Immediate-early protooncogene expression and liver function following various extents of partial hepatectomy in the rat

Immediate-early protooncogenes (IEP) are thought to play an important role in hepatocyte replication. Whether the extent of their expression correlate s with the strength of the proliferative stimulus and subsequent regenerati ve activity has yet to be documented in vivo. Data are also lacking with re spect to the level at which liver disease is associated with biochemical ev idence of hepatic dysfunction. Thus, the objectives of this study were to d etermine whether a correlation exists between IEP gene mRNA expression and varying extents of partial hepatectomy (PHx) and to document the extent of resection required to result in increases in serum bilirubin levels. Eighty -nine adult, male Sprague-Dawley rats underwent either sham surgery or 20%, 35%, 55%, 70% or 90% PHx. Postoperatively, rats were killed (N = 3-6/group ) at 15 and 30 mins and 8 and 24 hrs for c-fos, c-jun, and c-myc mRNA expre ssion by northern blot analyses. Rats killed at 24 hrs also had hepatic reg enerative activity documented by [H-3]thymidine incorporation into hepatic DNA and serum bilirubin determinations. While c-fos mRNA expression at 15 m ins and c-myc mRNA expression at 8 hrs after PHx did not correlate with the extent of PHx (r(2) = 0.478 and 0.018, respectively), a weak correlation e xisted between c-jun mRNA expression at 30 mins and the extent of PHx (r(2) = 0.662, P < 0.05). In terms of IEP mRNA expression and hepatic regenerati ve activity, a strong correlation existed between c-fos mRNA expression and [H-3]thymidine incorporation (r(2) = 0.851, P < 0.01) but not c-jun or c-m yc mRNA expression. Compared to sham operated controls, [3H]thymidine incor poration was 2.0x, 3.4x, 3.2x, 7.8x, and 2.2x increased following 20%, 35%, 55%, 70%, and 90% PHx, respectively. Serum bilirubin levels remained uncha nged until 701e PHx, when they increased from baseline values of 0.54 +/- 0 .05 mg/dl to 1.02 +/- 0.15 mg/dl (P < 0.05). A further increase occurred fo llowing 90% PHx (1.83 <plus/minus> 0.30 mg/dl, P < 0.01). In conclusion the se findings indicate that c-fos mRNA expression 15 mins after PHx correlate s with hepatic regenerative activity but not the strength of the regenerati ve stimulus and that hepatic parenchymal loss of 55-70% must occur prior to the detection of elevated serum bilirubin levels. The results also indicat e that relative to a 70% PHx, 90% PHx is associated with decreased rather t han increased hepatic regenerative activity.