Bax-mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury

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Abstract
Retrorsine is a member of the pyrrolizidine alkaloid family of compounds whose toxic effects on the liver include a long-lasting inhibition of the proliferative capacity of hepatocytes. Despite the retrorsine-induced blockade of hepatocyte proliferation, retrorsine-exposed rats are able to reconstitute completely their liver mass after surgical partial hepatectomy (PH) via the sustained proliferation of a population of small, incompletely differentiated hepatocyte-like progenitor cells (SHPCs). The extensive proliferation of SHPCs in retrorsine-injured livers is accompanied by the progressive loss of irreversibly injured megalocytes. To study the mechanism by which retrorsine-damaged hepatocytes are removed after PH, we performed TUNEL analysis to establish apoptotic indices for hepatocytes in the livers of retrorsine-exposed and control rats up to 14 days post-PH. Apoptotic indices are highest (approximately 6.0%) in the livers of retrorsine-exposed rats at 1 day post-PH, gradually declining thereafter, yet remaining significantly elevated (approximately 1%) over control rats (P < .05). After PH, levels of the proapoptotic protein Bax are increased in livers from retrorsine-exposed rats relative to the levels observed in control livers. Similarly, levels of the antiapoptotic protein Bcl-xL are significantly decreased (P < .05) compared with controls at t = 0 resulting in an increased (approximately 3.5-fold) Bax/Bcl-x protein ratio that is significantly elevated (P < .05) compared with controls. Finally, increased levels of Bax protein are localized to the mitochondria of retrorsine-exposed rat livers after PH during the same time that cytochrome c is released. These observations combine to suggest that retrorsine-injured hepatocytes are removed after PH via apoptotic pathways dependent on relative levels and localization of Bax and Bcl-xL protein.