Transcription profiling distinguishes dose-dependent effects in the livers of rats treated with clofibrate.
Peroxisome proliferators such as the fibrates act via the peroxisome proliferator activated receptor (PPAR)-alpha 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.
Kramer
Jeffrey A
JA
Pharmacia Corporation, Global Toxicology, 800 N. Lindbergh Blvd., St Louis, Missouri 63167, USA. jeffrey.a.kramer@pharmacia.com
Blomme
Eric A G
EA
Bunch
Roderick T
RT
Davila
Julio C
JC
Jackson
Carmen J
CJ
Jones
Patrick F
PF
Kolaja
Kyle L
KL
Curtiss
Sandra W
SW
D000410:Alanine Transaminase / Q000187:drug effects; D000818:Animals; D002994:Clofibrate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020025:Peroxisome Proliferators / Q000633:toxicity*; D025341:Principal Component Analysis; D051381:Rats
D020025:Peroxisome Proliferators; D000410:Alanine Transaminase; D002994:Clofibrate