INITIATOR-SPECIFIC PROMOTION OF HEPATOCARCINOGENESIS BY WY-14,643 AND CLOFIBRATE

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-acetylaminofluorene (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.