title: Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin-induced hepatotoxicity.
abstract: Hepatocytes are used widely as a cell model for investigation of xenobiotic metabolism and the toxic mechanism of drugs. Simvastatin is the first statin drug used extensively in clinical practice for control of elevated cholesterol or hypercholesterolemia. However, it has also been reported to cause adverse effects in liver due to cellular damage. In this study, for proteomic and transcriptomic analysis, rat primary hepatocytes were exposed to simvastatin at IC20 concentration for 24 h. Among a total of 607 differentially expressed proteins, 61 upregulated and 29 downregulated proteins have been identified in the simvastatin-treated group. At the mRNA level, results of transcriptomic analysis revealed 206 upregulated and 41 downregulated genes in the simvastatin-treated group. Based on results of transcriptomic and proteomic analysis, NRF2-mediated oxidative stress response, xenobiotics by metabolism of cytochrome P450, fatty acid metabolism, bile metabolism, and urea cycle and inflammation metabolism pathways were focused using IPA software. Genes (FASN, UGT2B, ALDH1A1, CYP1A2, GSTA2, HAP90, IL-6, IL-1, FABP4, and ABC11) and proteins (FASN, CYP2D1, UG2TB, ALDH1A1, GSTA2, HSP90, FABP4, and ABCB11) related to several important pathways were confirmed by real-time PCR andWestern blot analysis, respectively. This study will provide new insight into the potential toxic pathways induced by simvastatin.
authors: Department of Molecular Medicine, Cell and Matrix Biology Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors: Young-Eun
authors: YE
authors: Cho
authors: Pyong-Gon
authors: PG
authors: Moon
authors: Jeong-Eun
authors: JE
authors: Lee
authors: Thoudam S K
authors: TS
authors: Singh
authors: Wonku
authors: W
authors: Kang
authors: Hyun-Chul
authors: HC
authors: Lee
authors: Myung-Hoon
authors: MH
authors: Lee
authors: Sang-Hyun
authors: SH
authors: Kim
authors: Moon-Chang
authors: MC
authors: Baek
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002853:Chromatography, Liquid / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006505:Hepatitis / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D019821:Simvastatin / Q000009:adverse effects* / Q000633:toxicity; D012984:Software; D014508:Urea / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011506:Proteins; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin