Timing of protooncogene expression varies in toxin‐induced liver regeneration

Abstract

Hepatic expression of the protooncogenes c-fos and c-myc occurs within 2 h after partial hepatectomy, and these immediate early genes are thought to prime the hepatocytes for subsequent proliferation. To examine whether such gene activation occurred in the setting of hepatocyte proliferation after toxic liver injury, protooncogene expression was examined during the regenerative response following liver injury from carbon tetrachloride (CCl4) or galactosamine (GalN). The pattern of protooncogene expression after CCl4 mirrored that seen after partial hepatectomy, with rises in c-fos and c-myc mRNA content within 2 h, and then a rapid return to baseline levels. In contrast, early c-fos and c-myc expression did not occur after GalN injury. Instead GalN-induced regeneration led to a delayed, and prolonged c-fos and c-myc activation which peaked 24-48 h after injury. Increases in c-jun, jun-B, and jun-D mRNA levels also occurred in both models at times similar to the rises of c-fos and c-myc expression. Although the timing of DNA synthesis was identical after GalN or CCl4 treatment, the proliferative response after GalN injury was significantly less than that of CCl4, and marked by the histologic appearance of oval cells. The coadministration of 2-acetylaminofluorene, an inhibitor of differentiated hepatocyte proliferation, together with CCl4 altered the usual pattern of post-CCl4 protooncogene expression to one resembling that seen after GalN injury. Thus, the timing of protooncogene expression during liver regeneration may vary considerably. These variations may influence the nature of the proliferative response in terms of which cell type(s) proliferates, and the amount of regeneration that ensues.

Identification of Differentially Expressed Genes in Hepatic HepG2 Cells Treated with Acetaminophen Using Suppression Subtractive Hybridization

“…30,31) Increased expression of c-myc was observed in a variety of hepatotoxin-treated animals and cells, including APAP-treated animals. 11,12,32,33) Since the translation of c-myc mRNA is regulated by the interaction with thymidylate synthase, the decreased expression of thymidylate synthase due to APAPtreatment would lead to increased translation of c-myc mRNA. Although the mechanism of inhibition of thymidylate synthase expression by APAP is unknown, the decreased expression of thymidylate synthase may be involved in APAP-induced hepatotoxicity.…”

Inhibition of c-Myc Expression Sensitizes Hepatocytes to Tumor Necrosis Factor-induced Apoptosis and Necrosis

“…Previous investigations in nonhepatic cells have consistently reported that increased c-Myc expression initiates or promotes TNFinduced apoptosis (24 -27). However, in TNF-dependent liver injury in vivo induced by the toxin galactosamine (6), TNF induces hepatocyte injury and death associated with a block in the up-regulation of c-myc mRNA expression that normally occurs during a hepatic proliferative response (28). These findings suggested that hepatocytes may undergo TNF-induced death in the absence of c-Myc expression or even become sensitized to TNF toxicity by a failure to up-regulate c-Myc.…”

Liver Injury Models for Induction of Hepatic Oval Cells in Rodents

“…Cellular injury does not guarantee oval cell proliferation [94]. The site of injury within the liver (centri-lobular vs peri-portal) influences the time taken and magnitude of oval cell response.…”

“…GaIN is administered intra-peritoneally as a single dose to rats between 50-140mg per 100g body weight. Maximal oval cell proliferation is seen between 2-5 days [94,111,112] and oval cells disappeared 7-10 days after the injection [113,114]. GaIN can also be given 2 weeks after retrorsine, a tumorigenic pyrrolizidine alkaloid, to generate greater numbers of oval cells [115].…”

“…Similar to APAP, CCl 4 preferentially damages the centri-lobular region [92]. Studies in rats have found that CCl4 alone cannot generate an oval cell response [94,114,129,130] although the converse has been reported [131]. In mice, few A6 positive oval cells were seen after chronic CCl4 exposure [130].…”