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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/G623    most recent 00521.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Nicoud, I. B. Articles by Chari, R. S. Search for Related Content PubMed PubMed Citation Articles by Nicoud, I. B. Articles by Chari, R. S.

LIVER AND BILIARY TRACT

2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake

¹Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, and ²Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee

Submitted 7 November 2006 ; accepted in final form 9 July 2007

Ischemia-reperfusion (I/R) injury is a commonly encountered clinical problem in liver surgery and transplantation. The pathogenesis of I/R injury is multifactorial, but mitochondrial Ca²⁺ overload plays a central role. We have previously defined a novel pathway for mitochondrial Ca²⁺ handling and now further characterize this pathway and investigate a novel Ca²⁺-channel inhibitor, 2-aminoethoxydiphenyl borate (2-APB), for preventing hepatic I/R injury. The effect of 2-APB on cellular and mitochondrial Ca²⁺ uptake was evaluated in vitro by using ⁴⁵Ca²⁺. Subsequently, 2-APB (2 mg/kg) or vehicle was injected into the portal vein of anesthetized rats either before or following 1 h of inflow occlusion to 70% of the liver. After 3 h of reperfusion, liver injury was assessed enzymatically and histologically. Hep G2 cells transfected with green fluorescent protein-tagged cytochrome c were used to evaluate mitochondrial permeability. 2-APB dose-dependently blocked Ca²⁺ uptake in isolated liver mitochondria and reduced cellular Ca²⁺ accumulation in Hep G2 cells. In vivo I/R increased liver enzymes 10-fold, and 2-APB prevented this when administered pre- or postischemia. 2-APB significantly reduced cellular damage determined by hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining of liver tissue. In vitro I/R caused a dissociation between cytochrome c and mitochondria in Hep G2 cells that was prevented by administration of 2-APB. These data further establish the role of cellular Ca²⁺ uptake and subsequent mitochondrial Ca²⁺ overload in I/R injury and identify 2-APB as a novel pharmacological inhibitor of liver I/R injury even when administered following a prolonged ischemic insult.

aminotransferase; terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling; mitochondria