Glutathione S-transferase P1 protects against Amodiaquine Quinoneimines-induced cytotoxicity but does not prevent activation of endoplasmic reticulum stress in HepG2 cells

Yongjie Zhang*, Shalenie P. den Braver-Sewradj, Michiel W. den Braver, Steven Hiemstra, Nico P.E. Vermeulen, Bob van de Water, Jan N.M. Commandeur, J. C. Vos

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Formation of the reactive amodiaquine quinoneimine (AQ-QI) and N-desethylamodiaquine quinoneimine (DEAQ-QI) plays an important role in the toxicity of the anti-malaria drug amodiaquine (AQ). Glutathione conjugation protects against AQ-induced toxicity and GSTP1 is able to conjugate its quinoneimine metabolites AQ-QI and DEA-QI with glutathione. In this study, HepG2 cells transiently transfected with the human GSTP1 construct were utilized to investigate the protective effect of GSTP1 in a cellular context. HepG2 cells were exposed to synthesized QIs, which bypasses the need for intracellular bioactivation of AQ or DEAQ. Exposure was accompanied by decreased cell viability, increased caspase 3 activity, and decreased intracellular GSH levels. Using high-content imaging-based BAC-GFP reporters, it was shown that AQ-QI and DEAQ-QI specifically activated the endoplasmic reticulum (ER) stress response. In contrast, oxidative stress, DNA damage, or inflammatory stress responses were not activated. Overexpression of GSTP1 resulted in a two-fold increase in GSH-conjugation of the QIs, attenuated QI-induced cytotoxicity especially under GSH-depletion condition, abolished QIs-induced apoptosis but did not significantly inhibit the activation of the ER stress response. In conclusion, these results indicate a protective role of GSTP1 by increasing enzymatic detoxification of AQ-QI and DEAQ-QI and suggest a second protective mechanism by interfering with ER stress induced apoptosis.

Original languageEnglish
Article number388
Pages (from-to)1-13
Number of pages13
JournalFrontiers in Pharmacology
Volume9
Issue numberAPRIL
DOIs
Publication statusPublished - 18 Apr 2018

Keywords

  • Amodiaquine
  • Cytotoxicity
  • Endoplasmic reticulum stress
  • Human glutathione S-transferases P1
  • Quinoneimine

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