Age-related susceptibility to the carcinogenic effect of the peroxisome proliferator WY-14,643 in rat liver.

The carcinogenicity of the peroxisome proliferator WY-14,643 was compared in young (starting age 2 months) and old (starting age 15 months) rats. Old rats had a 5- to 7-fold higher yield of grossly visible hepatic tumors following 22 weeks of dietary WY-14,643 when compared to young rats. Volume densities of foci with large cells and homogeneously basophilic cytoplasm, cytologically similar to adenomas and carcinomas, were also higher in old rats fed WY-14,643 when compared to young rats. Although peroxisome proliferation and sustained hepatocellular proliferation have been suggested as relevant for the mechanism of WY-14,643 carcinogenicity, neither response was exaggerated in old versus young rats. Since initiation is considered to occur spontaneously and irreversibly, old rats may have a greater accumulation of spontaneously initiated hepatocytes than young rats. If so, these results are consistent with the hypothesis that the carcinogenic mechanism of the peroxisome proliferator WY-14,643 is due to the promotion of spontaneously initiated hepatocytes.