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Human Nutrition and Metabolism

The Apparent Absorptions of Isoflavone Glucosides and Aglucons Are Similar in Women and Are Increased by Rapid Gut Transit Time and Low Fecal Isoflavone Degradation^1,2

Food Science and Human Nutrition, Iowa State University, Ames, IA 50011 and ^* Acatris Holding B.V., Giessen, The Netherlands

³To whom correspondence should be addressed. E-mail: shendric{at}iastate.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We hypothesized that there would be no difference in apparent absorption, as assessed by urinary excretion, between isoflavone sources rich in glucosides or aglucons and that subjects with rapid gut transit time (GTT) and low fecal isoflavone degradation phenotype would absorb more isoflavones. Women (n = 13) with a fecal daidzein degradation rate constant, D_k > 0.30 h^–1 (high degraders) and GTT of 106 ± 11 h and women (n = 12) with D_k < 0.20 h^–1 (low degraders) and GTT of 71 ± 12 h were randomly assigned to 3 treatments: soygerm (1.1 µmol/kg body weight, n = 5 high degraders, 4 low degraders), fermented soygerm (3.3 µmol/kg, n = 4 high and 4 low degraders) or Novasoy isoflavone extract (1.5 µmol/kg, n = 4 high and 4 low degraders) for 7 d. By HPLC analysis, 24-h urinary excretion of soygerm was greater than Novasoy (51 ± 6 vs. 26 ± 6% of ingested dose, P < 0.05). Women of the low daidzein degradation phenotype had greater urinary isoflavone excretion than did women of the high daidzein degradation phenotype (51.6 ± 4.8 vs. 33.8 ± 4.7%, P < 0.05, mean of d1 and 7). The plasma total isoflavone level (estimated as a percentage of the ingested amount, mean of d 1 and 7) differed between women who consumed fermented soygerm and soygerm 3 h after feeding (1.8 ± 0.3 vs. 0.5 ± 0.3%, P < 0.05). Urinary excretions of aglucons and glucosides did not differ. The study confirmed that rapid GTT and low fecal isoflavone degradation rate increased the apparent absorption of isoflavones.

KEY WORDS: • isoflavones • aglucons • glucosides • gut transit time • bioavailability

Soybean isoflavones are major phytoestrogens in the human food supply. Only soy protein containing 37 mg isoflavones/d lowered cholesterol in humans (1). Soy protein containing isoflavones also reduced bone loss from the lumbar spine in perimenopausal women (2). Soy intake is associated with less hormone-related cancer in premenopausal women (3).

To assess the health effects of isoflavones, their bioavailability must be better understood. Optimizing isoflavone bioavailability is likely to permit more conclusive studies of these compounds. Isoflavones exist mainly in soy foods as glucosides; fermentation, however, converts them to aglucons. It is unclear what forms of isoflavones are best absorbed and retained in the body. Tempeh, a fermented soybean product, had isoflavone bioavailability similar to that of cooked soybeans or tofu (4). Some studies showed that isoflavone bioavailability was greater when fermented soy foods were consumed (5,6). Isoflavone aglucons were absorbed more quickly and in greater amounts than their glucosides in humans (7). However, Setchell et al. (8) and Zubik and Meydani (9) reported little difference in plasma isoflavone concentrations over time in humans fed glucosides compared with aglucons. Furthermore, the bioavailability of isoflavones was not altered when aglucons hydrolyzed enzymatically from glucosides were consumed compared with glucosides (10). Isoflavone glucosides and aglucons merit more comparative study.

Many isoflavone bioavailability studies were cpmdicted recently, but most focused on isoflavone glucosides (11,12). Isoflavone excretion patterns and pharmacokinetics were examined in humans given 2.7 µmol daidzein and 3.6 µmol genistein/kg body weight; daidzein and genistein did not differ in terms of plasma concentrations, although urinary excretion of daidzein was greater than that of genistein (13). In a study in which 60 g baked soybean powder (103 µmol daidzein and 112 µmol genistein) was fed, genistein was the most important isoflavone in plasma compared with daidzein due to its greater concentration and longer half-life (14). However, because urinary excretion reflects overall isoflavone absorption and disposition, daidzein was shown to have 2–3 times greater apparent absorption than genistein (12,15,16). Glycitein is a minor soy food component accounting for 5–10% of total isoflavones except in soygerm, in which glycitein accounts for 40–50% of total isoflavones. Glycitein was equal to daidzein in bioavailability, and both were more available than genistein in terms of urinary excretion in humans (16). Glycitein was more estrogenic than genistein in mice (17); therefore, more studies of the effects and bioavailability of glycitein are warranted.

Isoflavone bioavailability varies greatly among individuals (12,16) and gut microorganisms degrade isoflavones, preventing their reabsorption after initial rapid biliary excretion. High, moderate, and low isoflavone degradation phenotypes were identified in humans (18). Gut transit time (GTT)⁴ was positively correlated with the daidzein degradation rate constant (r = 0.35, P < 0.05) and negatively correlated with total urinary isoflavone excretion (r = –0.24, P < 0.05) in 35 Asian and 31 Caucasian women who were identified within high, moderate and low daidzein degradation phenotypes, and who consumed a single dose of soy isoflavone (4.6 µmol/kg) (19). Thus, GTT may affect isoflavone bioavailability. Differences in isoflavone degradation phenotype and GTT may be responsible for much of the variation in isoflavone bioavailability among individuals (19). Further work on isoflavone degradation phenotype, GTT, and bioavailability of isoflavones may help in designing human feeding studies.

In the present study, we compared both the bioavailability of isoflavone aglucons and glucosides and various isoflavone sources rich in glycitein or genistein in women fed these sources at breakfast for 7 d. We determined whether daidzein degradation phenotype and GTT influenced urinary excretion and plasma concentrations of isoflavones over time.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Experimental procedures

    Chemicals. Isoflavone aglucons, daidzein, genistein, glycitein, and 2,4,4'-trihydroxybenzoin (THB) used as an internal standard were synthesized in Dr. Murphy’s laboratory, Iowa State University (20,21). Brain-heart infusion (BHI) medium was purchased from DIFCO Laboratories. Cysteine and resazurin were purchased from Aldrich Chemical. Milli-Q HPLC grade water (Millipore) was used. Other HPLC solvents were purchased from Fisher Scientific.

    Subjects. In vitro anaerobic fecal incubation was used to identify high and low daidzein degradation phenotypes in subjects. A freshly voided fecal sample was incubated anaerobically with autoclaved BHI culture medium and daidzein (100 µmol/L). The daidzein degradation rate constant, D_k, was calculated as the negative slope of the regression line plotted for isoflavone content of each sample over time (16). The participants in this study were 25 healthy women, 20 Caucasians and 5 Chinese; 13 were of the high daidzein degradation phenotype (including 1 Chinese) (D_k > 0.30 h^–1) and 12 (including 4 Chinese) of the low daidzein degradation phenotype (D_k < 0.20 h^–1), 18–40 y old, BMI, 23.2 ± 1.0 kg/m² (Table 1). The experimental procedures for this study were approved by the Human Subjects Committee of Iowa State University. Subjects gave their informed consent to the protocol.

Analytical methods

    Soy products analysis. Samples in duplicate from each source were extracted and isoflavone concentrations determined by HPLC (22,23) with THB as an internal standard. The total isoflavone content was the sum of mole amounts of total daidzein, genistein and glycitein normalized to the aglucon forms (Table 2).

    Plasma and urine isoflavone analysis. Urine samples were prepared by methods modified from Lundh et al. (24) as previously described (19). For plasma samples, 1 mL was incubated with 1 mL of 0.2 mol/L sodium acetate buffer (pH = 5.5), 50 µL ß-glucuronidase (H₂ type, Sigma Chemical), and 50 µL of 0.01 mol/L THB as an internal standard in 37°C water bath for 18 h. After incubation, 1 mL of 10 µmol/L sodium phosphate buffer (pH = 7.0) was added to the mixture, loaded onto a 5-mL Extrelut QE column (EM science), extracted with ethyl acetate, and eluents dried under N₂. Extracts were reconstituted in 200 µL methanol and water (80:20, v:v). The HPLC analysis followed Zhang et al. (16), but THB and the 3 isoflavone aglucons were separated and quantified on a YMC-Pack ODS-AM C₁₈ reverse-phase column (5 µm, 25 cm x 4.6 mm i.d., YMC); the mobile phase was 1 mL glacial acetic acid/L in water (A) and methanol (B). Compounds were detected by UV (190–350 nm scan) photodiode array detector on a Hewlett-Packard HPLC system (Agilent).

    Plasma isoflavones as a percentage of ingested dose. Because different doses of each isoflavone source were fed, plasma isoflavone content was expressed as an estimated percentage (mole based) of ingested dose present in plasma at the time point measured. Total plasma volume (L) was estimated based on subject body weight and height (25), and multiplied by isoflavone content/L; this total plasma isoflavone content was divided by the amount of isoflavone ingested at breakfast on d 1 or 7.

    Recovery studies. Synthesized daidzein, genistein, glycitein, THB, and blank urine and plasma samples from 1 subject were used to determine analytical recovery. Fifty µL of 0.01 mol/L THB and a series of external isoflavone standards, 6.25–100 µmol/L for daidzein and genistein and 6.55–131.5 µmol/L for glycitein, were added to urine and plasma samples. Each standard was assayed in duplicate using the same extraction and analysis method as above. Recoveries for urinary daidzein, genistein, glycitein, and THB were 82.2 ± 4.2, 79.3 ± 2.9, 84.5 ± 4.5, and 86.5 ± 2.1%, respectively. The mean recoveries for plasma daidzein, genistein, glycitein, and THB were 75.2 ± 5.2, 69.2 ± 4.6, 70.2 ± 4.4, and 79.5 ± 3.2% respectively. Plasma and urinary isoflavones from the feeding study were adjusted on the basis of recovery of the internal standard THB.

    Statistical analysis. Statistical analysis was performed by SAS (SAS Institute, version 8.2, 2001). ANOVA using general linear models was conducted to determine treatment, time, and phenotypic differences, as well as differences among the 3 isoflavones. When differences were found, multiple comparisons using Tukey’s test were performed to identify the difference. A cluster test (based on distance) was used to identify daidzein degradation phenotypes. Pearson correlation analysis was used to determine the correlation in plasma and urinary isoflavone contents between d 1 and 7, and between GTT, D_k, and urinary total isoflavone excretion. All results were reported as means ± SEM. Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Urinary excretion of isoflavones. The urinary isoflavone excretion expressed as a percentage of the ingested amount was calculated as the mean of d 1 and 7 for each subject because isoflavone excretions on the 2 d were correlated (r = 0.94, P < 0.001). The 3 groups differed in urinary total isoflavone excretion (Table 3). At 0–12 h, subjects who consumed fermented soygerm excreted greater amounts of isoflavones than did subjects who consumed Novasoy (P < 0.05). At 12–24 h, isoflavone excretion by subjects fed unfermented soygerm was greater than that of subjects that consumed Novasoy (P < 0.05). Total 24-h urinary isoflavone excretion by both groups fed soygerm was greater than that by subjects fed Novasoy (P < 0.05, Table 3). Urinary excretion of isoflavones over 24 h from the 2 soygerm-fed groups did not differ significantly. Urinary total isoflavone excretion was greater at 0–12 h than at 12–24 h in all groups (P < 0.05) (Table 3). The excretion during 0–12 h was correlated with 24-h excretion (r = 0.97, P < 0.0001).

Overall urinary total isoflavone excretion at 0–12 h and over 24 h differed between high and low daidzein degradation phenotypes (Table 4). Subjects of the low degradation phenotype excreted greater amounts of isoflavones than did subjects of the high degradation phenotype (P < 0.05). At 12–24 h, urinary excretion did not differ between degradation phenotypes. Urinary excretions of the individual isoflavones, daidzein and glycitein, were greater in subjects of the low daidzein degradation phenotype than in subjects of the high degradation phenotype (Table 5; P < 0.05). Urinary daidzein and glycitein were excreted more than genistein in all groups, but excretions of daidzein and glycitein did not differ (Table 5).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In the present study, urinary isoflavone excretion was significantly greater at 0–12 h than at 12–24 h. Total urinary isoflavone excretion at 0–12 h and that over 24 h were correlated (r = 0.97, P < 0.001). These results are consistent with previous work (12,13).

The overall bioavailability of isoflavones as reflected in urinary excretion did not differ between fermented soygerm (mostly isoflavone aglucons) and soygerm (mostly isoflavone glucosides, Table 3), but the pattern differed, with apparent absorption (urinary excretion) of fermented soygerm greater at 0–12 h and excretion of isoflavones from unfermented soygerm greater at 12–24 h. The glucoside moiety prevented absorption of the isoflavone; its cleavage, and therefore absorption of isoflavones from their glucosidic form, depended at least in part on lower gut microbes. The plasma kinetics of 0.2 mmol of pure daidzein, genistein, and their ß-glucosides were compared in 19 women; aglucons were absorbed more quickly, with t_max (time of peak plasma concentrations), of 5–6 h for aglucons and 9 h for glucosides, respectively (8). Izumi et al. (7) reported that soy isoflavone aglucons were absorbed more quickly and in greater amounts (P < 0.05) than isoflavone glucosides in 8 Japanese men and women at 2, 4, and 6 h after feeding (t_max of 2 h for aglucons, 4 h for glucosides, respectively); after 24 h, plasma isoflavones were slightly greater after feeding aglucons. Our plasma data also showed that 3 h after feeding, isoflavone aglucons were absorbed to a significantly greater extent than were isoflavone glucosides (Table 6). However, Richelle et al. (10) reported that t_max (7.2–8.3 h and 7.3–9.2 h for aglucones and glucosides, respectively) did not differ between these isoflavone forms in 6 European postmenopausal women after they consumed a single dose of 98% isoflavone glucosides or an isoflavone source containing 57% aglucons providing 3.6 µmol isoflavone aglucon/kg body weight. Because they fed an aglucon + glucoside mixture, any difference in isoflavone absorption between these forms may have been blunted. In a recent study, 15 American women were given a single bolus dose of either isoflavone aglucons or glucosides (0.12 mmol) in a crossover design (9). The mean t_max (4–5 h) for plasma daidzein and genistein after consumption of the aglucons did not differ from than that after glucoside intake. Differences in human intestinal glucosidase activity may be responsible for the differences observed between women in the United States (9) and Japanese subjects (7).

Setchell et al. (8) also compared systemic bioavailability and C_max (the maximum plasma concentration) between isoflavone aglucons and glucosides. The mean AUC (area under the curve) for genistein and daidzein was 17 and 12 µmol · h/L, respectively, whereas for genistin and daidzin, it was 11 µmol · h/L. The C_max for genistein and daidzein were 1.26 and 0.76 µmol/L and 1.22 and 1.55 µmol/L for genistin and daidzin, respectively. Richelle et al. (10) did not find differences in C_max and AUC between aglucones and glucosides. Zubik and Meydani (9) found no difference in C_max (0.5 vs. 0.5 µmol/L, respectively) and AUC over a 48-h period for genistein and genistin (8.3 ± 4.2 vs. 8.9 ± 4.7 µmol · 48 h/L, respectively). But they found a significantly higher C_max (0.5 vs. 0.4 µmol/L, respectively, P < 0.05) for plasma daidzein and difference in AUC between daidzein and daidzin (8.3 ± 2.6 vs. 6.2 ± 1.7 µmol · 48 h/L, respectively, P < 0.05). This difference occurred in part because daidzein was fed in a greater amount from the aglucon source than from the glucoside source. Overall results, including the present study, show that isoflavone aglucons were absorbed more rapidly but the isoflavone glucosides were absorbed to the same extent later; the total bioavailability of aglucons and glucosides as reflected in total urinary isoflavone excretion did not differ.

In either the aglucon or glucosidic form, the bioavailability of an isoflavone source rich in glycitein (soygerm and fermented soygerm) was significantly greater than that of an isoflavone source rich in genistein (Novasoy) at all time intervals as reflected in urinary excretion (Table 3). Comparing urinary isoflavone excretion of each of the 3 isoflavones, significantly greater amounts of daidzein and glycitein were excreted than genistein in all treatments (Table 5). Less excretion of genistein in urine compared with daidzein and glycitein may be due to structural differences. Griffiths and Smith (26) reported that genistein’s hydroxyl group at the 5 position of the A-ring is more degraded by gut microbes in rats than are compounds without this structure (e.g., daidzein, and glycitein). The more genistein is degraded, the less is recovered in urine. Sfakianos et al. (27) evaluated the intestinal uptake and biliary excretion of the isoflavone genistein in rats and found that the main metabolite of genistein was 7-O-ß glucuronide, which was excreted mainly into bile with only a small proportion into urine. After this "first-pass," isoflavones may undergo substantial gut microbial metabolism. Zhang et al. (16) reported that after consumption of soy foods by 14 subjects with moderate fecal isoflavone degradation, urinary excretion of genistein (as a percentage of ingested isoflavone) was less (P < 0.00l) than daidzein and glycitein. Glycitein had the same excretion pattern in urine as did daidzein. The current findings confirm this finding.

Due to the small number of subjects, GTT and urinary isoflavone excretion did not differ between high and low daidzein degradation phenotypes within each treatment. However, when data from the high and low daidzein degradation phenotypes were combined across the 3 treatments, urinary total isoflavone excretion was significantly greater in subjects of the low degradation phenotype who had significantly shorter GTT than in subjects of the high degradation phenotype with significantly longer GTT over 0–12 h and 0–24 h (Table 4). Furthermore, total urinary isoflavone excretion over 0–12 h was marginally negatively correlated with D_k and GTT among all of the subjects; urinary isoflavone excretion at 0–12 h contained most of the isoflavones excreted over the day. Bioavailability of genistein as reflected in urinary genistein excretion was significantly greater in subjects of a low genistein degradation phenotype with shorter GTT than in subjects of a high genistein degradation phenotype with longer GTT, after consumption of soymilk powder providing 4.6 µmol total isoflavone/kg body weight (19). GTT and gut microbial degradation of isoflavones may determine their bioavailability. Xu et al. (12) reported that 2 women who excreted significantly greater amounts of isoflavone in feces also had greater isoflavone in urine and plasma compared with 5 women who excreted little isoflavone in feces and urine, suggesting an influence of gut microbial degradation on isoflavone bioavailability. The low isoflavone degradation phenotype coupled with rapid GTT seemed to prevent isoflavone degradation; isoflavones were apparently absorbed to a greater extent in such individuals.

As expected, no fecal isoflavone degradation phenotypic differences were found in total and individual plasma isoflavones 3 h after feeding because this would be an insufficient amount of time for isoflavones to reach the lower gut. We did not find glycitein in plasma at 3 or 24 h after feeding. Glycitein may be absorbed more slowly than daidzein such that it is undetectable 3 h after feeding but cleared by 24 h. At 6 h after soymilk and soygerm consumption, plasma glycitein concentrations were significantly lower than that of daidzein (16), but glycitein reached a C_max 4 h after ingestion in 1 man (8). Genistein was detected in plasma 3 h after feeding in only 8 subjects, but genistein intakes were low in subjects fed soygerm flour. At 24 h after soy feeding, no isoflavones were detected in plasma, likely due to the detection limit (0.5 µmol/L).

In this study, the bioavailability of isoflavone aglucons and glucosides did not differ over 24 h, but genistein was less absorbed than glycitein or daidzein, as reflected in total urinary isoflavone excretion. Isoflavone aglucons were absorbed more rapidly than glucosides as reflected in plasma 3 h after feeding. Women of a low daidzein degradation phenotype with more rapid GTT had greater apparent isoflavone absorption than did women of a high daidzein degradation phenotype with slower GTT. This phenomenon should be considered in human feeding studies on the effects of isoflavones.

	FOOTNOTES

 
¹ Presented at Experimental Biology, Apr. 20–24, 2002, New Orleans, LA [Zheng, Y., Lee, S.-O., Hu, J., Verbruggen, M., Murphy, P. A. & Hendrich, S. (2002) Comparative bioavailability of isoflavone aglucons and glucosides in women. FASEB J. 16: 737.5 (abs.)].

² Supported by Acatris Holding B.V.

⁴ Abbreviations used: BHI, brain-heart infusion; D_k, daidzein degradation rate constant; GTT, gut transit time; THB, 2,4,4'-trihydroxybenzoin.

Manuscript received 5 March 2004. Initial review completed 15 May 2004. Revision accepted 12 July 2004.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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