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TOXICOLOGY

Mitochondrial Bax Translocation Accelerates DNA Fragmentation and Cell Necrosis in a Murine Model of Acetaminophen Hepatotoxicity

Liver Research Institute, University of Arizona, Tucson, Arizona (M.L.B., H.J.); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (M.L.B., H.J.); Department of Pathology, Brackenridge Hospital, Austin, Texas (A.F.); and Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.J.L.)

Mitochondria generate reactive oxygen and peroxynitrite and release endonucleases during acetaminophen (APAP) hepatotoxicity. Because mitochondrial translocation of Bax can initiate these events, we investigated the potential role of Bax in the pathophysiology of hepatic necrosis after 300 mg/kg APAP in fasted C57BL/6 mice. APAP overdose induced Bax translocation from the cytosol to the mitochondria as early as 1 h after APAP injection. At 6 h, there was extensive centrilobular nitrotyrosine staining (indicator for peroxynitrite formation) and nuclear DNA fragmentation. In addition, mitochondrial intermembrane proteins were released into the cytosol. Plasma alanine aminotransferase (ALT) activities of 5610 ± 600 U/l indicated extensive necrotic cell death. Conversely, Bax gene knockout (Bax^–/–) mice had 80% lower ALT activities, less DNA fragmentation, and less intermembrane protein release at 6 h. However, immunohistochemical staining for nitrotyrosine or APAP protein adducts did not show differences between wild-type and Bax^–/– mice. In contrast to the early hepatoprotection in Bax^–/– mice, plasma ALT activities (7605 ± 480 U/l) and area of necrosis (53 ± 6% hepatocytes) in wild-type animals was similar to values in Bax^–/– mice at 12 h. In addition, there was no difference in DNA fragmentation or nitrotyrosine immunostaining. We concluded that the rapid mitochondrial Bax translocation after APAP overdose has no effect on peroxynitrite formation but that it contributes to the mitochondrial release of proteins, which cause nuclear DNA fragmentation. However, the persistent oxidant stress and peroxynitrite formation in mitochondria may eventually trigger the permeability transition pore opening and release intermembrane proteins independently of Bax.

Address correspondence to: Dr. Hartmut Jaeschke, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., MS 1018, Kansas City, KS 66160. E-mail: hjaeschke{at}kumc.edu

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				M. L. Bajt, H.-M. Yan, A. Farhood, and H. Jaeschke Plasminogen Activator Inhibitor-1 Limits Liver Injury and Facilitates Regeneration after Acetaminophen Overdose Toxicol. Sci., August 1, 2008; 104(2): 419 - 427. [Abstract] [Full Text] [PDF]