Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells
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...
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| Format: | Article |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2018.00388/full |
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| author | Yongjie Zhang 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 |
| author_facet | Yongjie Zhang 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 |
| author_sort | Yongjie Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T17:29:51Z |
| format | Article |
| id | doaj.art-8167ea147acd4c4f8d185eef0cbbc4ab |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T17:29:51Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-8167ea147acd4c4f8d185eef0cbbc4ab2022-12-22T00:56:52ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-04-01910.3389/fphar.2018.00388354574Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 CellsYongjie Zhang0Yongjie Zhang1Shalenie P. den Braver-Sewradj2Michiel W. den Braver3Steven Hiemstra4Nico P. E. Vermeulen5Bob van de Water6Jan N. M. Commandeur7J. C. Vos8Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, NetherlandsClinical Pharmacokinetics Research Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, ChinaDivision of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, NetherlandsDivision of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, NetherlandsDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, NetherlandsDivision of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, NetherlandsDivision of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, NetherlandsDivision of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, NetherlandsDivision of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, NetherlandsFormation 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.http://journal.frontiersin.org/article/10.3389/fphar.2018.00388/fullamodiaquinequinoneiminecytotoxicityendoplasmic reticulum stresshuman glutathione S-transferases P1 |
| spellingShingle | Yongjie Zhang 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 Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells Frontiers in Pharmacology amodiaquine quinoneimine cytotoxicity endoplasmic reticulum stress human glutathione S-transferases P1 |
| title | Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells |
| title_full | Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells |
| title_fullStr | Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells |
| title_full_unstemmed | Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells |
| title_short | Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells |
| title_sort | glutathione s transferase p1 protects against amodiaquine quinoneimines induced cytotoxicity but does not prevent activation of endoplasmic reticulum stress in hepg2 cells |
| topic | amodiaquine quinoneimine cytotoxicity endoplasmic reticulum stress human glutathione S-transferases P1 |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2018.00388/full |
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