Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation.
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McCarthy TC, Pollak PT, Hanniman EA, Sinal CJ
Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation.
J Pharmacol Exp Ther. 2004 Dec;311(3):864-73. doi: 10.1124/jpet.104.072785. Epub 2004 Jul 20.
- PubMed ID
- 15265979 [ View in PubMed]
- Abstract
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-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- 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 PPARalpha 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 PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Amiodarone Peroxisome proliferator-activated receptor alpha Protein Humans UnknownAgonistDetails