Effect of ciprofibrate on fibrinogen synthesis in vitro on hepatoma cells and in vivo in genetically obese Zucker rats.
In this study, we have shown that oncostatin M and interleukin-6 induce a dose- and time-dependent increase in fibrinogen levels in the conditioned medium of human hepatoma cells (HepG2). When HepG2 cells were treated simultaneously with oncostatin M or interleukin-6 and ciprofibrate (100 nmol/l), the production of fibrinogen in the conditioned media was strongly affected and a significant decrease in the mRNA levels of the fibrinogen beta chain was observed. Oncostatin-M- and interleukin-6-induced fibrinogen release was inhibited in a dose-dependent manner by ciprofibrate and, to lesser extent, by bezafibrate, fenofibric acid and clofibric acid. In vivo, increased plasma and platelet levels of fibrinogen were observed in genetically obese Zucker rats (fa/fa) compared with Zucker lean (fa/-) rats. In these rats, a 14-day oral treatment with ciprofibrate (10 mg/kg, per. os.) induced a statistically significant decrease (P > 0.05) in plasma concentrations of total cholesterol and triglyceride but also in plasma and platelet levels of fibrinogen. In order to determine the consequences of such an effect on fibrinogen, the ability of ciprofibrate to affect venous stasis was determined in a stasis-induced venous thrombosis model in Zucker rats. Under low thrombogenic challenge, ciprofibrate significantly inhibited thrombus formation (67+/-12%, P > 0.05), demonstrating for the first time that a potent hypolipemic compound exhibits an antithrombotic effect.
Herbert
J M
JM
Department, Sanofi Recherche, Toulouse, France. jean-marc.herbert@sanofi.com
Bernat
A
A
Chatenet-Duchène
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D058607:Fibric Acids; D005340:Fibrinogen / Q000096:biosynthesis*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D058607:Fibric Acids; D000960:Hypolipidemic Agents; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D053683:Oncostatin M; D002995:Clofibric Acid; D005340:Fibrinogen; C019304:ciprofibrate