title: A gene expression signature for oxidant stress/reactive metabolites in rat liver.
abstract: 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. Many of the selected genes (e.g., aflatoxin aldehyde reductase, diaphorase, epoxide hydrolase, heme oxgenase and several glutathione transferases) are well-characterized oxidant stress/Nrf-2-responsive genes. Less than 10 other compounds co-cluster with our training and testing set compounds and these are known to generate OS/RMs as part of their mechanisms of toxicity. Using OS/RM signature gene sets, compounds previously associated with macrophage activation formed a distinct cluster separate from OS/RM and other compounds. A 69-gene set was chosen to maximally separate compounds in control, macrophage activator, peroxisome proliferator and OS/RM classes. The ease with which these 'oxidative stressor' classes can be separated indicates a role for microarray technology in early prediction and classification of hepatotoxicants. The ability to rapidly screen the oxidant stress potential of compounds may aid in avoidance of some idiosyncratic drug reactions as well as overtly toxic compounds.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ, USA. mmcmilli@prdus.jnj.com
authors.forename: Michael
authors.initials: M
authors.lastname: McMillian
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Nie
authors.forename: J Brandon
authors.initials: JB
authors.lastname: Parker
authors.forename: Angelique
authors.initials: A
authors.lastname: Leone
authors.forename: Stewart
authors.initials: S
authors.lastname: Bryant
authors.forename: Michael
authors.initials: M
authors.lastname: Kemmerer
authors.forename: Judy
authors.initials: J
authors.lastname: Herlich
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Lynn
authors.initials: L
authors.lastname: Yieh
authors.forename: Anton
authors.initials: A
authors.lastname: Bittner
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.forename: Jackson
authors.initials: J
authors.lastname: Wan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D008099:Liver / Q000502:physiology*; D016215:Macrophage-Activating Factors / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics*; D020025:Peroxisome Proliferators / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D016215:Macrophage-Activating Factors; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D020025:Peroxisome Proliferators; D015534:Trans-Activators