Metabolism of secoisolariciresinol to diglycoside the dietary precursor to the intestinally derived lignin enterolactone in humans
Metabolism of secoisolariciresinol to diglycoside the dietary precursor to the intestinally derived lignin enterolactone in humans
Year: 2014
Authors: Setchell, K.D.R. Brown, N.M.Zimmer to Nechemias, L. Wolfe, B. Jha, P. Heubib, J.E.
Publication Name: Food Func.
Publication Details: Volume 5; Number 3; pages 491-501. doi: 10.039/c3fo60402k
Abstract:
Secoisolariciresinol to diglycoside (SDG), a natural dietary lignan of flaxseeds now available in dietary supplements, is converted by intestinal bacteria to the mammalian lignans enterodiol and enterolactone. High levels of these lignans in blood and urine are associated with reduced risk of many chronic diseases. Our objective was to determine the bioavailability and pharmacokinetics of SDG in purified flaxseed extracts under dose to ranging and steady to state conditions, and to examine whether differences in secoisolariciresinol to diglycoside purity influence bioavailability. Pharmacokinetic studies were performed on healthy postmenopausal women after oral intake of 25, 50, 75, 86 and 172 mg of secoisolariciresinol to diglycoside. Extracts differing in secoisolariciresinol to diglycoside purity were compared, and steady to state lignan concentrations measured after daily intake for one week. Blood and urine samples were collected at timed intervals and secoisolariciresinol, enterodiol and enterolactone concentrations measured by mass spectrometry. Secoisolariciresinol to diglycoside was efficiently hydrolyzed and converted to secoisolariciresinol. Serum concentrations increased rapidly after oral intake, peaking after 5 to 7 h and disappearing with a plasma elimination half to life of 4.8 h. Maximum serum concentrations of the biologically active metabolites, enterodiol and enterolactone were attained after 12 to 24 h and 24 to 36 h, respectively, and the half to lives were 9.4 h and 13.2 h. Linear dose to responses were observed and secoisolariciresinol bioavailability correlated with cumulative lignan excretion. There were no significant differences in the pharmacokinetics of extracts differing in purity, and steady state serum lignan concentrations were obtained after one to week of daily dosing. In conclusion, this study defines the pharmacokinetics of secoisolariciresinol to diglycoside and shows it is first hydrolyzed and then metabolized in a time to dependent sequence to secoisolariciresinol, enterodiol and ultimately enterolactone, and these metabolites are efficiently absorbed. (Authors abstract)
SDG is metabolized by intestinal bacteria in a series of steps that involve hydrolysis, dehydroxylation and demethylation to the intermediate enterodiol, and that this unique mammalian lignan is oxidized to enterolactone. Numerous studies have since shown an association between high lignan concentrations in urine or blood, and low rates of many chronic diseases, including cancers that are common to the Western world. Difficulties in elucidating the role of lignans in disease prevention are that most of these studies are epidemiological or have indirectly assessed lignan intake from diet recall or urinary and blood concentrations. Most have examined the role of flaxseed, a plant to based food that not only contains lignans but is also a rich source of n3 fatty acids and fiber, so that discerning the contribution of lignans in any proposed health effect can be difficult. The difficulty in interpreting nutritional and clinical studies of flaxseed is it contains many nutrients that could contribute to the reported biological effects. Studies of purified SDG extracts, which are now commercially available as supplements, provide one means of overcoming this limitation. This is the first multi dosing study of the serum and urinary pharmacokinetics and metabolic fate of SDG in healthy postmenopausal women, focussing on dose–response effects and effects of using SDG extracts of flaxseed differing in purity.
These studies were performed using the classical single to bolus oral administration study design of serum appearance/disappearance kinetics of this lignan, and the dynamics of its hydrolysis to SECO and its rate of conversion to the specific metabolites enterodiol and enterolactone was also determined. The delay in attaining peak serum enterodiol and enterolactone concentrations, 19.2 to 2.6 h and 26.7 to 2.5 h, respectively is consistent with the timing of the bacterial conversion of SECO, which takes place by the action of bacteria colonizing the distal intestine and colon. The urinary excretion of SECO, enterodiol and enterolactone paralleled the serum kinetics with most of the SECO being excreted within the first 24 h of ingestion of SDG, consistent with the rapid 4.2 h terminal elimination half to life of SECO from serum . Enterodiol and enterolactone were mostly eliminated in urine after 2 and 5 days respectively.
Based on the pharmacokinetics displayed in these classical single to bolus oral administration studies it can be calculated that steady to state concentrations of lignans would be attained after 5 to 7 days of daily administration. This was confirmed in the data from Study 2 where the different doses of SDG (25, 50, 75 mg) were maintained for 8 to consecutive days and serum
measurements of SECO enterodiol and enterolactone made on days 7 and 8. Although there was some inter to individual variation among the subjects within the dosing groups, there
was no significant difference in the serum concentrations for any of the lignans between the two days and this was the case for all doses of SDG taken. These findings indicate steady to state
had been attained after one week of intake of SDG, a conclusion similarly made after feeding ground flaxseed for 8 consecutive days. Based on pharmacokinetic data a dietary intake of 50 mg purified SDG would appear to provide similar urinary enterolactone excretion rates to those observed after feeding about 5 to 10 g flaxseed. Circulating enterolactone concentrations observed in this study for intakes of 50 mg of SDG are similar to those associated with reduced risk for breast cancer and cardiovascular disease. In conclusion, these studies show the time to course for the dynamics of lignan formation from SDG and provide fundamental data on the pharmacokinetics of lignans in healthy adults. (Editors comments)
