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Characterization of Hepatic Mitochondrial Injury Induced by Fatty Acid Oxidation Inhibitors

Drug Safety Evaluation, Allergan, Inc., Irvine, California, USA

Correspondence: Alison Vickers, PhD, 2525 Dupont Drive, Irvine, CA 92623, USA; e-mail:vickers_alison{at}allergan.com.

Impairment of liver mitochondrial β-oxidation is an important mechanism of drug-induced liver injury. Four inhibitors of fatty acid oxidation were compared in short-term rat in vivo studies in which the rats were administered one or four doses. The hepatocellular vacuolation represented ultra-structural mitochondrial changes. Urine nuclear magnetic resonance (NMR) spectroscopy revealed that both FOX988 and SDZ51-641 induced a persistent dicarboxylic aciduria, suggesting an inhibition of mitochondrial β-oxidation and incomplete fatty acid metabolism. Etomoxir caused minimal mitochondrial ultrastructural changes and induced only transient dicarboxylic aciduria. CPI975 served as a negative control, in that there were no significant perturbations to the mitochondrial ultrastructural morphology or in the urine NMR composition; however, compound exposure was confirmed by the up-regulation of liver gene expression compared to vehicle control. The liver gene expression changes that were altered by the compounds were indicative of mitochondria, general and oxidative stress, and peroxisomal enzymes involved in β-oxidation, suggestive of a compensatory response to the inhibition in the mitochondria. In addition, both FOX988 and SDZ51-641 up-regulated ribosomal genes associated with apoptosis, as well as p53 pathways linked with apoptosis. In summary, metabonomics and liver gene expression provided mechanistic information on mitochondrial dysfunction and impaired fatty acid oxidation to further define the clinical pathology and histopathology findings of hepatotoxicity.

Key Words: hepatic • in vitro toxicology • mechanisms of toxicity

Abbreviations: ALP, alkaline phosphatase • ALT, alanine aminotransferase • AST, aspartate aminotransferase • ATP, adenosine triphosphate • CPT-1, carnitine almitoyltransferase 1 • CPT-2, carnitine palmitoyltransferase 2 • FFA, free fatty acids • FIAU, fialuridine • GSH, glutathione • NIDDM, non-insulin–dependent diabetes mellitus • PPAR, peroxisome proliferator activated receptor • ROS, reactive oxygen species • UCP, uncoupling protein

Toxicologic Pathology, Vol. 37, No. 1, 78-88 (2009)
DOI: 10.1177/0192623308329285


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