Unanticipated differences in the rat plasma metabolome of genistein and daidzein

Genistein (GEN) and daidzein (DAI) are soy isoflavones known to bind to estrogen receptors. Overall health effects of GEN and DAI in humans exhibit a dual nature, presenting both health benefits and concerns related to their interaction with the estrogen receptor. The metabolomes of these isoflavones were determined in 28-day oral studies in male and female Wistar rats to elucidate (1) metabolites changes, (2) compare their metabolomes with other compounds and (3) identify toxicological modes of action (MoA). Dose levels for GEN were 1000 and 300 mg/kg bw by gavage and 1000 and 300 ppm (via diet). DAI gavage dose levels were 1000 and 100 mg/kg bw. Results were evaluated using the MetaMap^®Tox data base. Both compounds demonstrated metabolome profiles which were associated with estrogenic profiles and compounds, predominantly in females. However, the metabolomes were compound specific with relatively few common metabolite changes. There were no relevant matches between any GEN and any DAI treatment group indicating that both compounds are substantially different from metabolome perspective. Ranking of the metabolome patters for GEN and DAI with ≥ 1000 compounds in the MetaMap^®Tox database revealed correlations with estrogenic and other hormonally active compounds. GEN-treated females correlated best with Cabergoline, a dopamine D2 receptor agonist, DAI females with tamoxifen and diethylstilbestrol, suggesting that even their estrogenic activity may be different. Beyond estrogenic effects, the high dose (HD) DAI metabolome indicated altered fatty acid metabolism associated with PPAR-alpha activation. For GEN, there was an indication of ethanolamine-like liver effects. Dose levels without estrogenic effects for GEN were 1000 and 100 mg/kg bw for males and females respectively, there were no estrogenic effects in the feeding studies. For DAI males, the no estrogenic effect level was 300 mg/kg bw, for females < 100 mg/kg bw, suggesting that DAI may be a more potent estrogen than GEN in rats.