title: Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes.
abstract: The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD90) and 50% (APD50) repolarization, reduced the maximum upstroke velocity (dV/dtmax) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including IKr, IKs, INa, and ICa. Among them, IKr and INa showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K(+) channels.
authors.affiliation: Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, South Korea. Electronic address: crystalee@gmail.com.
authors.forename: Sujeong
authors.initials: S
authors.lastname: Lee
authors.affiliation: Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, South Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea; Human and Environmental Toxicology Program, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, South Korea. Electronic address: hyangaelee@gmail.com.
authors.forename: Hyang-Ae
authors.initials: HA
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea. Electronic address: djmaya@snu.ac.kr.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea. Electronic address: sjoonkim@snu.ac.kr.
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, South Korea; Human and Environmental Toxicology Program, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, South Korea. Electronic address: idkks00@gmail.com.
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D066126:Cardiotoxicity / Q000378:metabolism / Q000473:pathology; D054715:Cardiotoxins / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000633:toxicity*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D054715:Cardiotoxins; D007473:Ion Channels; D010879:Piperazines; D014230:Triazoles; C051752:nefazodone
keywords: Action potentials; Cardiotoxicity; Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs); Ion channels; Nefazodone; Patch clamp