Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men

Busby, Marjorie G.; Jeffcoat, A; Bloedon, LeAnne T.; Koch, Matthew; Black, Tracy; Dix, Kelly J.; Heizer, William D.; Thomas, Brian F.; Hill, Judith; Crowell, James A.; Zeisel, Steven H.

doi:10.1093/ajcn/75.1.126

Cited by 242 publications

(186 citation statements)

References 37 publications

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“…Further, the total excreted by individuals consuming B was less than that excreted with the consumption of F, as noted by others (Busby et al, 2002). Of particular interest was whether a minority of individuals who excreted substantial amounts of equol, a metabolite of daidzein and hence of formononetin, showed a different LDL-C response than nonequol excretors, despite formononetin itself having no effect.…”

Section: Resultsmentioning

confidence: 78%

A biochanin-enriched isoflavone from red clover lowers LDL cholesterol in men

et al. 2004

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Objective: To determine whether the two major isoflavones in red clover differ in their effect on low-density lipoprotein cholesterol (LDL-C). Design: A randomised, placebo-controlled, double-blind trial; two parallel groups taking one of the two isoflavones within which treatment and placebo were administered in a crossover design. Setting: Free-living volunteers. Subjects: A total of 46 middle-aged men and 34 postmenopausal women. Intervention: Two mixtures of red clover isoflavones enriched in either biochanin (n ¼ 40) or formononetin (n ¼ 40) were compared. Placebo and active treatment (40 mg/day) were administered for 6 weeks each in a crossover design within the two parallel groups. Main outcome measures: Plasma lipids were measured twice at the end of each period. Results: Baseline LDL-C concentrations did not differ significantly between men (n ¼ 46) and women (n ¼ 34), nor between those randomised to biochanin or formononetin. Interaction between time and treatments, biochanin, formononetin and corresponding placebos (two-way ANOVA) on LDL-C showed a significant effect of biochanin treatment alone. The biochanin effect was confined to men; median LDL-C was 3.61 (3.05-4.14) mmol/l with biochanin and 3.99 (3.16-4.29) mmol/l with the corresponding placebo (RM ANOVA with Dunnett's adjustment Po0.05). The difference between placebo and biochanin effects on LDL-C was 9.5%. No other lipid was affected and women failed to respond significantly to treatment. Conclusion: Isolated isoflavones from red clover enriched in biochanin (genistein precursor) but not in formononetin (daidzein precursor), lowered LDL-C in men. This may partly explain the previous failure to demonstrate cholesterol-lowering effects with mixed isoflavones studied predominantly in women.

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Section: Resultsmentioning

confidence: 78%

A biochanin-enriched isoflavone from red clover lowers LDL cholesterol in men

et al. 2004

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“…A significant, but not insurmountable, issue is that the oral bioavailabilities of genistein and genistin are modest, with in vivo plasma concentrations of genistein Ϸ0.1-8 M at a dose of 16 mg͞kg of body weight (12,13,57). Liu and Hu's (58) study using Caco-2 cells and perfused rat intestinal models shows that genistein is efficiently absorbed into the intestine, but extensive first-pass metabolism results in formation of 7-OH-glucuronic acid as the major metabolite.…”

Section: Discussionmentioning

confidence: 99%

“…The half-life of genistein in plasma was determined to be 3.2 h for men and 3.8 h for women. These appealing pharmacokinetics suggest that a slow-release formula could be useful (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6,7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11)(12)(13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.…”

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confidence: 99%

“…The benefits of using such a nutraceutical are many; it is possible that some patients may benefit simply from increasing their intake of soy products or adding a soy-based supplement to their diets, but further research is needed. The wealth of toxicity information on genistein suggests that it is safe for human consumption, even at the high concentrations used for cancer trials (11)(12)(13). This compound, however, is known to target multiple pathways (7,50) and, as such, must be used cautiously.…”

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confidence: 99%

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Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

Green

Foss

Kelly

2005

Proc. Natl. Acad. Sci. U.S.A.

109

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The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K d1 ‫؍‬ 40 nM, Kd2 ‫؍‬ 1.4 M). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements.amyloidogenesis inhibitor ͉ kinetic stabilization F or many years nutritionists and dieticians have noted the health benefits of a soy-based diet, citing the much lower incidence of cancer, including breast cancer, in Asian countries (1-4). The isoflavone genistein (compound 1 in Fig. 1), found in various soy foods at concentrations of 1.9-229 g͞g, is the component of soy implicated in cancer chemoprevention (5). An additional 71-968 g͞g of genistein is present as its O-glucoside conjugate, genistin (2), which is rapidly deglycosylated by intestinal bacteria in vivo. Genistein is being evaluated in preliminary trials for treatment of breast, prostate, and uterine cancers (6, 7), as well as for osteoporosis (8), cardiovascular disease (9), and treatment of menopausal symptoms (10). Toxicity studies reveal that this isoflavone does not appear to cause adverse health effects, even at the relatively high concentrations used (11-13). The isoflavone daidzein (3), lacking the hydroxyl group at the 5 position of genistein, is also found in soy foods, but no chemoprotective effects have been attributed to it.Transthyretin (TTR) is a tetrameric protein composed of identical 127-aa ␤-sheet sandwich subunits (14, 15). TTR functions to transport holo-retinol-binding protein and thyroxine (T4) in the blood and cerebrospinal fluid (16,17). Under denaturing con...

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