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

The possibility that selection of an initiating agent couldhave a significant impact on the ability to detect subsequentpromoting 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-14,643or clofibrate were each fed (0.1% of diet) for up to 37 weeks.Both WY-14,643 and clofibrate lacked promoting activity, asmeasured by increases in the volume density of homogeneous basophilicfoci and incidence or multiplicity of hepatocellular neoplasiafollowing 2-AAF initiation compared to non-initiated controls.These negative results sharply contrasted with the observedpromoting activity of dietary WY-14,643 and clofibrate followingDEN initiation. Peroxisome proliferation, measured as inductionof acyl-CoA oxidase activity, was consistently observed in peroxisomeproliferator-fed rats despite prior initiation with 2-AAF orDEN. These results suggest that detection of promoting activityfor peroxisome proliferators depends on selection of the initiatingagent.