Gene Expression Profiling of Rat Livers Reveals Indicators of Potential Adverse Effects

National Center for Toxicogenomics, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709, USA.
Toxicological Sciences (Impact Factor: 3.85). 08/2004; 80(1):193-202. DOI: 10.1093/toxsci/kfh145
Source: PubMed


This study tested the hypothesis that gene expression profiling can reveal indicators of subtle injury to the liver induced by a low dose of a substance that does not cause overt toxicity as defined by conventional criteria of toxicology (e.g., abnormal clinical chemistry and histopathology). For the purpose of this study we defined this low dose as subtoxic, i.e., a dose that elicits effects which are below the detection of conventional toxicological parameters. Acetaminophen (APAP) was selected as a model hepatotoxicant because (1) considerable information exists concerning the mechanism of APAP hepatotoxicity that can occur following high doses, (2) intoxication with APAP is the leading cause of emergency room visits involving acute liver failure within the United States, and (3) conventional clinical markers have poor predictive value. Rats treated with a single dose of 0, 50, 150, or 1500 mg/kg APAP were examined at 6, 24, or 48 h after exposure for conventional toxicological parameters and for gene expression alterations. Patterns of gene expression were found which indicated cellular energy loss as a consequence of APAP toxicity. Elements of these patterns were apparent even after exposure to subtoxic doses. With increasing dose, the magnitude of changes increased and additional members of the same biological pathways were differentially expressed. The energy loss suggested by gene expression changes was confirmed at the 1500 mg/kg dose exposure by measuring ATP levels. Only by ultrastructural examination could any indication of toxicity be identified after exposure to a subtoxic dose of APAP and that was occasional mitochondrial damage. In conclusion, this study provides evidence that supports the hypothesis that gene expression profiling may be a sensitive means of identifying indicators of potential adverse effects in the absence of the occurrence of overt toxicity.

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Available from: Richard Paules, Sep 10, 2014
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    • "Importantly, under overnight fasting conditions, a significant difference in liver injury among wildtype and HCV-Tg mice was observed when 200 mg/kg of acetaminophen was administered for 24 h. The mitochondria are an early target for and a sensitive bellwether of acetaminophen-induced liver injury (Heinloth et al., 2004). Acetaminophen-induced mitochondrial dysfunction has been reported in vivo in mice (Jaeschke and Bajt, 2006), in vitro in human metabolically-active HepaRG cells (McGill et al., 2011), and in human subjects (McGill et al., 2012). "
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    • "Toxicogenomics is a relatively new tool incorporating genomics and proteomics and can prove useful in short-term drug toxicity studies because gene and protein changes can be detected before drug induced morphologic changes [15]. A study involving acetaminophen toxicity demonstrated that gene expression profiling serves as an important indicator of potential toxic effects in the absence of apparent toxicity [16]. Collection of samples for gene expression analysis is not done routinely in exploratory toxicology studies. "
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