Gj. Gordon et al., Bax-mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury, HEPATOLOGY, 32(2), 2000, pp. 312-320
Retrorsine is a member of the pyrrolizidine alkaloid family of compounds wh
ose toxic effects on the liver include a long-lasting inhibition of the pro
liferative capacity of hepatocytes. Despite the retrorsine-induced blockade
of hepatocyte proliferation, retrorsine-exposed rats are able to reconstit
ute completely their liver mass after surgical partial hepatectomy (PH) via
the sustained proliferation of a population of small, incompletely differe
ntiated hepatocyte-like progenitor cells (SHPCs). The extensive proliferati
on of SHPCs in retrorsine-injured livers is accompanied by the progressive
loss of irreversibly injured megalocytes. To study the mechanism by which r
etrorsine-damaged hepatocytes are removed after PH, we performed TUNEL anal
ysis to establish apoptotic indices for hepatocytes in the livers of retror
sine-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 el
evated (approximately 1%) over control rats (<0.1%) at 14 days post-PH (P <
.05), After PH, levels of the proapoptotic protein Bax are increased in li
vers from retrorsine-exposed rats relative to the levels observed in contro
l livers. Similarly, levels of the antiapoptotic protein Bcl-x(L) are signi
ficantly decreased (P < .05) compared with controls at t = 0 resulting in a
n increased (approximately 3.4-fold) Bax/Bcl-x protein ratio that is signif
icantly elevated (P < .05) compared with controls. Finally, increased level
s of Bax protein are localized to the mitochondria of retrorsine-exposed ra
t livers after PH during the same time that cytochrome c is released. These
observations combine to suggest that retrorsine-injured hepatocytes are re
moved after PH via apoptotic pathways dependent on relative levels and loca
lization of Bax and Bcl-xL protein.