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

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-␣ (PPAR␣), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPAR␣ knockout [PPAR␣(Ϫ/Ϫ)] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPAR␣ gene. Compared to wildtype mice, treatment of PPAR␣(Ϫ/Ϫ) 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.

Gene Expression Profiling of Rat Liver Treated With Serum Triglyceride-Decreasing Compounds

“…Interestingly, AM had small PC 1 values, while near zero in PC 2. This result is supported by previous reports that AM induces the expression of PPARα target genes (McCarthy et al, 2004) and lowers serum TH level (De Sandro et al, 1991). Thus, these two directions might have been balanced in the case of the plasma TG reduction by AM.…”

Development of a Highly Sensitive Cytotoxicity Assay System for CYP3A4-Mediated Metabolic Activation

“…It has already been reported that the hepatotoxicity of some drugs is associated with the metabolic activation mediated by CYP3A4. The major metabolite of amiodarone, desethylamiodarone, was reported to cause cytotoxicity in HepG2 cells and rat hepatocytes at lower concentrations than the parent drug amiodarone (McCarthy et al, 2004). Desethylamiodarone is produced mainly by CYP3A4 and by CYP2C8 in humans (Ohyama et al, 2000).…”

Genomic Cluster and Network Analysis for Predictive Screening for Hepatotoxicity

“…Of the genes regulated by the above transcription factors, there were SCD, FADS, and fatty acid elongation-related (ELOVL6) genes, as well as glycerolipid biosynthesis-related gene (GPAM), and lipogenesis and beta oxidation of lipidrelated genes (CPT1 and 2). AD has been reported to inhibit the hepatic mitochondrial N-oxidation of fatty acids, resulting in an increase in hepatic triglyceride accumulation and a decrease in the hepatic secretion of triglycerides into the blood (McCarthy et al, 2004), as well as in microvesicular steatosis of the liver (Fromenty et al, 1990). AD has been also reported to induce hypercholesterolemia associated with a decrease in liver LDL receptor mRNA (Hudig et al, 1994).…”