ToxSci Advance Access published online on December 15, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi065
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1 Liver Research Institute, University of Arizona, Tucson, AZ 85737
* To whom correspondence should be addressed. DNA fragmentation in hepatocytes occurs early after acetaminophen (AAP) overdose in mice. DNA strandbreaks can induce excessive activation of poly(ADP-ribose) polymerases (PARP), which may lead to oncotic necrosis. Based on controversial findings with chemical PARP inhibitors, the role of PARP-1 activation in AAP hepatotoxicity remains unclear. To investigate PARP-1 activation and evaluate a pathophysiological role of PARP-1, we used both PARP inhibitors (3-aminobenzamide; 5-aminoisoquinolinone) and PARP gene knock-out mice (PARP-/-). Treatment of C3Heb/FeJ mice with 300 mg/kg AAP resulted in DNA fragmentation and ALT release as early as 3 h with further increase of these parameters up to 12 h. Few nuclei of hepatocytes stained positive for poly-ADP-ribosylated nuclear proteins (PAR) as indicator for PARP-1 activation at 4.5 h. However, the number of PAR-positive cells and staining intensity increased substantially at 6 and 12 h. Pretreatment with 500 mg/kg 3-aminobenzamide before AAP attenuated hepatic glutathione depletion and completely eliminated DNA fragmentation and liver injury. Delayed treatment several hours after AAP was still partially protective. On the other hand, liver injury was not attenuated in PARP-/- mice compared to wildtype animals. Similarly, the specific PARP-1 inhibitor 5-aminoisoquinolinone (5 mg/kg) was not protective. However, 3-aminobenzamide attenuated liver injury in WT and PARP-/- mice. Conclusion: PARP-1 activation is a consequence of DNA fragmentation after AAP overdose. However, PARP-1 activation is not a relevant event for AAP-induced oncotic necrosis. The protection of 3-aminobenzamide against AAP-induced liver injury was due to reduced metabolic activation and potentially its antioxidant effect but independent of PARP-1 inhibition.
Received October 19, 2004
Accepted December 2, 2004
Systems Toxicology
Pathophysiological Role of Poly(ADP-Ribose) Polymerase (PARP) Activation During Acetaminophen-Induced Liver Cell Necrosis in Mice
2 Department of Medicine, Medical University of Graz, Graz, Austria
3 Department of Pathology, Medical University of Graz, Graz, Austria
4 Department of Pathology, University of Texas Health Science Center, Houston, TX
Hartmut Jaeschke, E-mail: jaeschke{at}email.arizona.edu
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