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RIKILT-Institute of Food Safety, Wageningen UR, 6700 AE, Wageningen, The Netherlands and * Institute of Anaesthesiology, University Medical Centre Sint Radboud, 6500 HB Nijmegen, The Netherlands
2To whom correspondence should be addressed. E-mail: peter.hollman{at}wur.nl.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • enterodiol • enterolactone • lignans • secoisolariciresinol diglucoside • bioavailability
Enterolactone and enterodiol, also called enterolignans, are phytoestrogens with structural similarity to endogenous estrogens. Enterolignans have demonstrated antioxidant and weak (anti-)estrogenic effects (1–4). They are capable of induction of NADPH:quinone reductase (phase II enzymes) (5) and can inhibit enzymes involved in the metabolism of sex hormones [e.g., SHBG, 5
-reductase, and 17ß-hydroxysteroid dehydrogenase (6–8)]. Because of these activities, enterolignans may affect the development of chronic diseases. Epidemiological studies suggest that high plasma concentrations of enterolactone are associated with a lower risk of acute coronary events (9,10). Associations between enterolignans and cancer are unclear. Inverse associations were reported only for case-control studies (11–13), whereas no associations between enterolignans and breast or prostate cancer were found in 3 prospective studies (14–16) [reviewed by Arts and Hollman (17)]. Enterolactone and enterodiol are products of bacterial conversion of plant lignans in the human colon (18–20). Plant lignans are naturally occurring compounds that have a polyphenolic structure. Dietary sources of plant lignans are flax, grains, seeds, fruits and vegetables, olive oil, and beverages such as tea, coffee, and wine (21–28).
Secoisolariciresinol, one of the plant lignans, is converted to enterodiol and subsequently to enterolactone by intestinal bacteria (29) (Fig. 1). Matairesinol, another plant lignan, is converted directly to enterolactone. Other precursors of enterolignans are pinoresinol, lariciresinol, isolariciresinol, and syringaresinol (30). Enterodiol and enterolactone are absorbed from the large intestine. They are mainly present as glucuronide and sulfate conjugates in body fluids and are excreted via urine (31). Due to different consumption patterns (32), variation in microflora, and use of antibiotics (19,33), among other things, plasma concentrations of enterodiol and enterolactone vary widely among people. We know little about the kinetics of absorption and distribution of enterodiol and enterolactone in the body.
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In the present study, we investigated the absorption and excretion of enterodiol and enterolactone in healthy men and women consuming a single dose of secoisolariciresinol diglucoside (SDG),3 which is the major lignan in flax. Based on a pilot study we designed an optimal sampling schedule, which covered the increase in plasma and urine concentrations of enterolignans and their return to baseline. This is the first report describing the pharmacokinetics of enterodiol and enterolactone.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Diet. To avoid interference from other dietary sources of lignans, the participants started a diet poor in lignans 7 d prior to the study and followed it throughout the experiment. The participants were given a list of lignan-containing foods and beverages and were asked to avoid them. They avoided dried fruits, berries, several vegetables (e.g., asparagus, broccoli, and zucchini), legumes, seeds and nuts (e.g., flax, sesame, and peanut), breakfast cereals, cereal and muesli bars, whole-grain products (e.g., rye bread, whole grain bread, and brown rice), olives, virgin olive oil, herbal tea, grape juice, and orange juice. Furthermore, they limited their consumption of black tea and coffee to a maximum of 2 cups (500 mL) a day. Consumption of selected wheat products (white bread, pasta), white rice, milk products (milk, yogurt, cheese), meat and fish, several fruits (e.g., apple, pear), and vegetables (e.g., cucumber, tomato, paprika, cabbage) was allowed so that, in principle, the intake of micro- and macronutrients was adequate. To ensure an adequate fiber intake, wheat bread with a low lignan concentration (370 nmol lignans/100 g bread) was supplied daily. Bread is an important source of fiber in the Netherlands. Every day a standard breakfast (low lignans) was provided at the Division of Human Nutrition. Lunch and dinner were also provided on the first 2 d of the study.
Lignan supplement. On d 1 of the study after a 12-h overnight fast, the subjects consumed 1.31 µmol SDG/kg body wt (0.9 mg SDG/kg body wt) in water, just before having their breakfast at around 0800 h. SDG was obtained from the Institute of Food Chemistry, Technical University of Braunschweig. SDG was isolated from a natural source, i.e., flax (Linum usitatissimum L.) (41). For isolation, extraction, and purification of SDG only p.a. quality solvents (food grade) were used. In order to remove remaining traces of solvents the SDG extract was freeze-dried. The purity was above 93%. One day before consumption, the supplement was weighed, dissolved in 50 mL water, and then kept at –20°C. The supplement was thawed 1 h before consumption.
Collection of samples. Venous blood samples were taken into vacuum tubes containing EDTA immediately before the intake of SDG (0 h), every 3 h over the next 36 h, and at time points 48, 72, and 96 h. Samples were centrifuged within 30 min at 1187 x g for 10 min at 4°C, and plasma was stored at –80°C until analysis.
Urine samples were collected beginning 24 h prior to the intake of SDG until 72 h after the intake of SDG. The participants stored each bottle on dry ice immediately after voiding. Each day, urine samples were transported from the participants’ homes to the laboratory, where they were kept at –20°C. At the laboratory, urine samples were thawed and homogenized. To obtain 24-h urine samples, the samples of 1 d were pooled per subject.
Logistics. During the study, blood samples t = 0–12 h and t = 24–96 h were taken at the Division of Human Nutrition at Wageningen University. Samples t = 15–21 h, which were collected during the night, were drawn at the hospital Gelderse Vallei in Ede, where the subjects stayed overnight. Volunteers were transported between the 2 sites under supervision of a research nurse.
Analytical methods. Total enterodiol and enterolactone concentrations were measured in plasma and urine after hydrolysis of conjugates using a freshly prepared enzyme mixture of ß-glucuronidase sulfatase from Helix Pomatia (G1512, Sigma) in sodium acetate buffer (0.5 mol/L, pH 5.0).
Urine analyses. Quantification of enterodiol and enterolactone in urine was performed by HPLC with electrochemical detection as described previously (42). The original method was slightly modified. Briefly, 200 µL of urine was mixed with an equal amount of buffer and 40 µL enzymes (50 g/L). Subsequently, samples were incubated at 37°C for 2 h and extracted twice with diethyl ether. Prior to the analysis, extracts were filtered, transferred into vials, and injected into the HPLC system. To separate the enterolignans from other compounds, we used a binary gradient. Mobile phase A consisted of 15% acetonitrile in 50 mmol/L sodium acetate buffer (pH 5.0). Mobile phase B consisted of 60% acetonitrile in 50 mmol/L sodium acetate buffer (pH 5.0). A total of 100 µL extract was injected onto 2 Chromolith columns (100 x 4.6 mm each; Merck) in series. The gradient at a flow rate of 2.5 mL/min was as follows: 0–8.5 min, linear from 0 to 15% mobile phase B; 8.5–14.5 min, linear from 15 to 38% B; 14.5–14.7 min linear from 38 to 100% B; 14.7–16.7 min, isocratic at 100% B; 16.7–17.0 min, linear return from 100 to 0% B; 17.0–21.0 min, isocratic at 0% B to equilibrate. For detection and quantification of enterolignans, we used a 4-channel Coularray HPLC detection system. Enterodiol and enterolactone were quantified at 650 mV. Determinations in urine were carried out in duplicate. The limit of detection of enterodiol and enterolactone was 3 nmol/L. The recovery of enterodiol and enterolactone was 115 ± 20% (n = 2). The within-run CV of enterodiol was 3% and that of enterolactone was 4% (n = 6). The between-run CV of both enterolignans was 13% (n = 4).
Plasma analyses. Plasma samples contained much lower concentrations of enterolignans than urine samples. When plasma samples were measured with electrochemical detection, the resolution was inadequate. Thus HPLC with MS/MS detection, which has excellent specificity, was chosen instead. The sample preparation as described above was adjusted for plasma. First, we added 10 µL of a mixture of 13C3-labeled enterodiol and enterolactone (500 nmol/L each; purchased from Dr. Botting, University of St. Andrews) into vials. Subsequently, 300 µL sodium acetate buffer (0.1 mol/L, pH 5.0), 60 µL enzyme mixture (100 g/L), and 300 µL plasma were added. Plasma samples were incubated at 37°C for 4 h and subsequently extracted twice with 1.5 mL diethyl ether. The mixtures were shaken with a Vortex mixer for 5 s and centrifuged after each extraction (2300 x g, 10 min, 10°C). The 2 ether fractions were combined and transferred into new tubes containing 500 µL of 40% methanol:water (v:v). The ether fraction was evaporated under a gentle stream of nitrogen at 30°C with a Turbovap evaporator. The tubes were shaken with a Vortex mixer for 10 s. Prior to analysis, extracts were filtered, transferred into vials, and injected into the LC-MS system. We used a Waters Alliance 2690 HPLC pump, which consisted of a chromatographic system, and an autoinjector with a cooled sample tray set at 10°C. Separations were performed with an XTerra C18 column (3.0 x 50 mm, 5 µm, Waters), which was placed into a thermostatic column chamber set at 40°C. Mobile phases A and B consisted of water and methanol, respectively. The gradient at a flow rate of 0.4 mL/min was as follows: 0–1.0 min, isocratic at 10% mobile phase B; 1.0–7.0 min, linear from 10 to 80% B; 7.0–7.5 min isocratic at 80% B; 7.5–8.0 min, linear return from 80 to 10% B; 7.0–11.0 min, isocratic at 10% B to equilibrate. The total run time for each sample was 11 min. The sample injection volume was 100 µL. The divert valve was programmed to allow flow into the mass spectrometer from 4 to 9 min of each run. Detection was performed with a Micromass Quatro Ultima MS equipped with an electrospray probe in negative ion mode, with the capillary voltage at 2.5 kV. We used nitrogen at a flow rate of 550 L/h as the desolvation gas. Source and desolvation gas temperatures were set at 120 and 350°C, respectively. Daughter ions were formed by collision-induced dissociation with argon as collision gas at a pressure of 2.3 x 10–3 mbar, with collision energy ranging from 20 to 36 eV. Multiple reaction monitoring was performed with the following precursor/product combinations: enterodiol (301.1:253.1) and enterolactone (297.1:253.1) with 13C3-labeled internal standards enterodiol (304.1:256.1), and enterolactone (300.1:255.1). Integration of peak areas was performed using Mass Lynx (Micromass). The limit of detection, i.e., the concentration producing a peak height 3 times the SD of the baseline noise, was 0.2 nmol/L for enterodiol and 0.6 nmol/L for enterolactone. The recovery of 10 nmol/L enterodiol and enterolactone aglycone was 98 ± 16% (mean ± SD, n = 6). The within-run CV was 6% for enterodiol and 3% for enterolactone (n = 6), and the between-run CV was 16–18% for both enterolignans (n = 12).
Pharmacokinetic analysis. A 1-compartmental pharmacokinetic model was used to describe the absorption and disposition of lignans (MW/Pharm, Mediware) (43). The area under the curve (AUC) for plasma was calculated using the trapezoidal rule. When participants followed a diet low in lignans for 7 d, total enterolignan concentrations in plasma were reduced by half (data not shown). However, due to the abundance of lignans in foods, plasma concentrations of enterodiol were not zero at the start of the study. Baseline plasma concentrations of enterodiol fluctuated between 0.3 and 12 nmol/L (mean 3.4 nmol/L), and concentrations of enterolactone fluctuated between 3.3 and 15 nmol/L (mean 7.2 nmol/L). To calculate the AUC and maximum concentration, baseline values for each person were subtracted from the crude pharmacokinetic parameters.
Statistical analysis.
An independent t test was used to study sex differences. Two-sided Pearson correlation coefficients were calculated. In all tests, differences were considered significant at P 
0.05. Differences between enterodiol and enterolactone were not tested because the pharmacokinetic parameters are not independent. All statistical analyses were performed using the SPSS statistical software package (version 10.0). Data are means ± SD, unless stated differently.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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8–10 h (Table 1) before both enterolignans appeared in plasma. Although the maximum plasma concentration of enterodiol (73 ± 40 nmol/L), corrected for baseline, exceeded the maximum plasma concentration of enterolactone (56 ± 30 nmol/L), the AUC of enterolactone (1762 nmol/L · h) was approximately twice that of enterodiol (966 nmol/L · h). As expected, we found clear differences in the plasma concentration-time course for enterodiol and enterolactone. The maximum concentration of enterodiol was reached 14.8 ± 5.1 h after consumption of SDG, while the maximum concentration of enterolactone was reached 19.7 ± 6.2 h postdose. In addition, the elimination half-life of enterodiol (4.4 ± 1.3 h) was much shorter than that of enterolactone (12.6 ± 5.6 h). The residence time of enterodiol was 21 h and that of enterolactone was 36 h.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The delayed appearance of enterodiol and enterolactone in plasma indicates that absorption of lignans occurs in the colon. Other studies observed the same delayed appearance of 8–9 h with lignan-rich products (24,40), suggesting that the food matrix did not play an important role in the release of enterolignans.
The difference in time to reach the maximum plasma concentration between enterodiol and enterolactone might be overestimated. Data points from the enterohepatic circulation (second peak) were used in the 1-compartmental model, and thus the time to reach the maximum plasma concentration might be overestimated, especially for enterolactone. A similar problem may have influenced the absorption and elimination half-lives. A specific kinetic model, which takes into account enterohepatic circulation, may lead to more precise kinetic parameters. However, this is only feasible when there are enough data points to calculate the enterohepatic contribution. This kind of experiment would impose a considerable burden to the volunteers involved. The order in which SDG is converted, SDG >> enterodiol >> enterolactone, is consistent with the difference in absorption half-life between enterodiol and enterolactone. In a number of subjects the absorption and elimination half-lives were identical for both compounds. This means that the absorption governs the elimination, that the intrinsic elimination of the compound is faster than measured here, and that the observed elimination half-life is apparent.
The difference between men and women in the time to reach the maximum plasma concentration might be explained by the smaller blood volume in women, even when adjusted for body weight (46), because the enterolignans are confined to the blood compartment. When this volume is smaller, enterolignans will reach maximum concentrations earlier, and maximum plasma concentrations will be higher.
In our study the percentage of enterolignans excreted via urine is higher than that in animal studies. In a study with rats 28–32% of the ingested [3H]SDG was excreted in urine within 48 h (47). Knudsen et al. (45) found that 24% of the ingested lignans were excreted as enterolignans via urine when pigs were fed a low-lignan wheat bread diet. However, only 14% of the ingested lignans were excreted via urine in rats fed a high-lignan diet. In humans, the excretion of enterolignans via urine was 47.3 µmol/d after consumption of flaxseed powder (10 g/d) (37). Unfortunately, the percentage of the ingested dose excreted via urine could not be calculated because the authors did not report the amount of lignan in the flaxseed powder.
We did not measure metabolites of SDG other than enterodiol and enterolactone or the plant lignan itself. Jacobs et al. (48) detected 9 hydroxylated metabolites of enterodiol and enterolactone in the urine of 4 humans ingesting flax for 5 d. These metabolites accounted for <5% of the total urinary lignan excretion. Additionally, enterodiol and enterolactone accounted for 82% of the total amount of lignans excreted in the urine of humans consuming their habitual diet (unpublished results, Tarja Nurmi, University of Kuopio, Finland). Thus, we expect enterodiol and enterolactone to be the main metabolites.
In 1 subject plasma concentrations of enterolactone did not increase after consumption of SDG, while plasma enterodiol concentrations did increase. The habitual concentrations of enterolactone, measured before the lignan-poor diet was begun, were also exceptionally low in this subject (3 nmol/L) compared to others (29 ± 7 nmol/L). The urinary enterolactone excretion after consumption of SDG was also low, only 4% of the ingested dose, whereas the total amount of enterolignans excreted was approximately the same as in other subjects. This suggests that this subject was not able to convert enterodiol to enterolactone, likely due to the absence of specific bacteria in the colon that are responsible for the oxidation of enterodiol. The enterolactone present was likely formed from other lignan precursors in the diet, such as matairesinol, which can be directly converted to enterolactone. A similar observation was made by Nesbitt et al. (40), who found that 2 of 9 subjects produced little or no enterolactone during flaxseed supplementation for 7 d.
As demonstrated in other studies (37,40,49), we observed a wide variation in both urinary excretion and plasma concentrations of enterolignans among subjects. The variation is most likely due to differences in microflora between subjects. Other factors that could explain variation, such as background diet and age, were controlled for in our study. SDG was consumed purified; therefore, the food matrix could not have contributed to the variation either.
The health implications of the higher systemic exposure to enterolactone than to enterodiol are not clear. Thus far, most studies investigated only the effect of enterolactone. A few studies compared the effects of enterolactone and enterodiol and showed that they have similar antioxidant activities (1,2). However, enterolactone had a greater ability than enterodiol to inhibit the binding of estradiol and testosterone to sex steroid binding protein (50) or to inhibit human aromatase in vitro (51). Further studies are necessary to determine whether the physiological effects of enterodiol and enterolactone are different. Therefore, investigators must quantify concentrations of enterodiol and enterolactone in experimental and epidemiological studies in order to understand the metabolism and effect of both compounds. Furthermore, bioavailability studies for other important dietary enterolignan precursors, such as pinoresinol and lariciresinol, are needed. Whether the absorption, distribution, and elimination are influenced by other factors, such as food matrix, is also of interest.
Our data show that at least 40% of the ingested SDG is available for the body. The measured residence time and elimination half-life indicate that enterolignans will accumulate in plasma when consumed 2–3 times a day. Thus steady-state plasma concentrations of enterodiol and enterolactone are likely to be achieved because plant lignans are present in many foods and beverages (21–26). As a result, plasma enterolignan concentrations are expected to be suitable biomarkers of lignan exposure and may be used to evaluate the effects of lignans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AUC, area under the curve; SDG, secoisolariciresinol diglucoside; tlag, onset of the plasma curve.
Manuscript received 23 November 2004. Initial review completed 6 January 2005. Revision accepted 21 January 2005.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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