Increased susceptibility of aged rats to hepatocarcinogenesis by the peroxisome proliferator nafenopin and the possible involvement of altered liver foci occurring spontaneously.

We investigated the mechanism of the hepatocarcinogenic action of nafenopin (NAF), a nongenotoxic peroxisome proliferator. Groups of male rats aged 13 wk (designated "young") or 57 wk (designated "old") were fed NAF for 13 mo; additional groups received a basal diet or a phenobarbital (PB)-containing diet as positive control. The following results were obtained. (a) NAF produced numerous hepatocellular adenomas and carcinomas in old animals but very few in young animals. A similar result, although less pronounced, was seen with PB. Adenomas of PB-treated groups mostly consisted of eosinophilic and glycogen-storing cells. However, adenomas and carcinomas of NAF-treated livers were composed of weakly basophilic cells. (b) Phenotypically altered foci, evaluated in hematoxylin:eosin-stained sections, appeared spontaneously in untreated livers. The majority of these foci was either of the eosinophilic-clear cell or the tigroid cell type. In addition, we identified foci which are characterized by weak, diffuse cytoplasmatic basophilia. Their phenotype was similar to that of adenomas and carcinomas in NAF-treated rats. The number and size of eosinophilic-clear cell and of tigroid cell foci increased considerably with the age of the animals. At the end of the experiment, approximately 2.4% of liver tissue was occupied by focal cells. NAF, but not PB, treatment led to a selective increase in number and size of weakly basophilic foci. This subtype has previously been described as a likely precursor lesion for liver tumors induced by an aflatoxin B1-NAF initiation-promotion regimen (B. Kraupp-Grasl et al., Cancer Res., 50:3701-3708, 1990). These findings suggest that the peroxisome proliferator NAF leads to tumor development in aging rat liver by promotion of spontaneously occurring preneoplastic lesions. The type of lesion appears to be different from that promotable by PB.