Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases
| Autor: | Joseph J. Korte, Sigmund J. Degitz, Phillip C. Hartig, Jessica P Christensen, Jennifer H Olker, Paige M Kent, Carsten Knutsen, Mary C. Cardon, Michael W. Hornung, Jeffrey S. Denny |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Deiodinase Selective inhibition Transfection Toxicology Iodide Peroxidase Article Adenoviridae Small Molecule Libraries Inhibitory Concentration 50 03 medical and health sciences 0302 clinical medicine medicine Humans Enzyme Inhibitors chemistry.chemical_classification Triiodothyronine Dose-Response Relationship Drug biology Thyroid In vitro toxicology Iodides HEK293 Cells 030104 developmental biology Enzyme medicine.anatomical_structure chemistry Biochemistry biology.protein Biological Assay 030217 neurology & neurosurgery Homeostasis Hormone |
| Zdroj: | Toxicological Sciences. 168:430-442 |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Deiodinase enzymes play an essential role in converting thyroid hormones between active and inactive forms by deiodinating the pro-hormone thyroxine (T4) to the active hormone triiodothyronine (T3) and modifying T4 and T3 to inactive forms. Chemical inhibition of deiodinase activity has been identified as an important endpoint to include in screening chemicals for thyroid hormone disruption. To address the lack of data regarding chemicals that inhibit the deiodinase enzymes, we developed robust in vitro assays that utilized human deiodinase types 1, 2, and 3 and screened over 1,800 unique chemicals from the U.S. EPA’s ToxCast phase 1_v2, phase 2, and e1k libraries. Initial testing at a single concentration identified 411 putative deiodinase inhibitors that produced inhibition of 20% or greater in at least one of the three deiodinase assays, including chemicals that have not previously been shown to inhibit deiodinases. Of these, 228 chemicals produced enzyme inhibition of 50% or greater; these chemicals were further tested in concentration-response to determine relative potency. Comparisons across these deiodinase assays identified 81 chemicals that produced selective inhibition, with 50% inhibition or greater of only one of the deiodinases. This set of three deiodinase inhibition assays provides a significant contribution towards expanding the limited number of in vitro assays used to identify chemicals with the potential to interfere with thyroid hormone homeostasis. Additionally, these results set the groundwork for development and evaluation of structure-activity relationships for deiodinase inhibition, and inform targeted selection of chemicals for further testing to identify adverse outcomes of deiodinase inhibition. |
| Databáze: | OpenAIRE |
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