Expanded high-throughput screening and chemotype-enrichment analysis of the phase II: e1k ToxCast library for human sodium-iodide symporter (NIS) inhibition
| Autor: | Mahmoud Shobair, Susan C. Laws, Ashley S. Murr, Tammy E. Stoker, Ryan Lougee, Daniel R. Hallinger, Angela R. Buckalew, Jun Wang, Ann M. Richard |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Sodium-iodide symporter Cell Survival Health Toxicology and Mutagenesis High-throughput screening Thyroid Gland 010501 environmental sciences Toxicology 01 natural sciences Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Animals Humans Viability assay Cytotoxicity 0105 earth and related environmental sciences Symporters Biological Transport General Medicine Iodides In vitro High-Throughput Screening Assays 030104 developmental biology HEK293 Cells Endocrine disruptor chemistry Biochemistry Symporter Biological Assay Xenobiotic |
| Zdroj: | Arch Toxicol |
| ISSN: | 1432-0738 |
| Popis: | The sodium-iodide symporter (NIS) mediates the uptake of iodide into the thyroid. Inhibition of NIS function by xenobiotics has been demonstrated to suppress circulating thyroid hormones and perturb related physiological functions. Until recently, few environmental chemicals had been screened for NIS inhibition activity. We previously screened over 1000 chemicals from the ToxCast Phase II (ph1v2 and ph2) libraries using an in vitro radioactive iodide uptake (RAIU) with the hNIS-HEK293T cell line to identify NIS inhibitors. Here, we broaden the chemical space by expanding screening to include the ToxCast e1k library (804 unique chemicals) with initial screening for RAIU at 1 × 10–4 M. Then 209 chemicals demonstrating > 20% RAIU inhibition were further tested in multiple-concentration, parallel RAIU and cell viability assays. This identified 55 chemicals as active, noncytotoxic RAIU inhibitors. Further cytotoxicity-adjusted potency scoring (with NaClO4 having a reference score of 200) revealed five chemicals with moderate to strong RAIU inhibition (scored > 100). These data were combined with our previous PhII screening data to produce binary hit-calls for ~ 1800 unique chemicals (PhII + e1k) with and without cytotoxicity filtering. Results were analyzed with a ToxPrint chemotype-enrichment workflow to identify substructural features significantly enriched in the NIS inhibition hit-call space. We assessed the applicability of enriched PhII chemotypes to prospectively predict NIS inhibition in the e1k dataset. Chemotype enrichments derived for the combined ~ 1800 dataset also identified additional enriched features, as well as chemotypes affiliated with cytotoxicity. These enriched chemotypes provide important new information that can support future data interpretation, structure–activity relationship, chemical use, and regulation. |
| Databáze: | OpenAIRE |
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