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TOXICOLOGY

Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-Target Gene Activation

Department of Pharmacology (T.C.M, P.T.P, E.A.H., C.J.S.) and Department of Medicine (P.T.P), Dalhousie University, Halifax, Nova Scotia, Canada

Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor- (PPAR), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPAR knockout [PPAR(—/—)] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPAR gene. Compared to wild-type mice, treatment of PPAR(—/—) mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPAR transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPAR target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPAR protects against amiodarone-induced hepatotoxicity.

Address correspondence to: Christopher J. Sinal, Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5. E-mail: csinal{at}dal.ca.