In vitro screening for chemical inhibition of the iodide recycling enzyme, iodotyrosine deiodinase
| Autor: | Sigmund J. Degitz, Jennifer H Olker, Phillip C. Hartig, Mary C. Cardon, Jonathan T. Haselman, Joseph J. Korte, Jeffrey S. Denny, Michael W. Hornung |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Deiodinase Toxicology Iodide Peroxidase Article 03 medical and health sciences 0302 clinical medicine In vivo Enzyme Inhibitors music IC50 chemistry.chemical_classification music.instrument biology In vitro toxicology General Medicine In vitro Enzyme assay Recombinant Proteins High-Throughput Screening Assays 030104 developmental biology Enzyme chemistry Biochemistry 030220 oncology & carcinogenesis biology.protein Iodotyrosine deiodinase Biological Assay Baculoviridae |
| Zdroj: | Toxicol In Vitro |
| ISSN: | 1879-3177 |
| Popis: | The iodide recycling enzyme, iodotyrosine deiodinase (IYD), is a largely unstudied molecular mechanism through which environmental chemicals can potentially cause thyroid disruption. This highly conserved enzyme plays an essential role in maintaining adequate levels of free iodide for thyroid hormone synthesis. Thyroid disruption following in vivo IYD inhibition has been documented in mammalian and amphibian models; however, few chemicals have been tested for IYD inhibition in either in vivo or in vitro assays. Presented here are the development and application of a screening assay to assess susceptibility of IYD to chemical inhibition. With recombinant human IYD enzyme, a 96-well plate in vitro assay was developed and then used to screen over 1800 unique substances from the U.S. EPA ToxCast screening library. Through a tiered screening approach, 194 IYD inhibitors were identified (inhibited IYD enzyme activity by 20% or greater at target concentration of 200 μM). 154 chemicals were further tested in concentration-response (0.032–200 μM) to determine IC50 and rank-order potency. This work broadens the coverage of thyroid-relevant molecular targets for chemical screening, provides the largest set of chemicals tested for IYD inhibition, and aids in prioritizing chemicals for targeted in vivo testing to evaluate thyroid-related adverse outcomes. |
| Databáze: | OpenAIRE |
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