Drug-induced oxidative stress in rat liver from a toxicogenomics perspective

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• 作者：Michael McMillian ; Alex Nie ; J. Br ; on Parker ; Angelique Leone ; Michael Kemmerer ; Stewart Bryant ; Judy Herlich ; Lynn Yieh ; Anton Bittner ; Xuejun Liu ; Jackson Wan ; Mark D. Johnson ; Peter Lord
• 关键词：Macrophage activators ; Peroxisome proliferators ; Liver ; Reactive metabolites
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2005
• 出版时间：1 September 2005
• 年：2005
• 卷：207
• 期：2, Supplement 1
• 页码：171-178
• 全文大小：564 K

文摘

Macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) all produce oxidative stress and hepatotoxicity in rats. However, these three classes of hepatotoxicants give three distinct gene transcriptional profiles on cDNA microarrays, an indication that rat hepatocytes respond/adapt quite differently to these three classes of oxidative stressors. The differential gene responses largely reflect differential activation of transcription factors: MA activate Stat-3 and NFkB, PP activate PPARa, and OS/RM activate Nrf2. We have used gene signature profiles for each of these three classes of hepatotoxicants to categorize over 100 paradigm (and 50+ in-house proprietary) compounds as to their oxidative stress potential in rat liver. In addition to a role for microarrays in predictive toxicology, analyses of small subsets of these signature profiles, genes within a specific pathway, or even single genes often provide important insights into possible mechanisms involved in the toxicities of these compounds.