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 [3H]
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.