Isoflavone metabolites and their in vitro dual functions: they can act as an estrogenic agonist or antagonist depending on the estrogen concentration.
The major soy isoflavones are daidzin and genistin, the glycoside conjugates of daidzein (DZ) and genistein (GTN). After ingestion, they are metabolized into diverse compounds in the gut. The marked inter-individual variation has been suggested in their metabolism. The clinical effects may be modulated by the metabolic ability to produce a more potent metabolite than the precursor. Our study was, therefore, designed to analyze and compare in vitro biologic activities of their metabolites: DZ, GTN, dihydrogenistein (DGTN), dihydrodaidzein (DDZ), tetrahydrodaidzein (TDZ), O-desmethylangolensin (ODMA), and equol (EQL). Furthermore, we investigated their modulatory effects in the presence of estrogen using several in vitro systems. The intermediate metabolites, such as DGTN, DDZ, and TDZ, bind much weakly to both ERs and induce less potently in transcriptional activity, gene expression, and mammary cell proliferation than their precursors. EQL has the strongest binding affinities and estrogenic activities especially for ERbeta among the daidzin metabolites and shows the ability to suppress osteoclast formation at high doses. The test isoflavonoids act like estrogen antagonists with the premenopausal dose of E2 and thus inhibit estrogenic actions by E2, whereas they exert estrogen agonist activity with the lower dose of estrogen close to the serum levels of postmenopausal women. Our results suggest that phytoestrogens such as isoflavones may exert their effects as estrogen antagonists in a high estrogen environment, or they may act as estrogen agonists in a low estrogen environment.
Hwang
Chang Sun
CS
Division of Endocrinology, Department of Internal Medicine, Cheil General Hospital and Women's Healthcare Center, Sungkyunkwan University School of Medicine, 1-19 Choong Gu Mukjung-Dong, Seoul 100-380, Republic of Korea.
Kwak
Ho Seok
HS
Lim
Hwa Jae
HJ
Lee
Su Hee
SH
Kang
Young Soon
YS
Choe
Tae Boo
TB
Hur
Hor Gil
HG
Han
Ki Ok
KO
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000819:agonists*; D006801:Humans; D007529:Isoflavones / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010010:Osteoclasts / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007529:Isoflavones