RT Journal Article SR Electronic T1 Glutathione S-Transferase P Influences Redox Homeostasis and Response to Drugs that Induce the Unfolded Protein Response in Zebrafish JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP JPET-AR-2020-000417 DO 10.1124/jpet.120.000417 A1 Leilei Zhang A1 Seok-Hyung Kim A1 Ki-Hoon Park A1 Zhi-wei Ye A1 Jie Zhang A1 Danyelle Townsend A1 Kenneth D. Tew YR 2021 UL http://jpet.aspetjournals.org/content/early/2021/02/18/jpet.120.000417.abstract AB 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.