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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 377; no. 1; pp. 121 - 132
• Main Authors: Zhang, Leilei, Kim, Seok-Hyung, Park, Ki-Hoon, Zhi-Wei, Ye, Jie, Zhang, Townsend, Danyelle M, Tew, Kenneth D
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.04.2021
• Subjects: 4-Aminobenzoic Acid - toxicity; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animals; Cellular and Molecular; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Glutathione S-Transferase pi - genetics; Glutathione S-Transferase pi - metabolism; Homeostasis; Larva - drug effects; Larva - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nitric Oxide - toxicity; Oxidants - toxicity; Oxidation-Reduction; Transcriptome; Tunicamycin - toxicity; Unfolded Protein Response; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.120.000417

We have created a novel glutathione -transferase 1 ( ) knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis and response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, 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 with wild type, 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 and 0 -{2,4-dinitro-5-[4-( -methylamino)benzoyloxy]phenyl}1-( , -dimethylamino)diazen-1-ium-1,2-diolate (PABA/nitric oxide) activated inositol-requiring protein-1/X-box binding protein 1 pathways, whereas thapsigargin caused greater activation of protein kinase-like ER kinase/activating transcription factor 4/CHOP pathways. These results suggest that this teleost model is useful for 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 glutathione transferase 1 in development, redox homeostasis, and response to drugs that enact cytotoxicity through endoplasmic reticulum stress and induction of the unfolded protein response.