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3 Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; 4 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229; and 5 Sanitarium Development and Innovation, Cooranbong, NSW 2265, Australia
* To whom correspondence should be addressed. E-mail: kenneth.setchell{at}cchmc.org.
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ABSTRACT |
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 TOP ABSTRACT IntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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and ERß (11,12). S-Equol also is unique in that it is also a potent antagonist of dihydrotestosterone, a property that suggests a role for equol in androgen-mediated pathologies, such as prostate cancer and skin conditions (13).
Although almost every animal species studied produces equol when fed soy-containing diets (14), humans differ in that only 20–35% of the Western adult population is capable of producing S-equol when fed soy foods or isoflavone supplements (4,10,14–16). A higher frequency of equol producers, 
50–55%, is found in adults living in Asian countries where soy is consumed with regularity (17,18), and the reasons for this are most likely related to differences in the macrocomposition of the diets (14). Several recent studies suggest that those who are equol producers show more favorable responses to soy isoflavone-containing diets (14), indicating that the metabolite S-equol has greater biological potency than either daidzein or genistein, the aglycon forms of the 2 principal soy isoflavones.
The equol producer is defined from urinary or serum equol concentrations and determining this requires the consumption of the soy foods or isoflavone supplements containing daidzin or daidzein (4,15,16). Due to the fact that S-equol formation largely occurs in the distal intestine and colon (4), its formation is time dependent and, therefore, a single serving of soy or isoflavones may be insufficient to accurately define an equol producer. Because different arbitrary cutoffs for urinary and serum equol concentrations have been used to differentiate equol producers from nonproducers (14), the amount of isoflavone consumed will greatly influence this assignment. Variations in analytical measurement of S-equol (14) further compound the problem of using a specific threshold equol concentration that can be applied universally. There is thus a need to adopt a universal approach to defining equol-producer status so that accurate classification can facilitate clinical studies of soy foods where differences in clinical responses to isoflavones seem apparent (14). We propose an approach to resolve this problem, by expressing equol production on the basis of the log10-transformed ratio of S-equol concentration to its precursor daidzein after a soy isoflavone challenge, and have validated this in a cohort of healthy adults.
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Subjects and Methods |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Analytical methodology. S-Equol, daidzein, and genistein concentrations were measured in serum by GC-MS and in urine by HPLC with electrospray ionization (ESI)-MS. These methods have been described in detail elsewhere (19–21) and are outlined below.
Measurement of S-equol and isoflavone concentrations in serum by GC-MS. The concentration of S-equol, daidzein, and genistein in serum (0.5 mL) was measured by stable-isotope dilution GC-MS with selected ion monitoring after addition of [2-13C]equol, [2-13C]daidzein, and [2-13C]genistein, the stable-labeled analogs used as internal standards for quantification. Isoflavones were extracted on a solid-phase, octadecylsilane-bonded silica cartridge; hydrolyzed enzymatically with a mixed ß-glucuronidase-sulfatase preparation (Helix pomatia; Sigma Chemicals); and, after reextraction and purification, the tert-butyldimethylsilyl ether derivatives were prepared. The derivatized samples were analyzed by selected ion monitoring GC-MS as exactly described previously (19–21).
Measurement of S-equol and isoflavones in urine by ESI-MS. Urine (50 µL) samples were diluted with 10 mL of 0.05 mol/L sodium acetate buffer (pH 4.5) and hydrolyzed overnight with 0.1 mL of a mixed ß-glucuronidase-sulfatase preparation (H. pomatia; Sigma Chemicals). S-Equol and the soy isoflavones daidzein and genistein were then extracted by a solid-phase, octadecylsilane-bonded silica cartridge and recovered by elution with methanol (3 mL), which was evaporated under a stream of nitrogen gas. The urine extract was dissolved in 100 µL of the HPLC mobile phase and a 20-µL sample was injected on column. ESI-MS was performed on a Micromass Quattro liquid chromatography-MS. The HPLC effluent to the ESI probe was split 10:1. The desolvation temperature was 300°C and the source temperature was 100°C. The sampling cone was held at 50 volts and the extractor at 2 volts. Data were collected in the negative ion mode, and the [M-H]– ions monitored were mass:charge ratio (m/z) 241 (S-equol) and m/z 242 ([2-13C]S-equol), and m/z 255 (daidzein) and m/z 256 ([2-13C]daidzein). The identity of S-equol, daidzein, and genistein was based on the retention time of the eluting peak in the mass chromatogram compared with the mass chromatograms obtained for the added stable-labeled analogs. Quantification of S-equol, daidzein, and genistein was achieved by calculating the area ratio of the isoflavone to its stable-labeled analog and interpolation of this value against calibration curves constructed of known concentrations of pure standards.
Data analysis. Serum and urinary S-equol and daidzein concentrations were expressed as nanomoles/liter and micrograms/liter. These data were grouped according to dietary habit of the subject (vegetarian or nonvegetarian) and in ascending order of concentration, and when analyzed were expressed as mean ± SEM. The ratio of S-equol to daidzein was calculated, transformed, and expressed as log10. Subjects with a log10 urinary S-equol:daidzein concentration ratio above –1.75 on this scale were classified as equol producers. To measure the association between S-equol-producer status and dietary habits or gender, the odds ratio, its 95% CI, and a significance level were calculated under a logistic model (22).When this study was planned, we had no information on the order of magnitude of the frequency of S-equol producers we would find and could not specify any difference worth detecting. Accordingly, study power could only be estimated retrospectively.
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Results |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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Serum S-equol and daidzein concentrations ranged from 10–139 nmol/L (2.5–33.6 µg/L) and 16–1401 nmol/L (4.0–356 µg/L), respectively, whereas in urine the corresponding concentrations ranged from 16–12,574 nmol/L (4–3043 µg/L) and 539–26,834 nmol/L (137–6816 µg/L), respectively. The absolute serum and urinary S-equol concentrations in the individual subjects after consuming 500 mL of a soy milk drink (250 mL twice daily) for 3 consecutive days are shown (Fig. 1, upper panel). These graphs are expressed in rank order of serum S-equol concentration within the vegetarian and nonvegetarian groups, respectively. A wide variation in serum S-equol concentrations was observed, but within these defined groups the plots showed 2 distinct clusters: a group of subjects that had a very low serum S-equol concentration and a group with a progressively increasing concentration. A distinct separation between these 2 groups was noted at a serum S-equol concentration of 20 nmol/L (5 µg/L), and, using this threshold to differentiate equol producers from nonequol producers, the proportion of equol producers within the entire cohort was 46% (19 of 41). However, only 4 of 12 (33.3%) of the nonvegetarian group were equol producers compared with 15 of 29 (51.7%) of the vegetarians.
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The log10-transformed ratios of S-equol to daidzein concentrations for serum and urine are compared (Fig. 3). Using the log10-transformed data, a clear distinction was evident between equol producers and nonequol producers only for the urinary values. A cut-off log at –1.75 (absolute ratio = 0.018) for urine yielded a clear demarcation of 2 distinct groups, and, based on this threshold value, the overall proportion of equol producers within the entire cohort was 48.8% (20 of 41). Based on the log10-transformed data, the proportion of equol producers was 59% (17 of 29) in the vegetarian group and 25% (3 of 12) in the nonvegetarian group. Vegetarians were 4.25 times as likely to be S-equol producers (95% CI: 0.95–19; P = 0.059) as nonvegetarians. The log-transformed data for serum yielded a relatively linear curve for both the vegetarians and nonvegetarians, with no clear demarcation separating equol producers from nonequol producers, and this ratio was not useful in assigning equol-producer status.
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In considering gender differences within the total cohort, 15 of 23 (65%) of the males and 5 of 18 (28%) of the females produced S-equol. Men were 3.11 times more likely to be S-equol producers (95% CI: 0.86–11; P = 0.084) than women.
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Discussion |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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The assignment of equol-producer status has been rather arbitrarily determined by a number of different criteria. Threshold concentrations of S-equol in urine or serum have been chosen based upon the distinct clustering of subjects into low or negligible levels and those with significantly high levels (4,15,16). Inevitably there will always be a few subjects that may fall into an intermediary position, and whether this can be explained by recent use of antibiotics or other factors that transiently reduce the activity of the S-equol-producing bacterial enzymes remains a possibility. Alternatively, some subjects may have the ability to convert daidzein to dihydrodaidzein but not to proceed to S-equol; they are considered partial converters.
The threshold values used to define an equol producer have differed among studies, which may be due to analytical differences in measuring S-equol. There is consequently a need for a universal and consistent approach to defining equol-producing status. Using an absolute S-equol concentration threshold for either urine or serum is problematic because the concentration of S-equol in serum or urine is influenced by the mass of daidzein and its conjugates consumed, and by the pharmacokinetic behavior and bioavailability of isoflavones. Although the former can be controlled by a standardized challenge of soy isoflavones, as was advocated by Lampe et al. (15) and executed in this study (total daidzein aglycon equivalents consumed was 14 mg/d for 3 d), the latter is highly variable among individuals (17,19–21,28–31). Although dietary records were not obtained during the soy challenge, it was known from interviews during enrollment that a significant number of the participants in the study were long-term regular users of soy. Challenging these individuals with soy milk for 3 d consequently provides daidzein in addition to that derived from the usual dietary isoflavone intake, and this will consequently influence the absolute serum and urinary S-equol concentration measured, as will the timing of blood collection. Furthermore, an individual can only be an equol producer if soy isoflavones are ingested, and, therefore, in clinical studies compliance to isoflavone intake is crucial in defining equol status when adopting threshold values of S-equol concentrations.
In searching for a sounder basis for classifying equol-producing status and to overcome the above limitations in using absolute S-equol concentration, we examined several different treatments of the data generated from a cohort of healthy free-living subjects that included a high proportion of vegetarians. By first sorting the serum and urinary concentration data for the cohort into numerical order and plotting these data (Fig. 1), the presence of a step or inflection occurs at a dividing line between producers and nonproducers, with the threshold concentrations being, respectively, 20 nmol/L (5 µg/L) for serum and 82 nmol/L (20 µg/L) for urine. This has been a consistent observation in previous studies (4,15,16). Urine and serum S-equol levels were positively correlated (r = 0.69, n = 41, P < 0.001). However, the correlation is not sufficiently high (Fig. 2) to give a good predictive regression relation; only 48% of the variance is explained by the correlation (r2 = 0.48). We therefore expect that there will not be complete agreement between equol status classification based on absolute serum and urine concentrations as was evident from this study (Table 1). Where a subject is an obvious equol producer, the S-equol concentration in both urine and serum will be a long way from the threshold between equol producers and nonequol producers and quite large experimental variance will not affect the classification. It is in the region close to the threshold value that experimental variation will be significant and defining equol-producing status may be more difficult.
S-Equol is the specific metabolite and end product of daidzin or daidzein biotransformation by intestinal bacteria. Therefore, expressing this product-precursor relation as the ratio of S-equol to daidzein compensates for variability in isoflavone intake or systematic errors in methodologies for isoflavone measurement, and provides a more reliable indicator of the extent of conversion of daidzein into S-equol. Log-transforming these data permits a better definition of this breakpoint, and this is particularly the case for the urinary S-equol:daidzein ratio (Fig. 3). By contrast, plots of the log10-transformed S-equol:daidzein ratio for serum concentrations showed no clear demarcation, and this approach did not differentiate equol-producing status of an individual. The most likely reason for this is because the pharmacokinetics of daidzein and S-equol are markedly different (11,14), particularly with regard to renal clearance. Daidzein is more rapidly eliminated from the peripheral circulation than S-equol, and the dynamic changes in serum concentrations of the precursor and product will be amplified when the concentrations are expressed as a ratio. However, using urine measurements, dynamic changes in serum isoflavone concentrations are minimized, and it is this measurement that yields a more reliable classification of an equol producer. We have therefore designated a urinary log10 S-equol:daidzein ratio of greater than –1.75 as an indicator of an equol producer, and the advantage of this approach is that it is independent of the amount of daidzein ingested and of any the analytical differences among laboratories measuring isoflavones.
A striking finding from this study was the high frequency of equol producers observed within vegetarians, who were 4.25 times more likely to be S-equol producers as their nonvegetarian counterparts. Such association was of borderline significance, but it is likely that small sample size conditioned low statistical efficiency in the present study, as suggested by wide CIs. We retrospectively calculated that our study on 41 subjects attained a power of 0.36 in detecting a difference of the same magnitude as that observed between vegetarian habits, assuming a 2-sided risk of type I error of 0.05. The frequency of equol producers has been found to differ among populations (14). When equol was first identified more than 2 decades ago in human urine (2) and shown to be an intestinal bacterial metabolite derived from soy isoflavones (3,4), it was originally suggested that two-thirds of adults produced equol when consuming soy food (4). This frequency may have been overestimated due to the small sample size of only 6 adults studied or it has declined over the last 2 decades. More recent studies of Western populations have revealed a relatively lower frequency of equol producers, with the consensus of data indicating only about one-third of the adult population is capable of producing S-equol when fed soy foods (16,20,32,33). Studies from Japan have shown 55–60% of Japanese adults typically produce S-equol when consuming soy foods (17,18,34,35), and this striking difference in frequency is presumed to be accounted for by differences in the composition of the diet. Interestingly, the frequency of equol producers in young Japanese adults is much lower than in older Japanese adults and similar to that of Westerners (Professor Shaw Watanabe, Tokyo University of Agriculture, Japan personal communication). This difference has been claimed to be most likely due to the change in the Japanese diet, more evident in the younger Japanese. To our knowledge, there have been no previous reports of the frequency of equol production in vegetarians, but our finding that 59% of vegetarians are equol producers is similar to the frequency seen in Japanese adults (17,18,34,35) and would strongly implicate that differences in the composition of the diet may be crucial in facilitating intestinal bacterial metabolism of soy isoflavones. Identifying factors that govern equol production in adults has thus far proved elusive (10,14). It was previously reported that consuming a diet high in total carbohydrate and low in saturated fat is associated with equol production (16,32). This is supported by the observation that nonstarch polysaccharides enhance the conversion of daidzein to S-equol in an in vitro colonic model of cultured human fecal microflora by stimulating intraluminal fermentation (36). It is probable that vegetarian and Japanese diets provide more prebiotic components than a mixed omnivorous diet and this may be a key factor in the greater propensity to produce S-equol in these populations. However, several short-term dietary intervention studies of prebiotics and probiotics have failed to stimulate equol production in adults (37–40). Diet records were not obtained in this study, and, therefore, whether specific components of the diet were associated with equol production could not be determined. This was outside the scope of this work. History of soy food use was not recorded, but it is likely that many of the vegetarians were probably consuming soy foods as a protein source. It is doubtful that any prior soy food consumption could influence equol production based on the findings from a recent study showing no link between long-term soy food intake and ability to induce equol production in nonequol producers (41).
Finally, although there has been no previous association found between equol production and gender (42), within the limitations of the small sample size of this study, a male appeared to be 3.11 times more likely to be equol producer than a female.
In summary, we have described a more robust method of defining an equol producer based upon the log10-transformed urinary S-equol:daidzein ratio after a standard 3-d challenge of soy foods containing isoflavones. This approach has advantages over relying on absolute serum or urinary S-equol concentrations because it exploits the precursor-product relation between daidzein and equol, thereby minimizing the errors in using specific threshold S-equol concentrations that are subject to large variance due to differences in dietary isoflavone intake, pharmacokinetics, and methodologies for measuring S-equol. In this study of 41 healthy adults, 59% of the vegetarians were identified as equol producers compared with only 25% of the nonvegetarians, suggesting differences in diet play a key role in determining an individual's ability to make S-equol from ingested soy isoflavones.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 In memory of Dr. Sidney Cole, who passed away April 2, 2006.
6 Abbreviations used: equol, 7-hydroxy-3-(4'-hydroxyphenyl)-chroman; ER, estrogen receptor; m/z, mass:charge ratio.
Manuscript received 28 February 2006. Initial review completed 21 March 2006. Revision accepted 25 May 2006.
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LITERATURE CITED |
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TOPABSTRACTIntroductionSubjects and MethodsResultsDiscussionLITERATURE CITED |
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A. A Thorp, P. R. Howe, T. A Mori, A. M Coates, J. D Buckley, J. Hodgson, J. Mansour, and B. J Meyer Soy food consumption does not lower LDL cholesterol in either equol or nonequol producers Am. J. Clinical Nutrition, August 1, 2008; 88(2): 298 - 304. [Abstract] [Full Text] [PDF]
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C. Atkinson, K. M Newton, E. J A. Bowles, M. Yong, and J. W Lampe Demographic, anthropometric, and lifestyle factors and dietary intakes in relation to daidzein-metabolizing phenotypes among premenopausal women in the United States Am. J. Clinical Nutrition, March 1, 2008; 87(3): 679 - 687. [Abstract] [Full Text] [PDF]
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E. Brink, V. Coxam, S. Robins, K. Wahala, A. Cassidy, F. Branca, and on behalf of the PHYTOS Investigators Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study Am. J. Clinical Nutrition, March 1, 2008; 87(3): 761 - 770. [Abstract] [Full Text] [PDF]
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 B. J. Fuhrman, B. E. Teter, M. Barba, C. Byrne, A. Cavalleri, B. J. Grant, P. J. Horvath, D. Morelli, E. Venturelli, and P. C. Muti Equol Status Modifies the Association of Soy Intake and Mammographic Density in a Sample of Postmenopausal Women Cancer Epidemiol. Biomarkers Prev., January 1, 2008; 17(1): 33 - 42. [Abstract] [Full Text] [PDF]
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S. Bolca, S. Possemiers, A. Herregat, I. Huybrechts, A. Heyerick, S. De Vriese, M. Verbruggen, H. Depypere, D. De Keukeleire, M. Bracke, et al. Microbial and Dietary Factors Are Associated with the Equol Producer Phenotype in Healthy Postmenopausal Women J. Nutr., October 1, 2007; 137(10): 2242 - 2246. [Abstract] [Full Text] [PDF]
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C. Clerici, K. D. R. Setchell, P. M. Battezzati, M. Pirro, V. Giuliano, S. Asciutti, D. Castellani, E. Nardi, G. Sabatino, S. Orlandi, et al. Pasta Naturally Enriched with Isoflavone Aglycons from Soy Germ Reduces Serum Lipids and Improves Markers of Cardiovascular Risk J. Nutr., October 1, 2007; 137(10): 2270 - 2278. [Abstract] [Full Text] [PDF]
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