Toxicological Sciences 57, 338-344 (2000)
Copyright © 2000 by the Society of Toxicology
Systems Toxicology |
Peroxisome Proliferator-Activated Receptor Alpha-Null Mice Lack Resistance to Acetaminophen Hepatotoxicity following Clofibrate Exposure
* Toxicology Program, Department of Pharmaceutical Sciences and
Department of Pathobiology, University of Connecticut, Storrs, Connecticut 06269–2092; and
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709–2137
The purpose of this study was to investigate whether activation of the nuclear receptor PPAR
is needed for protection from acetaminophen (APAP) hepatotoxicity produced by repeated administration of the peroxisome proliferator clofibrate (CFB). Female wild-type and PPAR-null mice received corn oil vehicle or 500 mg CFB/kg, ip, daily for 10 days. They were then fasted overnight (18 h) and either killed at 4 or 24 h after challenge with 400 mg APAP/kg. Controls received 50% propylene glycol vehicle only. In this model of CFB hepatoprotection, liver injury was assessed by measuring plasma sorbitol dehydrogenase activity and by histopathology at 24 h after APAP challenge. Significant hepatocellular necrosis was evident in both corn oil-pretreated PPAR-null and wild-type mice at 24 h after APAP challenge. In agreement with previous studies, CFB-pretreated wild-type mice showed marked protection against APAP toxicity. In contrast, CFB did not provide protection against APAP hepatotoxicity in the PPAR-null mice. Similarly, at 4 h after APAP challenge, hepatic glutathione depletion and selective arylation of cytosolic proteins were reduced significantly in CFB-pretreated wild-type mice, but not in PPAR-null mice. The lack of changes in APAP binding and NPSH depletion in CFB-pretreated, PPAR-null mice is consistent with the presence of significant liver injury at 24 h in this treatment group. These findings demonstrate that the protection against APAP hepatotoxicity by peroxisome proliferator treatment is mediated by the activation of PPAR.
Key Words: acetaminophen (APAP); hepatoprotection; hepatotoxicity; PPAR; clofibrate.
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