Title

Mitochondrial Bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity

Document Type

Journal Article

Publication Date

1-1-2008

Journal

Journal of Pharmacology and Experimental Therapeutics

Volume

324

Issue

1

DOI

10.1124/jpet.107.129445

Abstract

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 wildtype 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. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

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