Structural basis for inhibition of 17β-hydroxysteroid dehydrogenases by phytoestrogens: The case of fungal 17β-HSDcl

Cassetta, Alberto; Stojan, Jure; Krastanova, I.; Kristan, Katja; Švegelj, Mojca Brunskole; Lamba, Doriano; Rižner, Tea Lanišnik

doi:10.1016/j.jsbmb.2017.02.020

Cited by 24 publications

(14 citation statements)

References 61 publications

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“…Based on increased E2 formation in the presence of genistein and daidzein, inhibition of 17β-HSD can be excluded. Our data are in contrast to a very recent study showing an inhibition of this enzyme by genistein ( Cassetta et al, 2017 ). This discrepancy might be explained by the fact that the authors used purified recombinant 17β-HSD from the filantous fungus Cochliobolus lunatus and not a human enzyme which might differ in activity.…”

Section: Discussioncontrasting

confidence: 99%

“…This prompted us to hypothesize that genistein and daidzein might dose-dependently alter steroid hormone levels by inhibiting the conjugation of estrogens and their precursors. Our hypothesis was supported by in vitro studies showing that soy isoflavonoids are able to inhibit various enzymes involved in the metabolism of estrogens, including cytochrome P450 3A4 (CYP3A4), 17β-HSD, SULTs, and UGTs ( Mesía-Vela and Kauffman, 2003 ; Mohamed and Frye, 2011 ; Ronis, 2016 ; Cassetta et al, 2017 ).…”

Section: Introductionmentioning

confidence: 61%

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The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A Targeted Metabolomics Approach

et al. 2017

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The beneficial effect of dietary soy food intake, especially for women diagnosed with breast cancer, is controversial, as in vitro data has shown that the soy isoflavones genistein and daidzein may even stimulate the proliferation of estrogen-receptor alpha positive (ERα+) breast cancer cells at low concentrations. As genistein and daidzein are known to inhibit key enzymes in the steroid metabolism pathway, and thus may influence levels of active estrogens, we investigated the impacts of genistein and daidzein on the formation of estrogen metabolites, namely 17β-estradiol (E2), 17β-estradiol-3-(β-D-glucuronide) (E2-G), 17β-estradiol-3-sulfate (E2-S) and estrone-3-sulfate (E1-S) in estrogen-dependent ERα+ MCF-7 cells. We found that both isoflavones were potent inhibitors of E1 and E2 sulfation (85–95% inhibition at 10 μM), but impeded E2 glucuronidation to a lesser extent (55–60% inhibition at 10 μM). The stronger inhibition of E1 and E2 sulfation compared with E2 glucuronidation was more evident for genistein, as indicated by significantly lower inhibition constants for genistein [Kis: E2-S (0.32 μM) < E1-S (0.76 μM) < E2-G (6.01 μM)] when compared with those for daidzein [Kis: E2-S (0.48 μM) < E1-S (1.64 μM) < E2-G (7.31 μM)]. Concomitant with the suppression of E1 and E2 conjugation, we observed a minor but statistically significant increase in E2 concentration of approximately 20%. As the content of genistein and daidzein in soy food is relatively low, an increased risk of breast cancer development and progression in women may only be observed following consumption of high-dose isoflavone supplements. Further long-term human studies monitoring free estrogens and their conjugates are therefore highly warranted to evaluate the potential side effects of high-dose genistein and daidzein, especially in patients diagnosed with ERα+ breast cancer.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 61%

The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A Targeted Metabolomics Approach

et al. 2017

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“…As for their effects on the estrogen metabolism and receptors, isoflavones are part of a group of substances of plant origin called “phytoestrogens” or “weak estrogens,” due to the modulatory effects that exert al level of estrogen receptors, pregnane X receptors, and constitutive androstane receptors . Although with an affinity approximately 5000 times lower than that of the estrogens, isoflavones can act as partial agonists or antagonists of the estrogen receptors, most probably through the inhibition of aromatase (CYP19), that is the enzyme that catalyzes the conversion of androstenedione and testosterone to estrone and estradiol respectively .…”

Section: Introductionmentioning

confidence: 99%

“…19 As for their effects on the estrogen metabolism and receptors, isoflavones are part of a group of substances of plant origin called "phytoestrogens" or "weak estrogens," due to the modulatory effects that exert al level of estrogen receptors, pregnane X receptors, and constitutive androstane receptors. [20][21][22] Although with an affinity approximately 5000 times lower than that of the estrogens, 23 isoflavones can act as partial agonists or antagonists of the estrogen receptors, most probably through the inhibition of aromatase (CYP19), [24][25][26] that is the enzyme that catalyzes the conversion of androstenedione and testosterone to estrone and estradiol respectively. 27 The estrogenic/antiestrogenic activity of isoflavones may also be due to an alteration of biosynthesis and subsequent secretion of luteinizing hormone (LH), that acts stimulating the production of testosterone in male testicles, and that it is therefore included in the Prohibited List of the World Anti-Doping Agency (WADA), in section S2 (Peptide hormones, growth factors, related substances and mimetics), 28 Water was obtained from a MilliQ water purification system (Millipore S.p.A., Milan, Italy).…”

Section: Introductionmentioning

confidence: 99%

Synthetic isoflavones and doping: A novel class of aromatase inhibitors?

Iannone

Botrè

Cardillo

et al. 2018

Drug Testing and Analysis

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Anectodical information suggests that flavonoids may be widely used among athletes for their multiple biochemical and pharmacological effects. We have evaluated in vitro the effects of two synthetic isoflavones, methoxyisoflavone and ipriflavone, on the catalytic activity of human aromatase (CYP19), the enzyme catalyzing the conversion of androgens (ie, testosterone or androstenedione) to estrogens (ie, estradiol and estrone). The potential inhibitory effect was evaluated by measuring the rate of aromatization of testosterone, monitored by gas chromatography-mass spectrometry (GC-MS), both in the presence and in the absence of methoxyisoflavone or ipriflavone, comparing their effects with those of synthetic aromatase inhibitors (formestane, anastrozole, and aminoglutethimide) presently included in the list of prohibited substances and methods, and of natural flavonoids (chrysin, quercetin, and daidzein), that are known inhibitors of CYP19. The preliminary results of our in vitro study show that methoxyisoflavone and ipriflavone act as competitive inhibitors of aromatase, the degree of inhibition measured in vitro being of the same order of magnitude of that of the aromatase inhibitors commonly used in anti-estrogenic therapies. Our preliminary in vitro results indicate that, in principle, a sufficiently large intake of isoflavones could alter the kinetics of the dynamic equilibria between androgens and estrogens, suggesting their monitoring in doping control routine analysis.

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“…Isoflavones are a class of flavonoids characterized by a structure that differs from the isomeric flavonoids only by the position of the phenyl B ring on the phenylchroman skeleton (Figure B). These compounds, due to their structural similarity with estradiol, are also called “phytoestrogens” . Because of their estrogen receptor modulation activity and because of their interactions with steroidogenic enzymes, isoflavones may be of interest in sport doping because they can be used by athletes during recovering periods after the administration of exogenous and pseudo‐endogenous anabolic steroids, to boost the natural production of luteinizing hormone (LH) and, in turn, to reactivate the biosynthesis of natural androgens…”

Section: Introductionmentioning

confidence: 99%

An investigation on the metabolic pathways of synthetic isoflavones by gas chromatography coupled to high accuracy mass spectrometry

Iannone

Botrè

Parenti

et al. 2019

Rapid Comm Mass Spectrometry

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Rationale:Isoflavones are a group of flavonoids that may be of interest in sport doping because they can be used by athletes in the recovery periods after the administration of anabolic steroids, with the aim of increasing the natural production of luteinizing hormone (LH) and, consequently, the biosynthesis of endogenous androgens. Methods:The in vivo metabolism of methoxyisoflavone (5-methyl-7methoxyisoflavone) and ipriflavone (7-isopropoxyisoflavone), respectively present in a dietary supplement and in a pharmaceutical preparation, was investigated. The study was carried out by the analysis of urinary samples collected from male Caucasian subjects before, during and after the oral administration of methoxyisoflavone or ipriflavone. After enzymatic hydrolysis and liquid-liquid extraction, all urinary samples were analyzed by gas chromatography/quadrupole time-of-flight (qTOF MS system/qTOF) electron ionization mass spectrometry (EI-MS).Results: Eight metabolites of methoxyisoflavone and six metabolites of ipriflavone were isolated. The corresponding accurate mass spectra are specific for isoflavone structures and revealed also a retro-Diels-Alder fragmentation. Conclusions:When excreted in large amounts, the urinary metabolites of methoxyisoflavone and ipriflavone can be traced to potential confounding factors in doping analysis. As methoxyisoflavone and ipriflavone have been shown to inhibit the enzyme aromatase, thus interfering with the normal metabolic pathways of testosterone, the detection of their intake, by screening for the presence of their main metabolites in urine, might be helpful in routine doping control analysis.

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Structural basis for inhibition of 17β-hydroxysteroid dehydrogenases by phytoestrogens: The case of fungal 17β-HSDcl

Cited by 24 publications

References 61 publications

The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A Targeted Metabolomics Approach

The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A Targeted Metabolomics Approach

Synthetic isoflavones and doping: A novel class of aromatase inhibitors?

An investigation on the metabolic pathways of synthetic isoflavones by gas chromatography coupled to high accuracy mass spectrometry

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