EFFECT OF THE PEROXISOME PROLIFERATORS CIPROFIBRATE AND PERFLUORODECANOIC ACID ON HEPATIC CELL-PROLIFERATION AND TOXICITY IN SPRAGUE-DAWLEYRATS

The objective of this study was to compare the effects of perfluorodec anoic acid (PFDA) and ciprofibrate on the induction of hepatic toxicit y and on hepatocellular proliferation in rats. In the first study, rat s were first subjected to partial hepatectomy and then injected with [ H-3]thymidine (20 mu Ci/injection) at 23, 24, 25, 47, 48 and 49 h afte rwards. After a 2 week recovery period, rats were injected with one of four levels of PFDA (0.3, 1.0, 3.0 or 10 mg/kg/injection) in four i.p . doses every 14 days, or were fed 0.01% or 0.003% ciprofibrate. Six d ays after the last PFDA injection and three days before the animals we re killed, an osmotic minipump containing 20 mg/ml 5-bromo-2'-deoxyuri dine (BrdU) was implanted s.c, for the measurement of DNA synthesis. P eroxisomal fatty acyl-CoA oxidase activity was significantly enhanced in both PFDA and ciprofibrate-treated groups in a dose-dependent manne r. Hepatotoxicity, measured as the loss of [H-3]thymidine from hepatic DNA, was not significantly affected by any of the treatments. Hepatic DNA synthesis was Significantly increased only in rats receiving the highest dose of PFDA, In order to determine the time course of ciprofi brate- and PFDA-induced cell proliferation, we conducted another study with more time points. Rats were fed 0.01% ciprofibrate or were injec ted every 14 days with 3 or 10 mg PFDA/kg body weight for 10 days, 24 days, 6 weeks, 26 weeks or 54 weeks. Cell proliferation was quantified as in the first study. Ciprofibrate increased cell proliferation at t he early but not the later time points, whereas PFDA increased cell pr oliferation at most times throughout the study. This study demonstrate s that PFDA and ciprofibrate do not selectively induce hepatic toxicit y and that their effects on cell proliferation do not correlate with t heir carcinogenic or promoting activities.