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-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.
Cattley
R C
RC
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Kato
M
M
Popp
J A
JA
Teets
V J
VJ
Voss
K S
KS
D015073:2-Acetylaminofluorene; D000818:Animals; D002994:Clofibrate / Q000633:toxicity*; D004052:Diethylnitrosamine; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D011743:Pyrimidines; D004052:Diethylnitrosamine; C006253:pirinixic acid; D015073:2-Acetylaminofluorene; D002994:Clofibrate