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Journal of Pharmacology and Experimental Therapeutics

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OtherCellular and Molecular

Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish

Leilei Zhang, Seok-Hyung Kim, Ki-Hoon Park, Zhi-wei Ye, Jie Zhang, Danyelle Townsend and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics February 18, 2021, JPET-AR-2020-000417; DOI: https://doi.org/10.1124/jpet.120.000417
Leilei Zhang
1MUSC, United States
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Seok-Hyung Kim
2MUSC, United States of America
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Ki-Hoon Park
2MUSC, United States of America
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Zhi-wei Ye
3Departments of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, United States of America
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Jie Zhang
2MUSC, United States of America
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Danyelle Townsend
4Department of Experimental Therapeutics, Medical University of South Carolina, United States
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Kenneth D. Tew
5Department of Pharmacology, MUSC, United States
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  • For correspondence: tewk@musc.edu
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Abstract

We have created a novel glutathione S-transferase Pi 1 (gstp1) knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis, response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, gstp1 KO larvae had higher expression of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) accompanied by a more reduced larval environment and a status consistent with reductive stress. Compared to wild type (WT), various UPR markers were decreased in KO larvae, but treatment with drugs that induce ER stress caused greater toxicities and increased expression of Nrf2 and UPR markers in KO; tunicamycin (TuM) and 02-{2,4-dinitro-5-[4-(N-methylamino) benzoyloxy] phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate (PABA/NO) activated IRE1/XBP1 pathways, while thapsigargin (ThG) caused greater activation of PERK/ATF4/CHOP pathways. These results suggest that this teleost model is useful in predicting how GSTP regulates organismal management of oxidative/reductive stress and is a determinant of response to drug-induced ER stress and the UPR.

Significance Statement A new zebrafish model has been created to study the importance of Gstp1 in development, redox homeostasis and response to drugs that enact cytotoxicity through ER-stress and induction of the UPR.

  • Endoplasmic reticulum stress
  • Gene editing/CRISPR
  • Glutathione S-transferase (GST)
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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OtherCellular and Molecular

Zebrafish Gstp1 drug response

Leilei Zhang, Seok-Hyung Kim, Ki-Hoon Park, Zhi-wei Ye, Jie Zhang, Danyelle Townsend and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics February 18, 2021, JPET-AR-2020-000417; DOI: https://doi.org/10.1124/jpet.120.000417

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OtherCellular and Molecular

Zebrafish Gstp1 drug response

Leilei Zhang, Seok-Hyung Kim, Ki-Hoon Park, Zhi-wei Ye, Jie Zhang, Danyelle Townsend and Kenneth D. Tew
Journal of Pharmacology and Experimental Therapeutics February 18, 2021, JPET-AR-2020-000417; DOI: https://doi.org/10.1124/jpet.120.000417
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