An Improved Nonradioactive Screening Method Identifies Genistein and Xanthohumol as Potent Inhibitors of Iodothyronine Deiodinases

Renko, Kostja; Schäche, Sonja; Hoefig, Carolin S.; Welsink, Tim; Schwiebert, Christian; Braun, Doreen; Becker, Niels-Peter; Köhrle, Josef; Schomburg, Lutz

doi:10.1089/thy.2015.0058

Cited by 69 publications

(43 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7). A more recent study examined compound effects on all three Dio isoforms individually and revealed xanthohumol as an inhibitor with micromolar potency on Dio1/2/3 (IC 50 1.5-3 mM), and genistein as a compound with similar potency (IC 50 3 mM), but specific for Dio1 (Renko et al 2015; Fig. 7).…”

Section: Propylthiouracil (Ptu)mentioning

confidence: 97%

New insights into the structure and mechanism of iodothyronine deiodinases

Schweizer¹,

Steegborn²

2015

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Iodothyronine deiodinases are a family of enzymes that remove specific iodine atoms from one of the two aromatic rings in thyroid hormones (THs). They thereby fine-tune local TH concentrations and cellular TH signaling. Deiodinases catalyze a remarkable biochemical reaction, i.e., the reductive elimination of a halogenide from an aromatic ring. In metazoans, deiodinases depend on the rare amino acid selenocysteine. The recent solution of the first experimental structure of a deiodinase catalytic domain allowed for a reappraisal of the many mechanistic and mutagenesis data that had been accumulated over more than 30 years. Hence, the structure generates new impetus for research directed at understanding catalytic mechanism, substrate specificity, and regulation of deiodinases. This review will focus on structural and mechanistic aspects of iodothyronine deiodinases and briefly compare these enzymes with dehalogenases, which catalyze related reactions. A general mechanism for the selenium-dependent deiodinase reaction will be described, which integrates the mouse deiodinase 3 crystal structure and biochemical studies. We will summarize further, sometimes isoform-specific molecular features of deiodinase catalysis and regulation, and we will then discuss available compounds for modulating deiodinase activity for therapeutic purposes.

show abstract

Section: Propylthiouracil (Ptu)mentioning

confidence: 97%

New insights into the structure and mechanism of iodothyronine deiodinases

Schweizer¹,

Steegborn²

2015

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…Supplementing the diet with IF was reported to triple the risk of overt hypothyroidism in patients with subclinical hypothyroidism [3]. Isoflavones may interact with various molecular targets of the thyroid hormone system: both genistein and daidzein can act as competitive substrates for thyroid peroxidase (TPO) [4,5]; genistein, and with a lower potency daidzein, inhibit binding of transthyretin (TTR) to thyroxin (T4) and triiodothyronine (T3) [6], while only genistein act as an inhibitor of type 1 deiodinase (Dio1) in vitro [7]. However, the goitrogenic potential of IF in vivo depends on numerous factors, including insufficient iodine in the diet or co-exposure with other goitrogen [8].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The isoflavones genistein and daidzein increase hepatic concentration of thyroid hormones and affect cholesterol metabolism in middle-aged male rats

Šošić‐Jurjević

Lütjohann

Renko

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

View full text Add to dashboard Cite

 We examined whether isoflavones increase hepatic thyroid hormone concentrations and affect cholesterol metabolism in middle-aged rats  Serum T3 was not affected while hepatic T3 was almost doubled, which supports increased local T3 availability.  Obtained results are compatible with displacement of TH from TTR, major transport protein in rodent blood and human CSF.  Hepatic increase of T3 correlated with up-regulated expression of the Cyp7a1 gene and elevated 7α-hydroxycholesterol  IF also lowered 24-hydroxycholesterol and desmosterol in liver and serum, while the total cholesterol levels remained unchanged.

show abstract

“…Besides TPO activity, discussed above, deiodination via 5DI can also be affected by baicalein, quercetin, kaempferol and rutin [69]. Xanthohumol FRTL-5 cells [89]; HEK293 cells [90] ↑IU [89]; iodothyronine deiodinases I [90] Effects listed in the right column and separated by semicolons have been derived from corresponding models shown in the middle column and separated by respective semicolons. 5DI, type I 5´-deiodinase; AC, anticancer; R, rat; ↑, increase; ↓, decrease; P, porcine; I , inhibit; G, goitrogenic; AT, antithyroid; HypoT, hypothyroidism; IU, iodide uptake; TH, thyroid hormone; M, mice; ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; PTC, papillary thyroid carcinoma; MTC, medullary thyroid carcinoma.…”

Section: Effects Of Phenolic Compounds On Thyroidmentioning

confidence: 99%

Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway

Paunkov

Chartoumpekis

Ziros

et al. 2019

CPD

View full text Add to dashboard Cite

Background: Natural compounds with potential antioxidant properties have been used in the form of food supplements or extracts with the intent to prevent or treat various diseases. Many of these compounds can activate the cytoprotective Nrf2 pathway. Besides, some of them are known to impact the thyroid gland, often with potential side-effects, but in other instances, with potential utility in the treatment of thyroid disorders. Objective: In view of recent data regarding the multiple roles of Nrf2 in the thyroid, this review summarizes the current bibliography on natural compounds that can have an effect on thyroid gland physiology and pathophysiology, and it discusses the potential implication of the Nrf2 system in the respective mechanisms. Method & Results: Literature searches for articles from 1950 to 2018 were performed in PubMed and Google Scholar using relevant keywords about phytochemicals, Nrf2 and thyroid. Natural substances were categorized into phenolic compounds, sulfur-containing compounds, quinones, terpenoids, or under the general category of plant extracts. For individual compounds in each category, respective data were summarized, as derived from in vitro (cell lines), preclinical (animal models) and clinical studies. The main emerging themes were as follows: phenolic compounds often showed potential to affect the production of thyroid hormones; sulfur-containing compounds impacted the pathogenesis of goiter and the proliferation of thyroid cancer cells; while quinones and terpenoids modified Nrf2 signaling in thyroid cell lines. Conclusion: Natural compounds that modify the activity of the Nrf2 pathway should be evaluated carefully, not only for their potential to be used as therapeutic agents for thyroid disorders, but also for their thyroidal safety when used for the prevention and treatment of non-thyroidal diseases.

show abstract

An Improved Nonradioactive Screening Method Identifies Genistein and Xanthohumol as Potent Inhibitors of Iodothyronine Deiodinases

Abstract: A rapid nonradioactive screening method based on the Sandell-Kolthoff reaction is suitable for identification of environmental, nutritive and pharmacological compounds modulating activities of human deiodinase enzymes.

Cited by 69 publications

References 24 publications

New insights into the structure and mechanism of iodothyronine deiodinases

New insights into the structure and mechanism of iodothyronine deiodinases

The isoflavones genistein and daidzein increase hepatic concentration of thyroid hormones and affect cholesterol metabolism in middle-aged male rats

Impact of Antioxidant Natural Compounds on the Thyroid Gland and Implication of the Keap1/Nrf2 Signaling Pathway

Contact Info

Product

Resources

About