thioacetamide and pirinixic-acid

Oxidative stress is a major pathogenetic factor in hepatic fibrosis. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor which is known to affect oxidative stress and PPARalpha ligands may have rescue effects on hepatic fibrosis. We tested this hypothesis using rat thioacetamide (TAA) models of liver cirrhosis. Rats were given intraperitoneal injection of TAA and treated with a diet containing one of the two PPARalpha ligands, Wy-14,643 (WY) or fenofibrate. WY treatment dramatically reduced hepatic fibrosis and also prevented the inhibition catalase of mRNA expression caused by TAA. Correspondingly, catalase activity increased in the TAA+WY group but decreased in the control TAA group. The antifibrotic action of fenofibrate in the TAA model was comparable with that of WY. PPARalpha ligands have an antifibrotic action in the rat TAA model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver.

Topics: Animals; Antioxidants; Blotting, Northern; Catalase; Densitometry; Fenofibrate; Fibrosis; Hydrogen Peroxide; Ligands; Liver; Liver Cirrhosis; Male; Models, Biological; Oxidative Stress; Peroxisome Proliferators; PPAR alpha; Pyrimidines; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Superoxide Dismutase; Thioacetamide

Cholesterol levels in plasma and different tissues were determined in Sprague-Dawley male rats, on standard and cholesterol-cholic acid enriched diets, after short term treatment with the absorbable hypolipidemic agents, clofibrate, WY-14,643 and Pirinixil (BR 931). The objective of the study was to evaluate the mode of action of these drugs in decreasing plasma cholesterol, be it by increased tissue mobilization, or by redistribution from plasma to tissues. After one or two weeks on a standard diet, none of the three agents significantly affected total body cholesterol stores. In spite of the liver enlargement induced by all three, in no case was total liver cholesterol significantly raised. Only clofibrate significantly increased colonic cholesterol concentrations. On a cholesterol-cholic acid regimen, some cholesterol mobilization was noted with all three drugs. However, only Pirinixil significantly reduced total liver cholesterol as well as the estimated total body cholesterol. A parallel effect of diet and drugs on plasma and body cholesterol pools is not constantly observed. In the examined rat model, clofibrate and two chemically unrelated compounds with a probably similar mechanism of action, markedly reduce plasma cholesterol levels while not affecting or decreasing total body cholesterol stores.

Topics: Animals; Anticholesteremic Agents; Aorta; Cholesterol; Cholesterol, Dietary; Clofibrate; Drug Evaluation, Preclinical; Intestinal Mucosa; Kidney; Liver; Lung; Male; Myocardium; Pyrimidines; Rats; Spleen; Thioacetamide