title: The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity.
abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamilinduced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity. [BMB Reports 2017; 50(2): 91-96].
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea.
authors.forename: Da Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Park
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Yu Seol
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Su Haeng
authors.initials: SH
authors.lastname: Sung
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Yong-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D014700:Verapamil