title: Characteristic molecular and proteomic signatures of drug-induced liver injury in a rat model.
abstract: Drug-induced liver injury (DILI) is a major safety concern during drug development and remains one of the main reasons for withdrawal of drugs from the market. Although it is crucial to develop methods that will detect potential hepatotoxicity of drug candidates as early and as quickly as possible, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data. Hence, in this study, we assessed characteristic molecular signatures in rat liver treated with drugs (pyrazinamide, ranitidine, enalapril, carbamazepine and chlorpromazine) that are known to cause DILI in humans. Unsupervised hierarchical clustering analysis of transcriptome changes induced by DILI-causing drugs resulted in three different subclusters on dendrogram, i.e., hepatocellular, cholestatic and mixed type of DILI at early time points (2 days), and multiclassification analysis suggested 31 genes as discernible markers for each DILI pattern. Further analysis for characteristic molecular signature of each DILI pattern provided a molecular basis for different modes of DILI action. A proteomics study of the same rat livers was used to confirm the results, and the two sets of data showed 60 matching classifiers. In conclusion, the data of different DILI-causing drug treatments from genomic analysis in a rat model suggest that DILI-specific molecular signatures can discriminate different patterns of DILI at an early exposure time point, and that they provide useful information for mechanistic studies that may lead to a better understanding of the molecular basis of DILI.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Bae
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Shen
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Woo Chan
authors.initials: WC
authors.lastname: Shin
authors.forename: Hee Doo
authors.initials: HD
authors.lastname: Yang
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Jin
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Ahn
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D002220:Carbamazepine / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002746:Chlorpromazine / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D004656:Enalapril / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D011718:Pyrazinamide / Q000633:toxicity; D011899:Ranitidine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000187:drug effects
chemical_list: D015415:Biomarkers; D011718:Pyrazinamide; D002220:Carbamazepine; D004656:Enalapril; D011899:Ranitidine; D002746:Chlorpromazine
keywords: Drug-induced liver injury; Gene expression; Hepatotoxicity; Molecular signature; Transcriptome