The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red clover

Abstract

A recent intervention study demonstrated the occurrence of irilone as second most abundant isoflavone next to daidzein in human plasma after consumption of a red clover-based dietary supplement (RCDS) containing predominately formononetin ≫ biochanin A > irilone (12 % of these isoflavones). To elucidate the relevance of this finding, in the present study (1) the representativeness of the isoflavone composition of the RCDS and (2) the estrogenic activity of irilone were investigated. Thus, major isoflavones were quantified in eight commercially available RCDS. Furthermore, the estrogenic activities of irilone and other isoflavones were determined by marker gene expression in Ishikawa and cell proliferation in MCF-7 cells. Irilone amounted to 1.8-10.9 mg/g capsule content and 5-18 % of the three major isoflavones, respectively, demonstrating the general occurrence of irilone in RCDS. Moreover, irilone significantly induced the activity of alkaline phosphatase (AlP) as well as AlP, progesterone receptor, and androgen receptor mRNA levels in Ishikawa cells. Furthermore, irilone significantly induced MCF-7 cell proliferation. Neither 17β-estradiol (E2)-induced AlP activity nor E2-induced MCF-7 cell proliferation was affected by irilone. ICI182,780 antagonized IRI-induced effects on both AlP activity and cell proliferation, suggesting an estrogen receptor agonistic mode of action. Taking into account the estrogenic activity of red clover isoflavones (formononetin, biochanin A, prunetin, glycitein) and their biotransformation products (daidzein, genistein, ethylphenol) as well as published plasma levels of isoflavones after consumption of RCDS, irilone could contribute approximately 50 % of the E2 equivalents estimated for daidzein.

Trifolium species – the latest findings on chemical profile, ethnomedicinal use and pharmacological properties

“…As ICI182,780 antagonized the influence of irilone, the estrogen receptor pathway is considered to be the most likely mechanism of irilone activity. [81] In a similar experimental model of MCF-7 cell line, measurements of the estrogenic activity of different batches of red clover demonstrated that both estradiol and red clover extracts increased the proliferation of MCF-7 in a concentration-dependent manner. The estrogenic potency was as follows E2 >>> genistein > biochanin A = daidzein > formononetin and increased with a decline of genistein concentration.…”

“…This interaction was used for the determination of molecular mechanisms of irilone effects on the examined cells. As ICI182,780 antagonized the influence of irilone, the estrogen receptor pathway is considered to be the most likely mechanism of irilone activity . In a similar experimental model of MCF‐7 cell line, measurements of the estrogenic activity of different batches of red clover demonstrated that both estradiol and red clover extracts increased the proliferation of MCF‐7 in a concentration‐dependent manner.…”

Metabolic profiling of rhizomes of native populations of the strictly endemic Croatian species Iris adriatica

“…Irilone (34) was shown to possess α-amylase inhibitory effects which would support antidiabetic action (Ibrahim et al 2017). The same compound (34) could also play a role as phytoestrogen as it was contributing to the oestrogenic activity of red clover extracts ((Lutter et al 2014). Hence, there is remarkable potential of I. adriatica constitutents to be explored further for antiinflammatory, chemopreventive, antidiabetic and phytoestrogenic effects.…”

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“…In these cancers, progesterone acts were associated with positive outcomes and reduced hazard of disease occurrence . 12,13 From the literature survey, it was found that the identification of the structural properties of the molecule under study had not been performed previously in the light of computational chemistry [14][15][16] and hence the study was undertaken. The main aim of the present study is to give a comprehensive description of the electronic properties andspectroscopic (FT-IR and UV-Vis) profiles of the novel antagonist irilone as a progesterone receptor (PR) effect supporter in endometrial and ovarian cancer cell lines by quantum-mechanical (QM) and molecular docking methods.It is believed that the outputs of this study will provide a deep and accurate understanding of the possible biological activities of the title compound.…”