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Updated: Jul 26, 2026
Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen
Published on: November 27, 2019
Expression profiling of acetaminophen liver toxicity in mice using microarray technology
T P Reilly1, M Bourdi, J N Brady
1Molecular and Cellular Toxicology Section, National Institutes of Health, Bethesda, Maryland, USA. ReillyT@nhlbi.nih.gov
Abstract:
Drug-induced hepatotoxicity causes significant morbidity and mortality and is a major concern in drug development. This is due, in large part, to insufficient knowledge of the mechanism(s) of drug-induced liver injury. In order to address this problem, we have evaluated the modulation of gene expression within the livers of mice treated with a hepatotoxic dose of acetaminophen (APAP) using high-density oligonucleotide microarrays capable of determining the expression profile of >11,000 genes and expressed sequence tags (ESTs). Significant alterations in gene expression, both positive and negative, were noted within the livers of APAP-treated mice. APAP-induced toxicity affected numerous aspects of liver physiology causing, for instance, >twofold increased expression of genes that encode for growth arrest and cell cycle regulatory proteins, stress-induced proteins, the transcription factor LRG-21, suppressor of cytokine signaling (SOCS)-2-protein, and plasminogen activator inhibitor-1 (PAI-1). A number of these and other genes and ESTs were detectable within the liver only after APAP treatment suggesting their potential importance in propagating or preventing further toxicity. These data provide new directions for mechanistic studies that may lead to a better understanding of the molecular basis of drug-induced liver injury and, ultimately, to a more rational design of safer drugs.
Insights
Acetaminophen (APAP) liver injury was studied by analyzing gene expression changes in mice. This research reveals key molecular pathways involved in drug-induced liver injury, aiding safer drug development.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- Drug-induced hepatotoxicity is a significant concern in drug development.
- Understanding the mechanisms of drug-induced liver injury (DILI) is crucial.
- Current knowledge of DILI mechanisms is insufficient.
Purpose of the Study:
- To investigate gene expression modulation in mouse livers following acetaminophen (APAP) administration.
- To identify genes and expressed sequence tags (ESTs) involved in APAP-induced liver injury.
- To provide insights into the molecular basis of DILI for safer drug design.
Main Methods:
- High-density oligonucleotide microarrays were used to analyze gene expression profiles.
- Over 11,000 genes and ESTs were evaluated in mouse liver tissue.
- Mice were treated with a hepatotoxic dose of acetaminophen (APAP).
Main Results:
- Significant alterations in gene expression were observed in APAP-treated mouse livers.
- Increased expression of genes related to growth arrest, cell cycle regulation, and stress responses was noted.
- Specific genes and ESTs, including LRG-21, SOCS-2, and PAI-1, were identified as potentially important in APAP toxicity.
Conclusions:
- Acetaminophen (APAP) significantly alters liver gene expression, impacting various physiological processes.
- The study identified novel genes and ESTs potentially involved in the propagation or prevention of drug-induced liver injury.
- These findings offer new directions for mechanistic studies to improve drug safety and design.
