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© 1994 Oxford University Press

research-article

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

Russell C. Cattley, Michiyuki Kato 1, James A. Popp 2, Vonda J. Teets 2 and Karin S. Voss 3

Chemical Industry Institute of Toxicology, Research Triangle Park NC 27709, USA
1Present address: Daiichi Pharmaceutical Co. Ltd. Tokyo, Japan
2Present address: Sterling Winthrop Pharmaceutical Research Division Collegeville PA, USA
3Present address: Harvard University School of Public Health Boston, MA, USA

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.


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