Initiator-specific promotion of hepatocarcinogenesis by WY-14,643 and clofibrate

Abstract

The possibility that selection of an initiating agent could have a significant impact on the ability to detect subsequent promoting activity of peroxisome proliferators was examined. Initiation was achieved by established methods using 2-acetyl-aminofluorene (2-AAF: 0.02% in diet for 8 weeks) or diethylnitrosamine (DEN; 150 mg/kg body wt by single i.p. injection) in male F344 rats. Following initiation, the peroxisome proliferators WY-14,643 or clofibrate were each fed (0.1% of diet) for up to 37 weeks. Both WY-14,643 and clofibrate lacked promoting activity, as measured by increases in the volume density of homogeneous basophilic foci and incidence or multiplicity of hepatocellular neoplasia following 2-AAF initiation compared to non-initiated controls. These negative results sharply contrasted with the observed promoting activity of dietary WY-14,643 and clofibrate following DEN initiation. Peroxisome proliferation, measured as induction of acyl-CoA oxidase activity, was consistently observed in peroxisome proliferator-fed rats despite prior initiation with 2-AAF or DEN. These results suggest that detection of promoting activity for peroxisome proliferators depends on selection of the initiating agent.

Involvement of PPARα and PPARγ in apoptosis and proliferation of human hepatocarcinoma HepG2 cells

“…Fibrate derivatives include agents that have been and still are widely used as hypolipidemic drugs, thanks to their ability to lower plasma triglyceride levels by accelerating mitochondrial fatty acid β‐oxidation through PPARα activation 5. Their administration to rats and mice causes peroxisome proliferation, liver hypertrophy and hyperplasia, and hepatocarcinogenesis;6, 7 thus fibric acid derivatives, such as clofibrate, have been widely employed in hepatocarcinogenesis protocols for rodents,8–10 in which its antiapoptotic action is assumed to play an importantrole. On the contrary, monkeys, pigs, and humans appear quite resistant to such effects 11–13.…”

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

“…The mechanism of rodent liver tumor promotion by PPs is unclear, and it is likely that peroxisome proliferation is either incidental or not the sole causative factor (23)(24)(25). Mounting evidence suggests that PPs have growth regulatory activities that are independent of peroxisome proliferation (26,27) and that differentially affect preneoplastic liver cells versus normal hepatocytes (28 -30).…”

Peroxisome Proliferators Activate Extracellular Signal-regulated Kinases in Immortalized Mouse Liver Cells

“…In rodents, PPs are nongenotoxic hepatocarcinogens (1); however, their mechanism of carcinogenesis is unclear. Evidence suggests that PPs possess growth-modulatory activities that are independent of peroxisome proliferation (2)(3)(4), and their role as tumor promoters is emerging (5,6). A mechanism for tumor promotion may involve the ability of the PPS to regulate liver cell replication in vivo (2,3,7), which could enhance the growth of spontaneously initiated cells.…”