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We have previously defined a novel pathway for mitochondrial Ca<jats:sup>2+<\/jats:sup> handling and now further characterize this pathway and investigate a novel Ca<jats:sup>2+<\/jats:sup>-channel inhibitor, 2-aminoethoxydiphenyl borate (2-APB), for preventing hepatic I\/R injury. The effect of 2-APB on cellular and mitochondrial Ca<jats:sup>2+<\/jats:sup> uptake was evaluated in vitro by using <jats:sup>45<\/jats:sup>Ca<jats:sup>2+<\/jats:sup>. 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<jats:sup>2+<\/jats:sup> uptake in isolated liver mitochondria and reduced cellular Ca<jats:sup>2+<\/jats:sup> 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<jats:sup>2+<\/jats:sup> uptake and subsequent mitochondrial Ca<jats:sup>2+<\/jats:sup> 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. <\/jats:p>","DOI":"10.1152\/ajpgi.00521.2006","type":"journal-article","created":{"date-parts":[[2007,7,13]],"date-time":"2007-07-13T01:02:00Z","timestamp":1184288520000},"page":"G623-G630","source":"Crossref","is-referenced-by-count":43,"title":["2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake"],"prefix":"10.1152","volume":"293","author":[{"given":"I. B.","family":"Nicoud","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. D.","family":"Knox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. 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