COMPARISON OF THE HEPATIC-EFFECTS OF NAFENOPIN AND WY-14,643 ON PEROXISOME PROLIFERATION AND CELL REPLICATION IN THE RAT AND SYRIAN-HAMSTER

Male Sprague-Dawley rats were fed control diet or diet containing 0.05% nafenopin (NAF) or 0.025% WY-14,643 (WY) and male Syrian hamsters were fed control diet or diet containing 0.25% NAF or 0.025% WY for periods of 1, 15, 40, and 60 weeks. Both NAF and WY produced a sustained increase in liver weight and induction of peroxisomal fatty acid beta-oxidation in the rat and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing [H-3] thymidine during weeks 0-1, 14-15, 39-40, and 59-60. Cell replication, determined either as the hepatocyte labelling index or by incorporation of radioactivity into liver whole homogenate DNA, was increased in rats given NAF and WY for 1 week. However, only WY produced a sustained increased in cell replication after 15-60 weeks. After 40 weeks, liver nodules and tumors were present in WY-treated rats, and these lesions were observed in all WY-treated and some NAF-treated rats after 60 weeks. In contrast to the rat, no marked effect on replicative DNA synthesis and no liver nodules and tumors were observed in Syrian hamsters given NAF and WY for up to 60 weeks. The rat study demonstrates that liver tumors are produced more rapidly by doses of peroxisome proliferators that produce a sustained stimulation of cell replication, whereas the hamster study suggests that species differences may exist in both peroxisome proliferator-induced cell replication and liver tumor formation.