Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cell proliferation and toxicity in Sprague--Dawley rats

The objective of this study was to compare the effects of perfluorodecanoicacid (PFDA) and ciprofibrate on the induction of hepatic toxicityand on hepatocellular proliferation in rats. In the first study,rats were first subjected to partial hepatectomy and then injectedwith ³H]thymidine (20 µCi/injection) at 23, 24, 25, 47,48 and 49 h afterwards. After a 2 week recovery period, ratswere injected with one of four levels of PFDA (03, 1.0, 3.0or 10 mg/kg/injection) in four i.p. doses every 14 days, orwere fed 0.01% or 0.003% ciprofibrate. Six days after the lastPFDA injection and three days before the animals were killed,an osmotic minipump containing 20 mg/ml 5-bromo-2’-deoxyuridine(BrdU) was implanted s.c for the measurement of DNA synthesis.Peroxisomal fatty acyl-CoA oxidase activity was significantlyenhanced in both PFDA and ciprofibrate-treated groups in a dose-dependentmanner. Hepatotoxicity, measured as the loss of ³H]thymldinefrom hepatic DNA, was not significantly affected by any of thetreatments. Hepatic DNA synthesis was significantly increasedonly in rats receiving the highest dose of PFDA. In order todetermine the time course of ciprofibrate- and PFDA-inducedcell proliferation, we conducted another study with more timepoints. Rats were fed 0.01% ciprofibrate or were injected every14 days with 3 or 10 mg PFDA/kg body weight for 10 days, 24days, 6 weeks, 26 weeks or 54 weeks. Cell proliferation wasquantified as in the first study. Ciprofibrate increased cellproliferation at the early but not the later time points, whereasPFDA increased cell proliferation at most times throughout thestudy. This study demonstrates that PFDA and ciprofibrate donot selectively induce hepatic toxicity and that their effectson cell proliferation do not correlate with their carcinogenicor promoting activities.