% formic acid aqueous solution and acetonitrile (70:30 v:v). The other conditions were as follows: PDA range of 210–400 nm, detection wavelength of 276 nm, flow rate of 0.6 mL/min, run time of 20 min, column temperature of 30°C, sample temperature of 10°C, and injection volume of 10 µL.

Pharmacokinetic parameters, the postprandial maximum concentration (Cmax), time to the maximum concentration (tmax), and area under the curve (AUC), were determined from the serum concentration curves for isoflavones.

    Statistical analysis. Data were expressed as means ± SEM. The means were compared using SAS, version 5.0 (SAS Institute), by 2-way ANOVA (serum concentration of isoflavone and urinary excretion of isoflavone) or 1-way ANOVA (pharmacokinetic) and subsequent paired t test with the Bonferroni correction. The recoveries of daidzein to genistein in urine were compared by paired t test. Differences were considered significant at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
Discussion
 LITERATURE CITED
 
    Serum isoflavones. Before subjects consumed the soymilk preparations, serum concentrations of isoflavones were undetectable. After the ingestion of ESM and FSM, they increased rapidly (Figs. 1, 2). The tmax of total isoflavones was 1 h (Table 2). In contrast, after ingesting soymilk, isoflavone concentrations increased gradually, and the tmax was 6 h. The concentrations of daidzein, genistein, and total isoflavones were significantly higher in the ESM and FSM periods than in the soymilk period until 4 h after ingestion. The Cmax and AUC0–24h of daidzein, genistein, and total isoflavones were significantly greater in the ESM and FSM periods than in the soymilk period. The pattern of absorption was similar for each isoflavone (daidzein and genistein) in the same samples. However, the pattern of absorption of glycitein differed from that of daidzein or genistein; the Cmax and AUC of glycitein did not differ among the 3 periods.


Figure 1
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  		Figure 1  Serum concentrations of daidzein (A), genistein (B), and glycitein (C) in healthy adult subjects after ingestion of soymilk, ESM, and FSM. Values are means ± SE, n = 12. Means at a time without a common letter differ, P < 0.05.

 

Figure 2
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  		Figure 2  Serum concentration of total isoflavones in healthy adult subjects after ingestion of soymilk, ESM, and FSM. Values are means ± SE, n = 12. Means at a time without a common letter differ, P < 0.05.

 

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  		TABLE 2 Maximum concentration of healthy adult serum, time taken for the maximum concentration to be reached, and area under the curve for serum isoflavones after the ingestion of soymilk, ESM, or FSM

 
    Isoflavones in urine. The urinary excretion of daidzein, genistein, and total isoflavones was higher (P < 0.05) in the ESM and FSM periods than in the soymilk period until 8 h after ingestion, but did not differ between the ESM and FSM groups (Fig. 3, 4). Urinary excretion of total isoflavones did not differ among ESM, FSM, and soymilk during the 48-h period after consumption. The percentages of the ingested daidzein and genistein recovered in urine over the 48-h period were 37.3 ± 4.0% and 20.2 ± 3.3% for soymilk (P = 0.004), 46.4 ± 3.6% and 30.3 ± 3.7% for ESM (P = 0.006), and 46.3 ± 3.7% and 28.0 ± 3.6% for FSM (P = 0.002).


Figure 3
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  		Figure 3  Urinary excretion of daidzein (A), genistein (B), and glycitein (C) in healthy adult subjects after ingestion of soymilk, ESM, and FSM. Values are means ± SE, n = 11. Means at a time without a common letter differ, P < 0.05.

 

Figure 4
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  		Figure 4  Urinary excretion of total isoflavones in healthy adult subjects after ingestion of soymilk, ESM and FSM. Values are means ± SE, n = 11. Means at a time without a common letter differ, P < 0.05.

 
    Urine isoflavone metabolites. In equol producers (n = 5), the ingestion of ESM tended to increase urinary excretion of equol compared with FSM (P = 0.08) while the excretion of O-DMA was not affected by the type of soymilk consumed (see Supplemental Fig. 1).


   Discussion
TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
LITERATURE CITED
 
The intestinal absorption of most isoflavones is thought to require a release of aglycone forms from glucoside conjugates (31). Thus, the intestinal absorption of the glucosides is thought to be delayed (17,32). However, Richelle et al. (20) and Zubik et al. (21) report that the absorbability of isoflavones does not differ when ingested as either corresponding aglycones or glucosides. These conflicting reports confuse the issue. Isoflavone aglycones may be absorbed faster than glucosides because they have greater hydrophobicity and a smaller molecular weight (33) and also because glucosides have less absorbability and must be converted to aglycone forms (12).

In most of these reports, isoflavone supplements or soy extracts were administered as tablets (17,21) or beverages (18,20). In contrast, in Japan, soy products like soymilk, tofu, and miso are consumed daily, and supplements with isolated isoflavones are not popular. This study was undertaken to determine the bioavailability of isoflavones in soymilks.

Serum isoflavones that were converted to aglycones were absorbed more quickly and in greater amounts than the glucoside forms. There was an initial rapid increase in isoflavone concentrations in serum at 1 h after ingestion, followed by a plateau and then a second increase, indicating enterohepatic circulation (20). The concentrations of isoflavones in serum did not differ when subjects consumed the 2 aglyconized soymilks, so the method of conversion of glucoside to aglycone, probiotics, and fermented products (e.g., organic acids) did not affect the pharmacokinetics of isoflavones in serum. Our study using soymilk showed a clear difference in the absorbability of isoflavones between aglycone- and glucoside-enriched preparations. Recently, Tsangalis et al. (22) reported no significant difference in absorption between aglycone-rich fermented soymilk and glucoside-rich soymilk. But the isoflavone concentrations in their samples appeared to differ greatly from those in ours. For example, the percentage of aglycone in our fermented soymilk was high (93%) but that in the preparation used by Tsangalis et al. was considerably lower (36–69%). This might explain why there is no significant difference in absorption.

In addition to the proportion of aglycone in the soymilk preparation, the indeterminacy of the absorbability of isoflavones is considered to arise from other conditions, especially the background of the subjects, as pointed out by Zubik et al. (21). The absorption of isoflavones differs between Japanese and Americans because intestinal microflora, dietary habits, and ethnic background all have an effect (21). However, Hutchins et al. (34) showed, in a nonpharmacokinetic study of American men, that isoflavones from fermented products (tempeh) are more available than those from unfermented products (soybean). Furthermore, another study reports that ß-glucosidase activity in the intestine increases with the chronic ingestion of soy (35). Recently, the consumption of soy products has decreased in Japan because of Western influences on the culture, particularly among those of the younger generation (36). The subjects in our experiments were relatively young (33.9 ± 7 y) and background diet did not affect the bioavailability of isoflavones in the short term (37). These findings indicate that racial background is not related to the absorbability. To clarify the influence of the background of subjects, studies of Americans using soymilk would be effective as would direct comparative studies using the same dietary treatment in various kinds of ethnic groups.

The intestinal metabolism of isoflavones is considered to affect their bioavailability (38). We observed a weak difference (P = 0.08) in the urinary excretion of equol between ESM and FSM for 48 h, despite a similar absorbability. Live bacteria (B. breve and L. mali) unable to produce equol, were included in FSM, but not in ESM. B. breve strain Yakult, in particular, has probiotic properties that would affect intestinal flora (39,40). Tamura et al. (41) showed that the administration of L. gasseri, not an equol-producer, can cause a change in the production of equol (decreased urinary amounts) in mice. Thus, the bacteria contained in FSM might affect the intestinal metabolism of isoflavone. In contrast, previous papers have reported an inverse relation between equol and O-DMA excretion (42,43), but our study did not show a relation (data not shown).

In summary, in humans, isoflavone aglycones were absorbed faster and in greater amounts than glucosides when ingested in the form of a beverage like soymilk. Probiotics might influence whether colonic microflora produce equol.


   ACKNOWLEDGMENTS
 
We thank Noboru Nakamichi of the Jikei University School of Medicine, Ryuichiro Tanaka of the Yakult Central Institute for Microbiological Research, and Tatsuyuki Kudo of Yakult Honsha, for their helpful discussions and suggestions. We also thank Takashi Ikeda of the Yakult Central Institute for Microbiological Research, for the NMR analysis of O-DMA.


   FOOTNOTES
 
1 Supplemental Figure 1 and other supplementary data are available with the online posting of this paper at jn.nutrition.org. Back

2 Abbreviations used: AUC, area under the curve; Cmax, maximum concentration; ESM, ß-glucosidase–treated soymilk; FSM, fermented soymilk; O-DMA, O-desmethylangolensin; tmax, time at the maximum concentration. Back

Manuscript received 27 December 2005. Initial review completed 24 January 2006. Revision accepted 26 May 2006.


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TOP
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 Discussion
 LITERATURE CITED
 

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