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. 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.
McMillian
Michael
M
Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ 08869, USA. mmcmilli@prdus.jnj.com
Nie
Alex
A
Parker
J Brandon
JB
Leone
Angelique
A
Kemmerer
Michael
M
Bryant
Stewart
S
Herlich
Judy
J
Yieh
Lynn
L
Bittner
Anton
A
Liu
Xuejun
X
Wan
Jackson
J
Johnson
Mark D
MD
Lord
Peter
P
D000818:Animals; D020869:Gene Expression Profiling; D023281:Genomics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D051381:Rats; D014116:Toxicology