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Human Nutrition and Metabolism

Hydrolysis of Isoflavone Glycosides to Aglycones by ß-Glycosidase Does Not Alter Plasma and Urine Isoflavone Pharmacokinetics in Postmenopausal Women

Myriam Richelle^*1, Sylvie Pridmore-Merten^*, Stefan Bodenstab, Marc Enslen^* and Elizabeth A. Offord^*

^* Department of Nutrition, Nestlé Research Center, Lausanne, Switzerland and Nestlé Product Technology Centre Konolfingen, Konolfingen, Switzerland

¹To whom correspondence should be addressed. E-mail: myriam.richelle{at}rdls.nestle.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We investigated whether the bioavailability of isoflavones could be enhanced by enzymatic hydrolysis of glycosides to aglycones before consumption of a nonfermented soy food. Two drinks were formulated with an enriched isoflavone extract from soy germ (Fujiflavone P10), one of which was hydrolyzed enzymatically with ß-glucosidase to produce aglycones. In a randomized, double-blinded, cross-over study, six European, postmenopausal women consumed each soy drink at a 1-wk interval at a concentration of 1 mg total isoflavones/kg body. The plasma and urinary pharmacokinetics of daidzein, genistein and glycitein did not differ after consumption of the two beverages. Plasma total isoflavone concentrations reached 4–5 µmol/L. The pharmacokinetics of glycitein were similar to those of daidzein. The isoflavone secondary metabolites detected were dihydrodaidzein in plasma and O-desmethylangolensin, equol, and dihydrogenistein in urine. The ratios of individual isoflavones to one another were not conserved from food to plasma to urine, indicating that the individual isoflavones do not have the same absorptions and body retentions. In conclusion, previous hydrolysis of glycosides to aglycones does not enhance the bioavailability of isoflavones in humans.

KEY WORDS: • isoflavones • soy • bioavailability • excretion • glycosides • plasma • humans

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Consumption of soy-based foods is associated with a number of health benefits, including lower risk of cardiovascular disease, breast and prostate cancer, attenuated menopausal symptoms and prevention of bone loss with age (1 –7 ).

Soy isoflavones are found mainly as glycosides in soybeans and in unfermented soy foods (8 ). Effective absorption of the isoflavones likely requires the conversion of glycosides to aglycones via the action of ß-glycosidase from bacteria that colonize the small and the large intestine (9 ,10 ). The large interindividual variation in gut microflora affects the metabolism of isoflavones whether it be conversion from glycosides to aglycones or production of secondary metabolites such as equol and dihydrogenistein (11 –16 ). More recent evidence suggests that glycoside isoflavones can in part be metabolized to aglycones via endogenous ß-glycosidases present in the small intestine (17 –19 ).

Traditional fermented soy foods such as tempeh, natto and soy sauce are richer in aglycone isoflavones than unfermented soy (20 ). Isoflavones from fermented products are more available to humans (14 ,15 ,21 ) than from unfermented products. In this study, we investigated whether prehydrolysis of isoflavone glycosides in food could be an alternative to fermentation to improve isoflavone bioavailability. The advantage would be to reduce the intervariability response of the population but also to provide the health benefits of isoflavones with a lower dose in the food product. We used an enzymatic hydrolysis with ß-glycosidases to generate isoflavone aglycones in a soy drink and compared the pharmacokinetics of plasma and urine isoflavones in six postmenopausal women of European origin. In addition, the plasma pharmacokinetics of individual isoflavones, i.e., genistein, daidzein and glycitein, were characterized.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Materials.

The following materials were used in this study: Fujiflavone P10 (Fujikko, Japan), commercial ß-glucosidases (Novozym 188; Nordisk, Bagsraerd, Denmark), commercial ß-glucuronidase from Helix pomatia containing ß-glucuronidase and sulfatase activity (Sigma G 7017; Sigma, St. Louis, MO).

Subjects.

Six postmenopausal women [age: 55.5 ± 5 y; body weight: 70.3 ± 6.5 kg; body mass index (BMI)² : 26.0 ± 2.4 kg/m²; mean ± SD] participated in this study. They fulfilled the following criteria: nonsmoking, menopaused for more than 6 mo, not under hormone replacement therapy. The protocol was approved by the ethical committee of Nestlé. All volunteers signed informed consent before entering the study and could withdraw from the study at any time if desired. Body weight, dietary habits and physical activity remained constant throughout the study. All the enrolled subjects completed the study.

Hydrolysis of isoflavone extract.

Hydrolysis of the isoflavones in the soy extract was performed by incubation with ß-glycosidase for 2 h at 60°C. The isoflavone compositions of the hydrolyzed and nonhydrolyzed extracts are presented in Table 1 . The glycoside beverage contained 98% of isoflavones as glycosides, whereas the aglycone beverage contained 57% of isoflavones as aglycones due to partial hydrolysis of genistin and glycitin.

Beverages were prepared by mixing the hydrolyzed or nonhydrolyzed isoflavone extract with water, sugar and orange flavor. These beverages were packed in Tetra Brik 200 mL and stored at room temperature until consumption. The concentration of total isoflavones was determined in the beverages before the initiation of the study. The volume of beverage to be consumed by the subject was adjusted to provide 1 mg isoflavone aglycone equivalent/kg body (3.6 µmol isoflavone aglycone equivalent/kg body based on an average molecular weight of 274).

Study protocol.

The study was a randomized, double-blinded, cross-over design. Subjects were asked to refrain from soy containing food 1 wk before the test until the completion of the study. The study was divided into two phases to allow the characterization of both the absorption and elimination phases of isoflavones following the previously validated two-phase study design by King and Bursill (22 ).

Test 1 (absorption) was designed to characterize the absorption phase until reaching the maximum plasma isoflavone concentration. After an overnight fast, the subjects consumed the drink at 0800 h and blood samples were collected every hour for 8 h and a last one at 24 h postmeal. Subjects ate a standard meal, free of isoflavones, for lunch.

Test II (elimination) was designed to determine the elimination half-life of plasma isoflavones. The subjects consumed the drink at 2200 h, 3 h after their evening meal, free of isoflavones. Fasting subjects came to the Metabolic Unit the following morning at 0800 h. Blood samples were collected every hour between 10 h and 18 h postmeal and a last one at 34 h postmeal. The subjects were allowed to eat a standard meal, free of isoflavones, for lunch at 1200 h.

Every woman consumed each soy drink (aglycone and glycoside) for both tests (absorption and elimination), making altogether four interventions which were performed in random order with at least a 1-wk interval.

Collection and analysis of blood and urine samples.

Blood samples were drawn via venipuncture from the arm into evacuated tubes containing potassium EDTA. Blood samples were immediately placed on ice and then centrifuged (10 min, 4°C, 3000 x g) to separate the plasma, which was stored at -80°C until analysis.

During the elimination test, urine was collected for 34 h in five different containers according to time (fraction 1: before drink consumption; fraction 2: 0–8 h postmeal; fraction 3: 8–14 h postmeal; fraction 4: 14–24 h postmeal; and fraction 5: 24–34 h postmeal). An aliquot of each urine fraction was stored at -80°C until analysis.

Sample preparation and analysis of plasma and urine isoflavones were performed according to the method of Franke et al. (23 ) with minor modifications. Plasma (50 µL) diluted twice with distilled water, and urine (100 µL) were subjected to enzymatic hydrolysis at 37°C for 15 h by the action of a combined sulfatase and glucuronidase enzyme preparation (23 ). Water (1 mL, pH 3) was added to this mixture and then applied to a Baker SPE column (Stehlin AG, Basel, Switzerland) preconditioned with methanol and water (pH 3). The isoflavones were eluted with methanol/water (8/2, v/v) and dried at 60°C under a nitrogen stream. The residue was dissolved in water (200 µL, pH 3) and 100 µL were injected into the HPLC system. Isoflavones from plasma and urine samples were separated using a C18 column (Nucleosil 120–3; Macherey-Nagel, Oensingen, Switzerland). The separation was achieved at 30°C using gradient conditions with solvent A, consisting of 999.5 g water and 2 g phosphoric acid and solvent B of acetonitrile. The gradient was started with 90% solvent A. After 20 min, solvent A was reduced to 72%, then at 25 min to 50%, at 35 min to 90% until 45 min. The flow rate was 0.8 mL/min. Data were simultaneously acquired at 257 nm (daidzein, glycitein and genistein) at 290 nm (dihydrogenistein); at 276 nm (dihydrodaidzein) but also with a fluorimetric detection at 280 nm excitation and 310 nm emission for equol. All solvents were HPLC grade and were used without purification. The detection limit was 75 nmol/L for daidzein, glycitein, genistein, equol, dihydrodaidzein, O-desmethylangolensin (ODMA), dihydrogenistein, and 6-ODMA. Results are expressed as aglycone equivalents.

Pharmacokinetic and statistical analyses.

The pharmacokinetic analysis of the results was carried out as independent model using Siphar/Win software (InnaPhase, Creteil, France). The pharmacokinetic analysis of plasma concentration vs. time curves of the studied products was done using an extravascular model. The following pharmacokinetic parameters were determined: maximal plasma concentration (C_max), time to reach the C_max (T_max), experimental area under the plasma concentration curves vs. time between 0 and 34 h (AUC_0–34h), apparent half-life of the absorption (T_abs) and apparent half-life of the elimination (T_elim). From the cumulative amount of product excreted in urine vs. time curves was calculated the AUC_0–34h and the rate of urinary flow for fixed time intervals.

A statistical analysis was performed to compare the homogeneity of the baseline values and the pharmacokinetic parameters between treatments. The parameter T_max was analyzed using the nonparametric Wilcoxon Signed Rank test. A paired t test was used on the other variables. Within treatment comparisons of different isoflavones were by repeated measures ANOVA with "subject" the repeated factor. All statistical analyses were done with NCSS2000 software (Kaysville, UT). Differnces with P < 0.05 were considered significant.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Effect of enzymatic hydrolysis on the plasma pharmacokinetics of isoflavones.

The pharmacokinetic parameters, such as T_abs, T_elim, C_max, T_max and AUC_0–34h, did not differ after the women comsumed the free and conjugated forms of isoflavones (Figs. 1 2 –3 ; Table 2 ). Therefore, enzymatic hydrolysis of glycosides to aglycones in the beverage before consumption did not alter the pharmacokinetic parameters of the individual isoflavones.

View larger version (11K): [in this window] [in a new window]   FIGURE 1 Pharmacokinetics of plasma daidzein in women after they consumed a beverage containing isoflavones (1 mg/kg body) as either aglycones or glycosides. Values are means ± SEM, n = 6. The graphs show two phases of plasma daidzein pharmacokinetics: absorption, the beverage was consumed at 0800 h and blood samples collected over the 0- to 8-h period and elimination, the beverage was consumed at 2200 h and blood samples were taken the next morning, representing the 10- to 34-h period.

View larger version (10K): [in this window] [in a new window]   FIGURE 2 Pharmacokinetic of plasma genistein in women after they consumed a beverage containing isoflavones (1 mg/kg body) as either aglycones or glycosides. Values are means ± SEM, n = 6. The graphs show two phases of plasma daidzein pharmacokinetics: absorption: the beverage was consumed at 0800 h and blood samples collected over the 0- to 8-h period and elimination: the beverage was consumed at 2200 h and blood samples were taken the next morning, representing the 10- to 34-h period.

View larger version (10K): [in this window] [in a new window]   FIGURE 3 Pharmacokinetic of plasma glycitein in women after they consumed a beverage containing isoflavones (1 mg/kg body) as either aglycones or glycosides. Values are means ± SEM, n = 6. The graphs show two phases of plasma daidzein pharmacokinetics: absorption: the beverage was consumed at 0800 h and blood samples collected over the 0- to 8-h period and elimination: the beverage was consumed at 2200 h and blood samples were taken the next morning, representing the 10- to 34-h period.

Before consumption of the soy beverages, plasma isoflavone concentrations were very low and mostly undetectable, indicating that the women had not ingested soy products. After consumption of both soy beverages, plasma isoflavone concentrations increased rapidly, leading to a first peak at 1–2 h postabsorption, then reaching a maximum at 7–9 h and finally declining slowly, resulting in still elevated concentrations at 24 h postabsorption (Figs. 1 2 3) . Plasma glycitein (Fig. 3) exhibited peaks at 1 h and 7–8 h that were more pronounced than those of daidzein (Fig. 1) and genistein (Fig. 2) .

Individual isoflavones had rapid apparent half-lives of absorption (T_abs), which did not differ among daidzein, genistein and glycitein nor did they differ after intake of the two soy beverages (Table 2) . After consumption of the glycoside beverage, the apparent half-life of the elimination (T_elim) was longer for genistein than daidzein and glycitein (P < 0.001), whereas after the aglycone beverage, T_elim did not differ among individual isoflavones. This difference may be partly explained by greater interindividual variation observed for aglycone than for glycoside treatment. The C_max and AUC_0–34h of individual isoflavones were related to their concentrations in the beverages. Thus, the C_max and AUC_0–34h of daidzein for both soy beverages were greater (P < 0.01) than those of glycitein and genistein (Table 2) . The T_max at 7–9 h did not differ among the three isoflavones.

Plasma metabolites of isoflavones.

Of the daidzein metabolites, dihydrodaizein, ODMA and equol, and of the genistein metabolites, dihydrogenistein and 6-ODMA, only dihydrodaidzein was detected, appearing in plasma 5 h after the consumption of both soy beverages. Its C_max was relatively low (0.27 and 0.36 µmol/L for the aglycone and glycoside beverages, respectively; Fig. 4 ).

View larger version (11K): [in this window] [in a new window]   FIGURE 4 Pharmacokinetic of plasma dihydrodaidzein in women after they consumed a beverage containing isoflavones (1 mg/kg body) as either aglycones or glycosides. Values are means ± SEM, n = 6. The graphs show two phases of plasma daidzein pharmacokinetics: absorption: the beverage was consumed at 0800 h and blood samples collected over the 0- to 8-h period and elimination: the beverage was consumed at 2200 h and blood samples were taken the next morning, representing the 10- to 34-h period.

At the start of the study, urinary isoflavone concentration was negligible, confirming that women had not consumed soy. After drinking the soy beverages, daidzein, glycitein and genistein appeared in urine (Table 3 ). Some metabolites of daidzein (dihydrodaidzein, ODMA and equol) and metabolites of genistein (dihydrogenistein and 6-ODMA) were also detected in urine. These metabolites appeared in urine with some delay compared with their parent molecules and their concentrations were quite low. Glycitein was clearly recovered in urine; however, no metabolites were measured for glycitein because standards for these metabolites are not available. The urinary recovery of isoflavones and their metabolites was completed during the first 24 h postmeal, with the exception of dihydrodaidzein, which was mainly recovered between 24 and 34 h. The percentage of the ingested isoflavone recovered in urine over the 34-h postmeal period was highest for daidzein (50% and 56% after drinking aglycone and glycoside beverages, respectively) followed by glycitein (29% and 38%); and finally by genistein (18% and 20%, respectively). However, isoflavone excretions did not differ after the women consumed the aglycone and glycoside beverages.

The relative ratios of individual isoflavones to one another in the soy beverages, plasma and urine are presented in Table 4 . The ratios were not the same in the three fluids.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

To study all of the pharmacokinetics of isoflavones, i.e., the absorption and elimination phases, each beverage was consumed twice by each subject: once at 0800 h for the absorption period and once at 2200 h for the elimination period followed by collection of blood samples at various time intervals (according to the study design of King and Bursill) (23 ). The plasma isoflavone concentration vs. time curves exhibited an early peak and a kink before the C_max (Figs. 1 2 3) , typical of compounds that undergo enterohepatic recycling. This is a phenomenon already described in previous studies using either soy-containing foods (13 ,23 ) or pure compounds such as daidzein and genistein isolates (24 ). Although most soy supplements and food sources contain glycitin, little information exists in the literature on the plasma pharmacokinetics of glycitein in humans. The double peak was particularly marked for glycitein, suggesting that it undergoes extensive enterohepatic recycling (Fig. 3) . The pharmacokinetic parameters of the plasma glycitein were very similar to those of daidzein (Table 2) .

The pharmacokinetic parameters of the aglycone and glycoside soy beverages were very similar. A recent study by Setchell et al. (24 ) found similar bioavailabilities of genistein and daidzein when given as pure aglycones or glycosides. However, they observed a delay in reaching the maximum concentration after the ingestion of glycoside isoflavones, suggesting that the rate-limiting factor in absorption was the initial hydrolysis of the sugar moiety. We did not observe this delay in absorption of the glycosides.

The plasma pharmacokinetics of isoflavones were characterized by a rapid absorption half-life of 2 h for both daidzein and genistein, and slow elimination half-lives of 5 h and 17 h for daidzein and genistein, respectively, leading to still elevated plasma isoflavone concentrations 34 h after the consumption of either soy beverage. Whereas the elimination half-life of daidzein is in accordance with those previously described in the literature ranging from 2.9 to 4.4 h, the observed elimination half-life of genistein in this study is considerably longer (17 h) than the previously reported values, which ranged from 3.8 to 6.7 h (23 ,25 ,26 ). More recently, Setchell et al. (24 ) reported T_abs of 6.6 ± 1.4 h and 9.3 ± 1.3 h for daidzein and genistein, respectively, after the consumption of 50 mg of pure daidzein or genistein. The difference between the reported and observed half-lives of absorption and elimination could be due to the food matrix in which the isoflavones were incorporated and whether they were given as pure isoflavones, as soy protein isolates or as enriched isoflavone extracts. Other factors may include the differences in the study design, especially the number of blood samples collected during the absorption and elimination phases, and the determination and sensitivity of the analytical methods.

Isoflavones were recovered in urine with the majority of them excreted during the first 24 h after intake. The recovery of isoflavones in urine was 50% for daidzein, 38% for glycitein and 20% for genistein. The urinary excretions of daidzein and genistein are in agreement with those previously reported (13 ,23 ,26 ), while other values have been reported that ranged from 16% (27 ) to 49% (28 ) for daidzein and from 10% (10 ,27 ) to 16% (28 ) for genistein. The lower urinary excretion of genistein could result from a difference in the partitioning of isoflavones in urine due to differences in solubility. In this study, isoflavone metabolism occurred to the same extent in the two beverages. A single metabolite, dihydrodaidzein, was detected in plasma after a delay of 5 h, which is consistent with the bacterial enzymes being of colonic origin. The concentration of this metabolite was, however, rather low and even absent in some subjects (three of six). Metabolites of daidzein and genistein were present in urine of all the women and were recovered mostly in urine collected between 14 and 24 h after soy beverage consumption. In our population, the interindividual variability in isoflavone metabolism was quite low.

In conclusion, this study demonstrates that enzyme hydrolysis of a purified, concentrated extract of isoflavones does not enhance the absorption of isoflavones in postmenopausal women. Similar plasma and urine pharmacokinetics were observed for the aglycone and glycoside drinks. The ratios of individual isoflavones to one another were not conserved from food to plasma to urine, indicating that they do not have the same distributions and body retentions. However, due to the relatively efficient uptake and the low elimination rates of isoflavones, chronic ingestion of soy products would result in a gradual rise in plasma concentrations.

	ACKNOWLEDGMENTS

 
We thank Isabelle Tavazzi for her excellent technical assistance and J. L. Veuthey, University of Geneva, for analysis of urinary isoflavones.

	FOOTNOTES

 
² Abbreviations used: AUC, area under the curve; BMI, body mass index; C_max, maximum concentration; EDTA, ethylenediamine tetraacetic acid; ODMA, O-desmethylangolensin; T_abs, apparent half-life of absorption; T_elim, apparent half-life of elimination; T_max, time at the maximum concentration.

Manuscript received 7 March 2002. Initial review completed 10 April 2002. Revision accepted 5 June 2002.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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