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Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin-induced hepatotoxicity.
MedLine Citation:
PMID:  23322611     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hepatocytes are used widely as a cell model for investigation of in vitro 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, and prevention of cardiovascular disease. However, it has also been reported to cause adverse effects in liver due to cellular damage. Relatively few studies on liver toxicity have been reported and the precise mechanisms underlying simvastatin-induced hepatotoxicity remain unclear. In this study, integrated toxicoproteomic and toxicotranscriptomic analysis was performed using rat primary hepatotoxicity in order to gain insight into the first pathway map related to simvastatin-induced hepatotoxicity. For proteomic and transcriptomic analysis, rat primary hepatocytes were exposed to simvastatin at IC(20) concentration for 24 h. In particular, 2D LC-MS/MS analysis and informatics-assisted label-free strategy for proteomic analysis were applied in order to increase the number of proteins and to improve the confidence of the quantitation results. Among a total of 607 differentially expressed proteins, 61 up-regulated and 29 down-regulated proteins have been identified in the simvastatin-treated group. At the mRNA level, results of transcriptomic analysis revealed 206 up-regulated and 41 down-regulated 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 and Western blot analysis, respectively. This study will provide new insight into the potential toxic pathways induced by simvastatin. Furthermore, these studies demonstrate that integrated transcriptomic and proteomic analyses can be used in discovery of potential toxic pathways induced by various drugs.
Authors:
Young-Eun Cho; Pyong-Gon Moon; Jeong-Eun Lee; Thoudam S K Singh; Wonku Kang; Hyun-Chul Lee; Myung-Hoon Lee; Sang-Hyun Kim; Moon-Chang Baek
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-16
Journal Detail:
Title:  Proteomics     Volume:  -     ISSN:  1615-9861     ISO Abbreviation:  Proteomics     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101092707     Medline TA:  Proteomics     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Affiliation:
Department of Molecular Medicine, Cell and Matrix Biology Research Institute, School of Medicine, Kyungpook National University, Daegu, 700-422, Republic of Korea.
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