title: Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity.
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.
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.
authors.forename: Yukti
authors.initials: Y
authors.lastname: Choudhury
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.|Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, 4 Engineering Drive 3, E4 #04-08, Singapore 117583, Republic of Singapore.
authors.forename: Yi Chin
authors.initials: YC
authors.lastname: Toh
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.
authors.forename: Jiangwa
authors.initials: J
authors.lastname: Xing
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Poh
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Medical Oncology, National Cancer Centre, Singapore 169610, Republic of Singapore.
authors.forename: Hui Shan
authors.initials: HS
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, National Cancer Centre, Singapore 169610, Republic of Singapore.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.|Yong Loo Lin School of Medicine and Mechanobiology Institute, National University of Singapore, Republic of Singapore.|Gastroenterology Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hanry
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Nanos #04-01, Singapore 138669, Republic of Singapore.|Division of Medical Oncology, National Cancer Centre, Singapore 169610, Republic of Singapore.
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Tan
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007191:Indazoles; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007501:Iron / Q000378:metabolism; D009928:Organ Specificity; D018384:Oxidative Stress / Q000187:drug effects; D025341:Principal Component Analysis; D011743:Pyrimidines / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000082:Acetaminophen; C516667:pazopanib; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D005978:Glutathione