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

Nicoud IB, Knox CD, Jones CM, Anderson CD, Pierce JM, Belous AE, Earl TM, Chari RS
Am J Physiol Gastrointest Liver Physiol. 2007 293 (3): G623-30

PMID: 17627971 · DOI:10.1152/ajpgi.00521.2006

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 Ca(2+) overload plays a central role. We have previously defined a novel pathway for mitochondrial Ca(2+) handling and now further characterize this pathway and investigate a novel Ca(2+)-channel inhibitor, 2-aminoethoxydiphenyl borate (2-APB), for preventing hepatic I/R injury. The effect of 2-APB on cellular and mitochondrial Ca(2+) uptake was evaluated in vitro by using (45)Ca(2+). 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 Ca(2+) uptake in isolated liver mitochondria and reduced cellular Ca(2+) 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 Ca(2+) uptake and subsequent mitochondrial Ca(2+) 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.

MeSH Terms (25)

Alanine Transaminase Animals Aspartate Aminotransferases Boron Compounds Calcium Calcium Channel Blockers Calcium Radioisotopes Cell Death Cell Line, Tumor Cytochromes c Disease Models, Animal Dose-Response Relationship, Drug Humans L-Lactate Dehydrogenase Liver Male Mitochondria, Liver Mitochondrial Membranes Permeability Rats Rats, Sprague-Dawley Recombinant Fusion Proteins Reperfusion Injury Time Factors Transfection

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