Fecal Lignan and Isoflavonoid Excretion in Premenopausal Women Consuming Flaxseed Powder1
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Vol. 4. .153-358. June 1995 Cancer Epidemiology, Biomarkers & Prevention 353 Fecal Lignan and Isoflavonoid Excretion in Premenopausal Women Consuming Flaxseed Powder1 Mindy S. Kurzer,2 Johanna W. Lampe, have shown important biological effects that contribute to their Margaret C. Martini, and Herman Adlercreutz potential as chemopreventive agents. Department of Food Science and Nutrition, University of Minnesota, St. Paul, Lignans have been shown to inhibit skin, breast, colon, Minnesota 55108 [M. S. K., J. W. L.. M. C. M.], and Department of Clinical and lung cancer cell growth (1, 2). Consumption of flaxsecd, a Chemistry, University of Helsinki, Meilahti Hospital, Helsinki, Finland [H. A.] concentrated source of lignans (3), has been shown to inhibit mammary tumor promotion (4) and development of early mark- ens of risk of mammary cancinogenesis (5). Proposed mecha- Abstract nisms by which lignans may inhibit carcinogenesis include Lignans and isoflavonoids are diphenolic compounds antivinal (6) and antioxidant (7) activities. In addition, the found in plant foods, particularly whole grains and similarities in structure among lignans, estradiol, and the syn- legumes. They have been shown to have anticarcinogenic thetic antiestrogen tamoxifen (Fig. 1) suggest that lignans may properties in animal and cell studies, and have been also exert their anticarcinogenic effects in part as a result of associated with reduced cancer risk in epidemiobogical antiestrogenic effects. In fact, lignans have been shown to studies. In order to perform further epidemiobogical and inhibit placental (8) and adipocyte (9) estrogen synthesis; to metabolic studies on these compounds, it is necessary to inhibit cstnadiol-induced proliferation of MCF-7 human breast be able to monitor concentrations in biological samples. carcinoma cells (10); and to stimulate sex hormone-binding In this study, we examined the effects of consumption of globulin synthesis, with subsequent decrease in free estradiol flaxseed, a concentrated source of lignans, on fecal lignan (11). Flaxseed consumption has been shown to alter the men- excretion and evaluated the effect of high lignan strual cycle in premenopausal women in a potentially cancer- consumption on fecal excretion of isoflavonoids. Thirteen preventive direction (12). women were studied for two diet periods of three Isoflavonoids have been reported to inhibit cancer cell menstrual cycles each in a cross-over design. During the growth and development in lung (13), stomach (14), lcukocyte control period, they consumed their usual diets; during (15, 16), and breast (17, 18) carcinoma cells. Proposed mech- the treatment period they consumed their usual diets anisms include in vitro inhibition of bacterial growth (19, 20), supplemented with 10 g/day ground flaxseed. Feces were as well as in vitro inhibition of placental (8) and adipocyte (9, collected on days 7-1 1 of the last menstrual cycle in each 21) estrogen synthesis. Isoflavonoids have been shown in viva diet period. Five-day fecal composites were analyzed for to have antispasmodic effects in guinea pig ileum (22), antihy- lignans and isoflavonoids by isotope dilution gas pertensive effects in rats (23), and hypolipemic effects in chromatography-mass spectrometry. Fecal excretion of rabbits (24). the lignans enterodiol, enterolactone, and matairesinob Despite great interest in the physiological effects of big- increased significantly with flax consumption, from nans and isoflavonoids, little is known about human metabo- 80.0 ± 80.0 (SD) to 2560 ± 3100; 640 ± 480 to 10,300 lism, absorption, and actual exposure. Mammalian lignans are ± 7580; and 7.33 ± 10.0 to 11.9 ± 8.06 nmol/day, synthesized by cobonic microflona from plant precursors found respectively. There were no differences in fecal excretion naturally in many plant foods, particularly oilseeds and grains of the isoflavonoids, daidzein, equol, genistein, and (3, 25). Flaxsecd is an oilseed known to be a concentrated O-demethylangolensin. source of lignan precursors (3). Consumption of flaxsced ne- suits in large increases in urinary excretion of entenodiol and Introduction enterolactone, the primary mammalian lignans derived from bacterial metabolism of their plant precursors, secoisolanicires- Numerous components of plant foods have been associated mob and matainesinol (26). Entenolactone also originates from with decreased cancer risk. Among these are lignans and isofla- bacterial oxidation of enterodiol. vones, two groups of diphenolic compounds most concentrated Genistein and daidzein arc the two primary dietary isofla- in whole grains and legumes (Fig. 1). Epidemiobogical studies vones found in high concentrations in legumes. Genistein and have shown decreased cancer risk with increased excretion of daidzein can also originate from bacterial metabolism of their these compounds, while animal, cellular, and metabolic studies respective glycosides, as well as metabolism of two other isoflavones, biochanin A and formononetin. Daidzein can be metabolized further by intestinal microfbora to the isofla- Received 9/2/94: revised 12/21/94: accepted 12/21/94. vonoids 0-Dma3 and equol (25, 27). I This research was supported by NCI Grant N01-CN-05288-O1 and Minnesota Human studies of the physiological effects of dietary big- Agricultural Experiment Station Project 18-34. J. W. L. was supported by nans and isoflavones require accurate measurement of these National (‘ancer Institute Grant 5T32-CA-09607. Development of the method was supported by NIH Grant I ROI CA 56289-01. 2 To whom requests for reprints should be addressed, at Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN 55108. 3 The abbreviation used is: 0-Dma, 0-demethylangolensin. Downloaded from cebp.aacrjournals.org on September 27, 2021. © 1995 American Association for Cancer Research. 354 Fecal Lignan and Isoflavonoid Excretion HO lignan consumption on isoflavonoid excretion. Entenobactone, enterodiol, matairesinob, genistein, daidzcin, equol, and 0-Dma were measured in 5-day fecab composites collected from 13 cIciOL healthy young women after 3 menstrual cycles on their habitual diets and after 3 menstrual cycles in which their usual diets Daidzein Genistein were supplemented with 10 g/day ground flaxseed. In addition to determining the fecal concentrations of individual com- OcHCHaNtcH3)2 pounds, correlations were performed to evaluate the associa- tions among individual isoflavonoids and bignans. Materials and Methods Subjects. This study was a substudy of a larger study of the effects of flaxseed consumption on lignan excretion and the menstrual cycle (12, 26). For the large study, 18 healthy pre- H3 “‘ H menopausal women were studied. Health status of the subjects Tamoxifen was verified by health history, routine blood and urine screen- ing, and physical exam. Selected subjects were sedentary, om- nivorous nonsmokers, who typically consumed diets containing HO, <10 g dietary fiber/day. All subjects reported regular menstrual cycles and stable body weights for at least I year, had not used oral contraceptives for at beast 3 months, had not been on antibiotics for the previous month, and were not on any regular medication. For this study, 13 women selected from the original 18 Enterodiol Enterolactone subjects were willing to collect feces. The prestudy averages for age, height, weight, and body mass index of these 13 subjects Fig. 1. Structures of selected isoflavones (daidzein and genistein), estrogens were 27.8 ± 4.3 year, 1.64 ± 0.05 m, 60.6 ± 8.5 kg, and (tamoxifen and estradiol). and lignans (enterodiol and enterolactone). 22.5 ± 2.2 kg/m2, respectively (Table 1). Study Design and Diet. The protocol for this study was ap- proved by the University of Minnesota Institutional Review compounds in biological fluids, yet few studies have reported Board Human Subjects Committee. The study design and diet such data. Adlercreutz et a!. (1 1, 28-30) have reported urinary have been described in detail previously (26). The study was and serum (31, 32) concentrations of entenolactone, enterodiol, performed as a balanced, randomized, cross-oven design fob- and matairesinol, as well as genistein, daidzein, equol, and bowing the individual menstrual cycles of each subject. After an 0-Dma, in cross-sections of omnivorous and vegetarian sub- acclimation period of I menstrual cycle, each subject was jects in Boston, Helsinki, and Japan. Xu ci a!. (33) have studied for 6 menstrual cycles. For the first 3 menstrual cycles, published the only human study of isoflavone bioavaibability, one-half of the subjects were on their habitual diets (control reporting plasma, urinary, and fecal daidzein and genistein diet) and one-half were on their habitual diets supplemented concentrations in adult women. Although they report fecal with 10 g/day ground flaxseed (Enneco Corp., Manitowoc, WI; isoflavone concentrations after consumption of isoflavone-nich treatment). For the last 3 menstrual cycles, the groups switched soymilk, Xu et a!. (33) include no baseline data. Recently, diets. Adlercreutz et a!. (34) described a method for simultaneous Subjects were free living during the entire study. Although measurement of fecal lignans and isoflavonoids, reporting pre- they consumed their habitual diets, they were given instructions liminary data in omnivorous and vegetarian women. There have to minimize isoflavone and lignan consumption by avoiding all been no further reports of fecal lignan concentrations. legumes (due to