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 perfluorodecanoic acid (PFDA) and ciprofibrate on the induction of hepatic toxicity and on hepatocellular proliferation in rats. In the first study, rats were first subjected to partial hepatectomy and then injected with [3H]thymidine (20 microCi/injection) at 23, 24, 25, 47, 48 and 49 h afterwards. 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 days after the last PFDA 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 significantly enhanced in both PFDA and ciprofibrate-treated groups in a dose-dependent manner. Hepatotoxicity, measured as the loss of [3H]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 ciprofibrate- and PFDA-induced cell proliferation, we conducted another study with more time points. Rats were fed 0.01% ciprofibrate or were injected 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 the early but not the later time points, whereas PFDA increased cell proliferation at most times throughout the study. This study demonstrates that PFDA and ciprofibrate do not selectively induce hepatic toxicity and that their effects on cell proliferation do not correlate with their carcinogenic or promoting activities.
Chen
H
H
Department of Nutrition and Food Science, University of Kentucky, Lexington 40506-0054.
Huang
C Y
CY
Wilson
M W
MW
Lay
L T
LT
Robertson
L W
LW
Chow
C K
CK
Glauert
H P
HP
D042962:Acyl-CoA Oxidase; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D058607:Fibric Acids; D005466:Fluorocarbons / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D003652:Decanoic Acids; D058607:Fibric Acids; D005466:Fluorocarbons; C036567:perfluorodecanoic acid; D002995:Clofibric Acid; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; C019304:ciprofibrate