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Title: Gene expression profiles of murine fatty liver induced by the administration of valproic acid

Abstract

Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, we profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 h after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 h with low-dose and at 24 h and 72 h with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P < 0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff > 1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biologicalmore » pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.« less

Authors:
 [1];  [2];  [1];  [2];  [3];  [2];  [1];  [2];  [3];  [2];  [4];  [2];  [5];  [2];  [6];  [2];  [7];  [2];  [7];  [2] more »;  [8] « less
  1. College of Pharmacy (Korea, Republic of)
  2. (Korea, Republic of)
  3. Seoul National University Biomedical Informatics College of Medicine (Korea, Republic of)
  4. Department of Veterinary Public Health College of Veterinary Medicine, Seoul National University, Seoul 151-742 (Korea, Republic of)
  5. Department of Biochemistry College of Medicine, Ewha Womans University, Seoul 158-710 (Korea, Republic of)
  6. School of Veterinary Medicine, Kangwon National University, Kangwon 200-701 (Korea, Republic of)
  7. Department of Pathology College of Medicine (Korea, Republic of)
  8. College of Pharmacy (Korea, Republic of) and Bio-MAX Institute (Korea, Republic of) and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 (Korea, Republic of). E-mail: molee@snu.ac.kr
Publication Date:
OSTI Identifier:
20976897
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 220; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.12.016; PII: S0041-008X(06)00487-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; ANTICONVULSANTS; BIOLOGICAL PATHWAYS; BIOSYNTHESIS; CATABOLISM; CHOLESTEROL; DATA ANALYSIS; DOSES; GENES; ION CYCLOTRON-RESONANCE; LIVER; MICE; NECROSIS; PATTERN RECOGNITION; SYMPTOMS; TRIGLYCERIDES

Citation Formats

Lee, Min-Ho, Bio-MAX Institute, Hong, Il, Bio-MAX Institute, Kim, Mingoo, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Lee, Byung Hoon, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kim, Ju-Han, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kang, Kyung-Sun, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kim, Hyung-Lae, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Yoon, Byung-Il, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Chung, Heekyoung, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kong, Gu, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, and Lee, Mi-Ock. Gene expression profiles of murine fatty liver induced by the administration of valproic acid. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.12.016.
Lee, Min-Ho, Bio-MAX Institute, Hong, Il, Bio-MAX Institute, Kim, Mingoo, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Lee, Byung Hoon, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kim, Ju-Han, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kang, Kyung-Sun, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kim, Hyung-Lae, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Yoon, Byung-Il, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Chung, Heekyoung, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kong, Gu, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, & Lee, Mi-Ock. Gene expression profiles of murine fatty liver induced by the administration of valproic acid. United States. doi:10.1016/j.taap.2006.12.016.
Lee, Min-Ho, Bio-MAX Institute, Hong, Il, Bio-MAX Institute, Kim, Mingoo, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Lee, Byung Hoon, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kim, Ju-Han, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kang, Kyung-Sun, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kim, Hyung-Lae, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Yoon, Byung-Il, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Chung, Heekyoung, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, Kong, Gu, Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791, and Lee, Mi-Ock. Sun . "Gene expression profiles of murine fatty liver induced by the administration of valproic acid". United States. doi:10.1016/j.taap.2006.12.016.
@article{osti_20976897,
title = {Gene expression profiles of murine fatty liver induced by the administration of valproic acid},
author = {Lee, Min-Ho and Bio-MAX Institute and Hong, Il and Bio-MAX Institute and Kim, Mingoo and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Lee, Byung Hoon and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Kim, Ju-Han and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Kang, Kyung-Sun and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Kim, Hyung-Lae and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Yoon, Byung-Il and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Chung, Heekyoung and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Kong, Gu and Toxicogenomics Research Consortium, Hanyang University, Seoul 133-791 and Lee, Mi-Ock},
abstractNote = {Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, we profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 h after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 h with low-dose and at 24 h and 72 h with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P < 0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff > 1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biological pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.},
doi = {10.1016/j.taap.2006.12.016},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 220,
place = {United States},
year = {Sun Apr 01 00:00:00 EDT 2007},
month = {Sun Apr 01 00:00:00 EDT 2007}
}