Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep41238
Title: Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity
Authors: Choudhury, Y
Toh, Y.C 
Xing, J
Qu, Y
Poh, J
Huan, L
Tan, H.S
Kanesvaran, R 
Yu, H 
Tan, M.-H 
Keywords: cytochrome P450 1A2
glutathione
iron
messenger RNA
paracetamol
pazopanib
pyrimidine derivative
reactive oxygen metabolite
sulfonamide
antibody specificity
cell differentiation
drug effect
gene expression regulation
genetic transcription
genetics
human
induced pluripotent stem cell
liver cell
metabolism
oxidative stress
pathology
principal component analysis
toxic hepatitis
Acetaminophen
Cell Differentiation
Chemical and Drug Induced Liver Injury
Cytochrome P-450 CYP1A2
Gene Expression Regulation
Glutathione
Hepatocytes
Humans
Induced Pluripotent Stem Cells
Iron
Organ Specificity
Oxidative Stress
Principal Component Analysis
Pyrimidines
Reactive Oxygen Species
RNA, Messenger
Sulfonamides
Transcription, Genetic
Issue Date: 2017
Citation: Choudhury, Y, Toh, Y.C, Xing, J, Qu, Y, Poh, J, Huan, L, Tan, H.S, Kanesvaran, R, Yu, H, Tan, M.-H (2017). Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity. Scientific Reports 7 : 41238. ScholarBank@NUS Repository. https://doi.org/10.1038/srep41238
Abstract: Idiosyncratic drug-induced hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant hepatotoxicity of unknown mechanistic basis. In vitro cytotoxicity assays confirmed that HLCs from patients with clinically identified hepatotoxicity were more sensitive to PZ-induced toxicity than other individuals, while a prototype hepatotoxin acetaminophen was similarly toxic to all HLCs studied. Transcriptional analyses showed that PZ induces oxidative stress (OS) in HLCs in general, but in HLCs from susceptible individuals, PZ causes relative disruption of iron metabolism and higher burden of OS. Our study establishes the first patient-specific HLC-based platform for idiosyncratic hepatotoxicity testing, incorporating multiple potential causative factors and permitting the correlation of transcriptomic and cellular responses to clinical phenotypes. Establishment of patient-specific HLCs with clinical phenotypes representing population variations will be valuable for pharmaceutical drug testing. © The Author(s) 2017.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/173945
ISSN: 20452322
DOI: 10.1038/srep41238
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