Integrative cross-omics analysis in primary mouse hepatocytes unravels mechanisms of cyclosporin A-induced hepatotoxicity

Autor: Anke Van Summeren, Will K. W. H. Wodzig, Karen Brauers, Arjen Lommen, Maarten L. J. Coonen, Wim F.P.M. Van den Hof, Jos C. S. Kleinjans, Marcel H. M. van Herwijnen
Přispěvatelé: RS: GROW - Oncology, RS: NUTRIM - R4 - Gene-environment interaction, RS: GROW - R1 - Prevention, Toxicogenomics, Promovendi ODB, Bureau FHML, Ondersteunend personeel ODB, Medische Microbiologie
Rok vydání: 2014
Předmět:
Male
Proteomics
Integrated analysis
translation
Pharmacology
Toxicology
drug-induced hepatotoxicity
BU Contaminants & Toxins
Mice
Cyclosporin a
Gene expression
Protein Interaction Mapping
Protein Interaction Maps
Cells
Cultured
Cholestasis
Systems Biology
Translation (biology)
Genomics
normalization
Liver
Toxicity
Cyclosporine
Chemical and Drug Induced Liver Injury
Immunosuppressive Agents
Genetic Markers
BU Contaminanten & Toxines
Primary Cell Culture
Biology
Risk Assessment
Primary mouse hepatocytes
Drug withdrawal
microRNA
medicine
Animals
Metabolomics
metabonomics
RNA
Messenger
micrornas
Gene Expression Profiling
Hepatotoxicity
biomarkers
medicine.disease
gene-expression
Mice
Inbred C57BL
Cyclosporin A
MicroRNAs
Gene Expression Regulation
Hepatocytes
activation
accumulation
repression
Drug metabolism
Zdroj: Toxicology 324 (2014)
Toxicology, 324, 18-26
Toxicology, 324, 18-26. Elsevier Ireland Ltd
ISSN: 1879-3185
0300-483X
Popis: The liver is responsible for drug metabolism and drug-induced hepatotoxicity is the most frequent reason for drug withdrawal, indicating that better pre-clinical toxicity tests are needed. In order to bypass animal models for toxicity screening, we exposed primary mouse hepatocytes for exploring the prototypical hepatotoxicant cyclosporin A. To elucidate the mechanisms underlying cyclosporin A-induced hepatotoxicity, we analyzed expression levels of proteins, mRNAs, microRNAs and metabolites. Integrative analysis of transcriptomics and proteomics showed that protein disulfide isomerase family A, member 4 was up-regulated on both the protein level and mRNA level. This protein is involved in protein folding and secretion in the endoplasmic reticulum. Furthermore, the microRNA mmu-miR-182-5p which is predicted to interact with the mRNA of this protein, was also differentially expressed, further emphasizing endoplasmic reticulum stress as important event in drug-induced toxicity. To further investigate the interaction between the significantly expressed proteins, a network was created including genes and microRNAs known to interact with these proteins and this network was used to visualize the experimental data. In total 6 clusters could be distinguished which appeared to be involved in several toxicity related processes, including alteration of protein folding and secretion in the endoplasmic reticulum. Metabonomic analyses resulted in 5 differentially expressed metabolites, indicative of an altered glucose, lipid and cholesterol homeostasis which can be related to cholestasis. Single and integrative analyses of transcriptomics, proteomics and metabonomics reveal mechanisms underlying cyclosporin A-induced cholestasis demonstrating that endoplasmic reticulum stress and the unfolded protein response are important processes in drug-induced liver toxicity.
Databáze: OpenAIRE
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