Effect of the peroxisome proliferator LY171883 on hepatocellular replication in female B6C3F1 mice

LY171883 was shown to increase the incidence of hepatocellular carcinomas and other proliferative lesions in female B6C3F1 mice. This appeared to be unrelated to the induction of peroxisomal β-oxidation. Experiments were conducted to determine the effect of dietary LY171883 for 7 or 94 days on hepatocellular replication using continuous 7-day infusion of bromodeoxyuridine. LY171883 caused a dose-related increase in hepatocyte replication during the first 7 days, with statistical significance in the two higher dose groups. There was no effect on hepatocyte replication after 94 days of treatment. Liver weight and peroxisomal β-oxidation were incerased in the two higher dose groups after 7 and 94 days, indicating there was not a general loss of hepatic responsiveness to LY171883. The data indicate that the hepatocarcinogenesis of LY171883 in female B6C3F1 mice is not associated with sustained replication in the general population of hepatocytes. It is possible that a mitogenic effect of LY171883 exerted on spontaneously initiated cells is involved in the development of the proliferative lesions; however, further work is needed to determine this.