Biological potential of basophilic hepatocellular foci and hepatic adenoma induced by the peroxisome proliferator, Wy-14,643.

The biological potential of hepatic foci and tumors induced by peroxisome proliferators such as Wy-14,643 has been poorly characterized. In this study, male F-344 rats (n = 20/group/time point) were fed Wy-14,643 (0.1%) for 22, 37 or 52 weeks ('W-22', 'W-37' or 'W-52' respectively). At each time point some rats were killed and additional Wy-14,643-fed rats were switched to basal diet (Wy-14,643/'stopped') for up to 104 weeks (referred to as 'W-22/S', 'W-37/S' and 'W-52/S'). Homogeneous basophilic foci, but not clear cell foci, increased in number and size in W-37 and W-52 rats. In W-37/S rats, clear cell foci replaced basophilic foci as the most frequent phenotype. In serial section overlays, adenosine triphosphatase deficient foci accounted for only 16% of basophilic foci in W-52 rats and 16% of clear cell foci in W-37/S rats at 52 weeks. The replication of basophilic foci of W-37 rats was markedly increased (focal labeling index, FLI = 61.8% versus non-focal labeling index, LI = 11.4%; control LI = 0.8%). Clear cell foci from W-37/S rats at 52 weeks had a FLI of 1.6% (non-focal LI = 0.6%). Hepatocellular adenomas were increased in W-37 (11/20 rats and 0.8 tumors/rat) and W-52 groups (19/20 rats and 2.8 tumors/rat). Prevalence of hepatocellular carcinomas was elevated in W-52 rats (6/20 rats) but not in W-22 or W-37 rats. Following removal of Wy-14,643, prevalence of animals with malignant, metastatic hepatocellular carcinomas in W-52/S rats was similar to the prevalence in W-52 rats. However, Wy-14,643-induced adenomas completely regressed in W-37/S and W-52/S groups. In summary, significant morphological continuity between highly proliferative basophilic foci and hepatocellular tumors was identified, emphasizing the superiority of basophilia as a marker for lesions leading to development of hepatocellular neoplasia in rats fed Wy-14,643. An important biological distinction was noted between regressive hepatic adenomas and progressive hepatocellular carcinomas induced by a peroxisome proliferator.