Response of hepatocytes transplanted into syngeneic hosts and heterotransplanted into athymic nude mice to peroxisome proliferators.

The development of a transplantation system by which rat hepatocytes can be implanted and remain viable in the dorsal fascia of two-thirds hepatectomized syngeneic hosts provides an opportunity to examine whether such transplanted hepatocytes retain the capacity to recognize and respond to the peroxisome proliferators 2-[4-(2,2- dichlorocyclopropyl )phenoxy]-2- methylpropionic acid (ciprofibrate), a hypolipidemic drug, and di-(2-ethylhexyl)phthalate (DEHP), an industrial plasticizer. Male F344 rats with transplanted rat hepatocytes were fed a control diet or a diet containing either 0.05% ciprofibrate (w/w) or 2% DEHP (v/w). After 4 weeks, the animals were sacrificed, and transplanted hepatocytes revealed a significant increase in the numerical density of peroxisomes in both ciprofibrate- and DEHP-fed rats. The volume density of peroxisomes in transplanted hepatocytes increased 9.2- and 5.3-fold, respectively, in ciprofibrate- and DEHP-fed rats, whereas the volume density of mitochondria remained essentially unchanged. The magnitude of increase in peroxisome volume density in transplanted hepatocytes was comparable to increases in the volume density of these organelles in the liver parenchymal cells of syngeneic hosts. The present study also demonstrates that hepatocytes isolated from cat liver and heterotransplanted into partially hepatectomized athymic nude mice retain their biological integrity and respond to the peroxisome proliferative effect of ciprofibrate. This observation suggests the possibility that hepatocytes obtained from small segments of liver of humans, primates, and other species and heterotransplanted into nude mice might provide a valuable model system for toxicological evaluation of chemicals. These studies suggest that hepatocytes, irrespective of their location in the body, recognize the peroxisome proliferator or its active metabolite(s), which stimulates the expression of peroxisome-specific genes in these cells.