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Original Research Communications |
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: Two experiments were conducted to determine 1) whether there is a dose response in urinary lignan excretion with increasing flaxseed intake, 2) whether flaxseed processing affects lignan excretion, 3) peak plasma lignan concentrations, and 4) plasma lignan concentrations after chronic supplementation.
Design: Nine healthy young women supplemented their diets with 5, 15, or 25 g raw or 25 g processed (muffin or bread) flaxseed for 7 d during the follicular phase of their menstrual cycles. Twenty-four–hour urine samples were collected at baseline and on the final day of supplementation. As an adjunct to the 25-g-flaxseed arm, subjects consumed the supplement for an additional day and blood and urine samples were collected at specific intervals. All blood and urine samples were analyzed for enterolactone and enterodiol by gas chromatography–mass spectroscopy.
Results: A dose-dependent urinary lignan response to raw flaxseed was observed (r = 0.72, P 
0.001). The processing of flaxseed as a muffin or bread did not affect the quantity of lignan excretion. Plasma lignan concentrations were greater (P 0.05) than baseline by 9 h after flaxseed ingestion (29.35 ± 3.69 and 51.75 ± 7.49 nmol/L, respectively). The total plasma area under the curve was higher on the eighth than on the first day (1840.15 ± 343.02 and 1027.15 ± 95.71 nmol
h/L, respectively).
Conclusion: Mammalian lignan production from flaxseed precursors is dependent on time and dose but not on processing.
Key Words: Flaxseed • lignans • enterodiol • enterolactone • urine • plasma • dose response • humans • metabolism • secoisolariciresinol diglycoside
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lignans from flaxseed have been shown to reduce mammary tumor size by >50% (3) and tumor number by 37% (4) in carcinogen-treated rats. Furthermore, it has been suggested that lignans influence circulating concentrations of sex hormones and produce alterations in menstrual cycle length. One particular study showed both an increased length and ratio of progesterone to estradiol in the luteal phase (5). The physiologic basis for these effects of lignan are purported to include estrogenic or antiestrogenic (6, 7), antitumorigenic (4, 7–9), and antioxidant (10) properties. Epidemiologic studies have also shown that the prevalence of breast cancer is lower in countries where the diet is vegetarian (11, 12) and that lignan concentrations are significantly lower in omnivores and in women with breast cancer (13, 14). Thus, it is becoming increasingly obvious that lignans possess many beneficial properties.
Studies in humans have reported significant increases in urinary lignan excretion with the consumption of flaxseed [eg, 5-fold (15), 11-fold (16), and 13-fold (17) increases]; however, the amount and method of flaxseed ingestion have varied (eg, 50 g flaxseed in 2 muffins/d, 13.5 g in 6 slices bread/d, and 10 g in 2–3 servings raw flaxseed powder/d, respectively). Thus, it would be useful to determine whether a standard amount of flaxseed would produce similar urinary lignan excretion when consumed in either a raw or a processed form. Also, urinary lignan excretion in rats was observe d to be dose dependent at from 0% to 5% flaxseed (by wt) but to plateau at the 5–10% level (18); however, a similar response has not yet been reported in humans. Furthermore, there are no data regarding the time it takes for plasma concentrations to peak or the quantities of circulating plasma lignans after flaxseed intake. Similarly, there are no reports on urinary lignan excretion at timed intervals after flaxseed intake. In planning lignan studies with flaxseed, it is important to understand the dose and length of time it takes for plasma lignans to peak and then maintain a constant plasma concentration. Once the plasma lignan concentrations after flaxseed ingestion have been determined, investigators can begin to compare physiologic concentrations with the in vitro concentrations required to show biological effects.
Thus, in this study, 2 experiments were conducted in women with the following objectives: 1) to determine whether there is a dose response in urinary lignan concentrations with different amounts of flaxseed, 2) to determine whether a 25-g dose of flaxseed ingested in a raw or processed (muffin and bread) form would produce similar quantities of urinary lignan, 3) to identify the length of time to obtain peak plasma lignan concentrations after flaxseed ingestion, 4) to determine whether plasma lignan concentrations would increase and maintain a uniform concentration after 1 wk of supplementation, and 5) to correlate urinary lignan excretion with plasma concentrations. An understanding of the metabolism, absorption, and excretion of mammalian lignans from flaxseed is of utmost importance when using flaxseed as a model source of lignans in human studies.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Women were chosen as subjects for this study because flaxseed has been used as a model to study the effects of mammalian lignans on breast cancer, which occurs almost exclusively in females. Furthermore, lignans have been purported to affect female sex hormones (5, 19, 20). These factors together with the reported sex differences in lignan metabolism (21), confined this study to women.
Experiment 1
In a randomized crossover design, subjects' self-selected diets were supplemented with 5, 15, or 25 g raw ground flaxseed (in 125 mL applesauce) or 25 g processed flaxseed (ie, incorporated into a standard muffin or bread formulation) for 7 d during the follicular phase of their menstrual cycles. The raw flaxseed used contained 2.93 µmol SDG/g as measured by HPLC (18). The stage of the menstrual cycle was controlled for because urinary excretion of enterolactone has been shown to increase significantly during the midluteal phase of the menstrual cycle (20). Recent studies have not supported this observed difference in urinary lignan excretion between the follicular and luteal phases (17); however, it was also suggested that the midfollicular phase provides a more stable sampling time for sex hormones (22). Furthermore, energy intake has been reported to increase during the luteal phase when compared with the follicular phase (23) and could potentially increase the intake of plant lignans in the basal diet. Thus, the stage of the menstrual cycle was carefully controlled with subjects consuming flaxseed supplements and collecting urine during the follicular phases of their cycles.
Beginning on day 3 of the menstrual cycle, subjects ingested a standard, low-fiber dinner; on day 4 they collected a 24-h urine sample while continuing to consume only the standard, low-fiber meals (5 g fiber/d) provided. The standard meals consisted primarily of white bread or a roll, cheese or turkey, spaghetti with meat sauce, arrowroot cookies, applesauce, milk, and a fruit drink. Flaxseed supplementation was provided at breakfast starting on day 5 of the cycle and continuing until day 11. The evening before the final flaxseed supplement (day 10), subjects consumed another standard, low-fiber dinner and on day 11 they collected a 24-h urine sample and consumed the low-fiber meals provided. Thus, two 24-h urine samples were collected per subject during each arm of the study (ie, 5, 15, and 25 g raw, and 25 g in muffin and bread)—one sample for lignan analysis at baseline and the other after supplementation. Subjects were able to self-select their diets during the noncollection days of supplementation but they were required to complete a food record for 3 of these 6 d. Subjects agreed to avoid defined flaxseed- or soy-related foods during the entire course of the study (
5 mo), whereas legumes and sesame seeds were avoided during the supplementation period only (ie, days 1–13 of the menstrual cycle). Subjects' menstrual cycle lengths were recorded throughout the study and weight was recorded before and after the study.
Experiment 2
As an adjunct to the 25 g raw flaxseed arm of experiment 1, subjects continued to ingest flaxseed for 1 more day, ie, subjects ingested 25 g raw flaxseed for 8 d rather than 7. On the first and eighth day of supplementation with 25 g raw flaxseed, timed urine (0–12 and 12–24 h) and blood samples (0, 3, 6, 9, 12, and 24 h) were collected in addition to the samples obtained from experiment 1. Again, the standard low-fiber diet was provided on all collection days to control for confounding ingestion of lignans from fruit, vegetables, and whole grains.
Lignan analysis
Total urinary lignans [enterodiol + enterolactone + secoisolariciresinol (Seco; the aglycone of SDG)] were analyzed by capillary gas chromatography–mass spectrometry (GC-MS) procedures (2, 18). To check the completeness of the urine collections, creatinine content was measured colorimetrically (24).
Plasma lignans were quantified in duplicate with slight modifications to the previously described isotope dilution GC-MS procedure (13, 25). Distilled water (1.2 mL), acetate buffer (0.8 mL; 1.5 mol/L; pH 5.0), and triethylammonium sulfate (4 mL; 0.5 mol/L; pH 5.0) were added to 2.0 mL plasma and vortex mixed before incubation at room temperature for 20 min. The mixture was centrifuged (252 x g) for 5 min at 18°C to precipitate proteins. The plasma supernate was applied to an activated C18 octadecylsilane-bonded column (140 mg/3 mL size; Scientific Products and Equipment Ltd, Concord, Canada) before washing with 3 mL acetate buffer (0.15 mol/L, pH 5.0) and elution of lignans with 4 mL 72% methanol. The eluent was dried on a rotary evaporator (60°C) and the residue redissolved in 2 mL ethylacetate and 2 mL HCl. After overnight incubation at 37°C, the sample was evaporated to dryness under nitrogen gas. The dry sample was dissolved in 1 mL acetate buffer (0.15 mol/L, pH 5.0) before hydrolysis with 50 µL purified ß-glucuronidase (Helix pomatia; Sigma Chemical Co, St Louis) at 37°C for 1 h, and then reapplied to an activated C18 column with final purification by a DEAE-Sephadex column (Pharmacia Biotech, Baie d'urfe, Canada).
Deuterated internal standards (10 ng [2H2]enterolactone and 10 ng [2H2]enterodiol) were added to the samples before derivatization. Lignans were analyzed by GC-MS (2, 18) using the selected ion-monitoring mode to increase sensitivity, and temperature programming was increased from 250 to 280°C. Calibration data were obtained by measuring the ion ratios of varying amounts of natural forms of enterodiol and enterolactone to the constant amount of their respective deuterated standards. Mean recoveries of enterodiol and enterolactone from plasma samples fortified with 50, 100, and 150 ng enterodiol and enterolactone were 84.64 ± 2.58% and 85.86 ± 2.25%, respectively.
Food record and statistical analyses
Food records were analyzed for macronutrient and dietary fiber content according to the condensed Canadian Nutrient File (26). Statistical analyses were performed by using the SAS 6.10 statistical package (SAS Institute, Cary, NC) for personal computers. Urinary and plasma lignan data were log-transformed to represent a normal distribution. Student's paired t test was used to test for differences between the plasma area under the curve (AUC) for days 1 and 8. Similarly, differences between the 0–12-h and 12–24-h and the day 1 compared with the day 8 timed urinary lignan excretions were performed by Student's paired t tests. The remaining urinary and plasma lignan data were analyzed by repeated-measures analysis of variance using the SAS general linear modeling procedure. If the model was significant, least-squares means were determined for pairwise comparisons. Regression analyses were conducted for dose responses to various amounts of flaxseed and for urinary lignan excretion compared with plasma lignan concentrations. Menstrual cycle lengths and 3-d food records were analyzed by general linear modeling, and pre- and poststudy BMI values were assessed by Student's paired t test. The acceptable level of significance for all statistical tests performed was P 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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the individual urinary lignans (enterodiol, enterolactone, and Seco) are listed for each supplemental arm and the corresponding baseline sample. There were no significant differences in the baseline excretions of enterodiol, enterolactone, or Seco among the flaxseed supplementation studies. All groups excreted significantly more enterodiol during flaxseed supplementation than at baseline, and for all but the 5-g flaxseed arm, there was significantly greater enterolactone excretion than at baseline. Similarly, all groups had significantly greater Seco excretion during supplementation than at baseline, except for the bread group. There were significant differences in the urinary excretion of enterodiol between the various flaxseed supplementation arms (P 0.0005). Pairwise comparisons showed that excretion was significantly lower during the 5-g arm than during the 15-g arm; excretion during both arms was significantly lower than during the 25-g raw, muffin, and bread arms. There were no significant differences in the excretion of enterolactone or Seco among the different supplementation arms. Statistical analysis of the ratio of enterodiol to enterolactone was not possible because of an occasional zero value for enterolactone in some subjects; however, there was a trend for the ratios to be greater than those at baseline during flaxseed supplementation.
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0.001 to 0.05). Furthermore, there were significant differences among the various flaxseed supplements (P 0.0001), with the 5-g flaxseed supplement resulting in significantly less total lignan excretion than all other arms (P 0.005) and the 15-g arm resulting in significantly less than the 25-g, muffin, and bread arms. However, no differences were seen among the 25-g flaxseed arms, whether ingested raw or processed as muffin or bread. A significant dose response was observed in urinary lignan excretion with increasing amounts of raw flaxseed (r = 0.72, P 0.001; y = 1.93x).
Experiment 2
On the first day of 25-g raw flaxseed supplementation, urinary enterodiol was significantly greater in the 12–24-h than in the 0–12-h interval, whereas no significant differences were observed in the excretion of enterolactone or Seco (Table 3). On the eighth day, no significant differences in urinary lignan excretion were seen between the 0–12-h and 12–24-h intervals. However, the urinary excretion of both enterodiol and enterolactone was significantly greater in the 0–12-h interval on the eighth day than on the first day. There was also a trend for the ratios of enterodiol to enterolactone to increase by the eighth day of intake.
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On the first day of flaxseed supplementation, baseline plasma total lignan (enterodiol + enterolactone) concentrations increased significantly by 9 h, after which they did not change significantly at 12 or 24 h (Table 4). However, on the eighth day of supplementation no significant differences in plasma total lignans were seen over the 24-h period. The mean 24-h AUC for plasma lignans on the eighth day (1840.15 ± 343.02 nmolh/L) was significantly higher (P 0.01) than that on the first day (1027.15 ± 95.71 nmolh/L) of intake. Regression analysis of plasma lignans (AUC for 0–12-h and 12–24-h intervals) versus urinary lignans, at the same intervals, on the first and eighth days showed a significant correlation for the eighth day only (r = 0.54, P 0.05; y = 2.20x + 663.37).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The timed total urinary lignan excretion on the first day of flaxseed ingestion showed that there was significantly more lignan excreted in the 12–24 h after ingestion than during the first 12 h. However, this was not the case by the eighth day, when the 0–12-h urinary lignan excretion did not differ from that at 12–24 h after ingestion but was significantly higher than that observed on the first day. Evidently, it takes >24 h and possibly as long as a week for urinary lignans to increase and level off with a once-daily supplementation with 25 g flaxseed.
Plasma total lignans were found to increase significantly by 9 h and were maintained at 12 and 24 h on the first day of flaxseed ingestion. In contrast, a bioavailability study with soy isoflavones showed a significant increase in plasma concentrations at 6.5 h with a return to near baseline values by 24 h (30). However, this observed peak may not have represented the true peak because there were only 3 sampling times in the study: ie, 0, 6.5, and 24 h. Nevertheless, this apparent difference between the soy isoflavones and flaxseed lignans may have been because the isoflavones were ingested in liquid soymilk, whereas lignans were ingested via flaxseed, a solid containing a significant quantity of fiber, which may slow down the digestive process. Furthermore, the plant precursors found in flaxseed require a greater biotransformation by colonic microflora to mammalian lignans than do the isoflavone precursors.
Plasma lignan concentrations did not return to baseline by 24 h after flaxseed ingestion. Thus, future studies measuring plasma or urinary lignans at timed intervals after flaxseed consumption should sample for up to 48–72 h after intake to determine the length of time for lignan concentrations to return to baseline. On the eighth day of supplementation, no significant differences in plasma total lignans were seen over the 24-h period, indicating for the first time that plasma concentrations can be maintained with a once-daily dose of 25 g flaxseed after only 1 wk of supplementation. This suggests that future human studies and clinical trials would only require subjects to ingest flaxseed once per day, potentially improving compliance.
Plasma concentrations have been reported in only a few studies, with values ranging from 29.9 (25) to 35.8 (13) nmol/L in omnivores, from 94.5 (25) to 269.9 (13) nmol/L in vegetarians, and from 645.3 (31) to 746.3 (32) nmol/L after flaxseed consumption. However, all of these studies had some limitations; for example, the researchers reporting plasma lignans in vegetarians (13) found a 3-fold decrease in values in their second study (25). Another study reported extremely high basal plasma lignan concentrations of 143.3 nmol/L and the plasma values after flaxseed ingestion (645.3 nmol/L) were for only 1 subject (31). Because of the high individual variability seen with urinary lignan excretion, it is conceivable that this subject may not be representative of the population. In the study by Morton et al (32), there are potential concerns with the design: subjects' diets were supplemented with red clover, soy, and flaxseed in a back-to-back randomized manner, with no washout period in between. In the present study, baseline plasma lignan concentrations were quite low, as would be expected with the low-lignan, low-fiber diet provided to subjects on sample collection days. Although the highest concentration of plasma lignans observed after flaxseed intake was 3- to 4-fold over baseline, the actual concentration was lower than quantities reported in other studies, suggesting that further work is required in this area to achieve a consensus in results.
Overall, the plasma and urinary lignan results showed that enterodiol is the lignan produced in the highest concentration after flaxseed ingestion, supporting in vitro (2), animal (4), and human (15) studies published previously. Thus, the high concentration of SDG precursor in flaxseed resulted in greater enterodiol than enterolactone or Seco excretion, which was also reflected in the high ratios of enterodiol to enterolactone. Previous studies have shown that enterolactone is the mammalian lignan in highest concentration (16, 33, 34); others have shown that there are individual variations in the enterodiol-enterolactone ratio after flaxseed ingestion (17). Two of the 9 subjects in this study produced little or no enterolactone during all of the flaxseed arms, suggesting that the ability of individuals to metabolize lignans is quite variable within the same sex.
At present, there is more evidence documenting beneficial effects of enterolactone, and it is generally more effective than enterodiol (6, 7, 35–37). For example, compared with enterodiol, enterolactone had a greater ability to inhibit the binding of estradiol and testosterone to sex steroid binding protein (7), to inhibit human aromatase in vitro (36), and to bind to rat 
-fetoprotein thereby competing with estrogen for binding sites (37). These characteristics are theorized to have a controlling effect on the growth and proliferation of cells, particularly cancer cells. However, in these studies enterolactone was only moderately more effective, suggesting that large amounts of enterodiol production from flaxseed may compensate for any reduced physiologic activity. Furthermore, high circulating concentrations of enterodiol provide the substrate for the oxidation of enterodiol to enterolactone. Future studies will be necessary to determine whether varying ratios of enterodiol to enterolactone are more effective in specific physiologic situations. Also, it is important for investigators quantifying urinary or plasma lignans to report both enterodiol and enterolactone, and the ratios of enterodiol to enterolactone in an attempt to understand the factors that affect the metabolism of these compounds.
The above-described studies on sex steroids, aromatase, and -fetoprotein showed activity of lignans with concentrations of 1–100 µmol/L, magnitudes that have been reported in urine (7, 36, 37). However, the highest mean plasma total lignan concentration attained with the ingestion of 25 g flaxseed with a low-fiber, low-lignan basal diet was 97.14 ± 27.06 nmol/L, although some subjects attained 519.23 nmol/L. Thus, future investigations will be necessary to find the effective concentrations and the mechanisms of action of both enterodiol and enterolactone.
In conclusion, these experiments showed that there is a linear dose response in urinary lignan excretion with ingestion of increasing quantities of flaxseed (25 g). Enterodiol was the lignan produced in the greatest quantity; however, the ratio of enterodiol to enterolactone was quite variable among individuals, suggesting that the ability to oxidize enterodiol to enterolactone is inconsistent within the same sex. There were no significant differences observed in urinary lignan excretion after the ingestion of raw compared with processed forms of flaxseed, indicating that the amount of flaxseed ingested is likely more important than the mode of consumption. Plasma lignan concentrations did not peak until 9 h after the initial consumption of flaxseed but were maintained for 24 h after intake, suggesting that the metabolism and absorption of lignans from flaxseed takes longer than that for soy isoflavones. Plasma and urinary lignan concentrations increased significantly after 1 wk of supplementation when compared with the first day of intake. Furthermore, plasma concentrations stabilized by the eighth day of ingestion, suggesting that a once-daily dose of flaxseed is sufficient to maintain plasma concentrations. Urinary lignan excretion showed a significant linear relation with plasma lignans by the eighth day of ingestion.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by the Natural Sciences and Engineering Research Council of Canada.
3 Address reprint requests to LU Thompson, Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College Street, Toronto, Ontario, Canada M5S 3E2. E-mail: lilian.thompson{at}utoronto.ca.
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A. M. Hutchins, M. C. Martini, B. A. Olson, W. Thomas, and J. L. Slavin Flaxseed Influences Urinary Lignan Excretion in a Dose-dependent Manner in Postmenopausal Women Cancer Epidemiol. Biomarkers Prev., October 1, 2000; 9(10): 1113 - 1118. [Abstract] [Full Text]
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S. E. Rickard and L. U. Thompson Urinary Composition and Postprandial Blood Changes in H-Secoisolariciresinol Diglycoside (SDG) Metabolites in Rats Do Not Differ between Acute and Chronic SDG Treatments J. Nutr., September 1, 2000; 130(9): 2299 - 2305. [Abstract] [Full Text]
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A. Scalbert and G. Williamson Dietary Intake and Bioavailability of Polyphenols J. Nutr., August 1, 2000; 130(8): 2073S - 2085. [Abstract] [Full Text]
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