Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 32, No. 2 suppl, 19-25 (2004)
DOI: 10.1080/01926230490451699

Microvesicular Steatosis Induced by a Short Chain Fatty Acid: Effects on Mitochondrial Function and Correlation with Gene Expression

Robert A. Jolly

Abbott Laboratories, North Chicago, Illinois 60064, USA

Rita Ciurlionis

Abbott Laboratories, North Chicago, Illinois 60064, USA

David Morfitt

Abbott Laboratories, North Chicago, Illinois 60064, USA

Mary Helgren

Abbott Laboratories, North Chicago, Illinois 60064, USA

Reid Patterson

Abbott Laboratories, North Chicago, Illinois 60064, USA

Roger G. Ulrich

Rosetta Inpharmatics, Kirkland, Washington 98109, USA

Jeffrey F. Waring

Abbott Laboratories, North Chicago, Illinois 60064, USA, jeff.waring{at}abbott.com

Hepatotoxicity characterized by microvesicular steatosis (MVS) is characterized by an abnormal accumulation of numerous small cytoplasmic lipid droplets in hepatocytes. Fulminant or progressive cases of microvesicular steatosis may lead to liver failure and death. Experimentally, short-chain carboxylic acids are known to induce microvesicular steatosis. The identification of gene changes that correlate with MVS concomitant with biochemical and histological indices could provide a better understanding of how this toxicity occurs as well as biomarkers that could be used to avoid this toxicity in the future. Sprague—Dawley rats were dosed days with cyclopropane carboxylic acid (CPCA) a short-chain fatty acid that can induce microvesicular steatosis, and with butyrate, a short chain fatty acid that served as a negative control. CPCA initiated microvesicular steatosis while butyrate did not. In addition, CPCA inhibited beta-oxidation in a concentration-dependent manner in vitro and caused a reduction in mitochondrial respiration ex vivo; no inhibition was evident with butyrate. Microarray results showed that gene expression changes with CPCA resulted in regulation of genes involved in beta-oxidation, as well as other genes associated with mitochondrial function. Overall, these results support altered hepatic mitochondrial function as a mechanism of the toxicity induced by a short-chain fatty acid and may provide potential biomarkers for this toxicity.

Key Words: Cyclopropane carboxylic acid • microvesicular steatosis • mitochondrial respiration • toxicogenomics • microarray • beta oxidation.


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