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Transcription Profiling Distinguishes Dose-Dependent Effects in the Livers of Rats Treated with Clofibrate

Pharmacia Corporation, Global Toxicology, 800 N. Lindbergh Blvd., St Louis, Missouri 63167, jeffrey.a.kramer{at}pharmacia.com

Eric A.G. Blomme

Pharmacia Corporation, Global Toxicology, 4901 Searle Parkway, Skokie, IL 60077

Roderick T. Bunch

Pharmacia Corporation, Global Toxicology, 4901 Searle Parkway, Skokie, IL 60077

Julio C. Davila

Pharmacia Corporation, Global Toxicology, 800 N. Lindbergh Blvd., St Louis, Missouri 63167

Carmen J. Jackson

Pharmacia Corporation, Global Toxicology, 800 N. Lindbergh Blvd., St Louis, Missouri 63167

Patrick F. Jones

Pharmacia Corporation, Global Toxicology, 800 N. Lindbergh Blvd., St Louis, Missouri 63167

Kyle L. Kolaja

Pharmacia Corporation, Global Toxicology, 4901 Searle Parkway, Skokie, IL 60077

Sandra W. Curtiss

Pharmacia Corporation, Global Toxicology, 800 N. Lindbergh Blvd., St Louis, Missouri 63167

Peroxisome proliferators such as the fibrates act via the peroxisome proliferator activated receptor (PPAR)- as hypolipidemic agents. Many peroxisome proliferators are also nongenotoxic hepatic carcinogens and hepatotoxicants in rodents. We performed transcription profiling using cDNA microarrays on livers of rats treated for 5 days with 3 doses of the peroxisome proliferator clofibrate. All 3 doses had hepatic effects as assessed by liver to body weight ratio, alanine aminotransferase (ALT) increases and histopathology examination. Analysis of the transcription profiling data identified changes in the expression of many genes within several mechanistic pathways that support existing hypotheses regarding peroxisome proliferator mediated carcinogenicity. Additionally, the transcription profiling, histopathology, and clinical chemistry results suggested a biphasic response to clofibrate. These findings provide insight into the pathogenesis of toxic and carcinogenic effects of clofibrate in rodents and demonstrate the ability of cDNA microarrays to provide information regarding mechanisms of toxicity identified during the drug development process.

Key Words: Peroxisome proliferators • toxicogenomics • transcription profiling • hepatic gene expression • clofibrate.

Toxicologic Pathology, Vol. 31, No. 4, 417-431 (2003)
DOI: 10.1080/01926230390202353


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