Use of toxicogenomics to understand mechanisms of drug-induced hepatotoxicity during drug discovery and development

被引：95
作者：
Blomme, Eric A. G. [1 ]
Yang, Yi [1 ]
Waring, Jeffrey F. [1 ]
机构：
[1] Abbott Labs, Dept Cellular Mol & Exploratory Toxicol, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA
来源：
TOXICOLOGY LETTERS | 2009年 / 186卷 / 01期
关键词：
Toxicogenomics; Hepatotoxicity; Mechanistic; Biomarker; Enzyme induction; GENE-EXPRESSION ANALYSIS; INDUCED LIVER-INJURY; IN-VITRO; INDUCED PHOSPHOLIPIDOSIS; HUMAN HEPATOCYTES; RAT-LIVER; OXIDATIVE STRESS; HEPG2; CELLS; CARBOXYLASE INHIBITORS; IDIOSYNCRATIC TOXICITY;
D O I：
10.1016/j.toxlet.2008.09.017
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
Hepatotoxicity is a common cause of failure in drug discovery and development and is also frequently the source of adverse drug reactions. Therefore, a better prediction, characterization and understanding of drug-induced hepatotoxicity could result in safer drugs and a more efficient drug discovery and development process. Among the 'omics technologies, toxicogenomics (or the use of gene expression profiling in toxicology) represents an attractive approach to predict toxicity and to gain a mechanistic understanding of toxic changes. In this review, we illustrate, using selected examples, how toxicogenomics can be applied to investigate drug-induced hepatotoxicity in animal models and in vitro systems. In general, this technology can not only improve the discipline of toxicology and risk assessment but also represent an extremely effective, hypothesis-generating alternative to rapidly understand mechanisms of hepatotoxicity. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码：22 / 31
页数：10
相关论文
共 84 条
[21]   Idiosyncratic reactions: New methods of identifying high-risk patients [J].
Glauser, TA .
EPILEPSIA, 2000, 41 :S16-S29
[22]   First dose of potential new medicines to humans: How animals help [J].
Greaves, P ;
Williams, A ;
Eve, M .
NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (03) :226-236
[23]   N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-CoA carboxylase inhibitors -: Improvement of cardiovascular and neurological liabilities via structural modifications [J].
Gu, Yu Gui ;
Weitzberg, Moshe ;
Clark, Richard F. ;
Xu, Xiangdong ;
Li, Qun ;
Lubbers, Nathan L. ;
Yang, Yi ;
Beno, David W. A. ;
Widomski, Deborah L. ;
Zhang, Tianyuan ;
Hansen, T. Matthew ;
Keyes, Robert F. ;
Waring, Jeffrey F. ;
Carroll, Sherry L. ;
Wang, Xiaojun ;
Wang, Rongqi ;
Healan-Greenberg, Christine H. ;
Blomme, Eric A. ;
Beutel, Bruce A. ;
Sham, Hing L. ;
Camp, Heidi S. .
JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (05) :1078-1082
[24]   Differences in hepatotoxicity and gene expression profiles by anti-diabetic PPARγ agonists on rat primary hepatocytes and human HepG2 cells [J].
Guo, Lei ;
Zhang, Lu ;
Sun, Yongming ;
Muskhelishvili, Levan ;
Blann, Ernice ;
Dial, Stacey ;
Shi, Leming ;
Schroth, Gary ;
Dragan, Yvonne P. .
MOLECULAR DIVERSITY, 2006, 10 (03) :349-360
[25]   Cationic amphiphilic drug-induced phospholipidosis [J].
Halliwell, WH .
TOXICOLOGIC PATHOLOGY, 1997, 25 (01) :53-60
[26]  
Hamadeh HK, 2002, TOXICOL SCI, V67, P219, DOI 10.1093/toxsci/67.2.219
[27]   Comparative hepatic toxicity: Prechronic/chronic liver toxicity in rodents [J].
Hardisty, JF ;
Brix, AE .
TOXICOLOGIC PATHOLOGY, 2005, 33 (01) :35-40
[28]   A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane x receptor [J].
Healan-Greenberg, Christine ;
Waring, Jeffrey F. ;
Kempf, Dale J. ;
Blomme, Eric A. G. ;
Tirona, Rommel G. ;
Kim, Richard B. .
DRUG METABOLISM AND DISPOSITION, 2008, 36 (03) :500-507
[29]   Forum - Mechanisms of hepatotoxicity [J].
Jaeschke, H ;
Gores, GJ ;
Cederbaum, AI ;
Hinson, JA ;
Pessayre, D ;
Lemasters, JJ .
TOXICOLOGICAL SCIENCES, 2002, 65 (02) :166-176
[30]   Acetaminophen-induced hepatotoxicity [J].
James, LP ;
Mayeux, PR ;
Hinson, JA .
DRUG METABOLISM AND DISPOSITION, 2003, 31 (12) :1499-1506
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