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

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.

A gene expression signature for oxidant stress/reactive metabolites in rat liver.

Formation of free radicals and other reactive molecules is responsible for the adverse effects produced by a number of hepatotoxic compounds. cDNA microarray technology was used to compare transcriptional profiles elicited by training and testing sets of 15 oxidant stressors/reactive metabolite treatments to those produced by approximately 85 other paradigm compounds (mostly hepatotoxicants) to determine a shared signature profile for oxidant stress-associated hepatotoxicity. Initially, 100 genes were chosen that responded significantly different to oxidant stressors/reactive metabolites (OS/RM) compared to other samples in the database, then a 25-gene subset was selected by multivariate analysis.

Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver.

Macrophage activation contributes to adverse effects produced by a number of hepatotoxic compounds. Transcriptional profiles elicited by two macrophage activators, LPS and zymosan A, were compared to those produced by 100 paradigm compounds (mostly hepatotoxicants) using cDNA microarrays. Several hepatotoxicants previously reported to activate liver macrophages produced transcriptional responses similar to LPS and zymosan, and these were used to construct a gene signature profile for macrophage activators in the liver.