Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver.
Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARalpha agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood. Cynomolgus monkeys were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Strong upregulation of many genes relating to fatty acid metabolism and mitochondrial oxidative phosphorylation was observed; this reflects the known pharmacology and activity of the fibrates. In addition, (1) many genes related to ribosome and proteasome biosynthesis were upregulated, (2) a large number of genes downregulated were in the complement and coagulation cascades, (3) a number of key regulatory genes, including members of the JUN, MYC, and NFkappaB families were downregulated, which appears to be in contrast to the rodent, where JUN and MYC are reported to upregulated after PPARalpha agonist treatment, (4) no transcriptional signal for DNA damage or oxidative stress was observed, and (5) transcriptional signals consistent with an anti-proliferative and a pro-apoptotic effect were seen. We also compared the primate data to literature reports of hepatic transcriptional profiling in PPARalpha-treated rodents, which showed that the magnitude of induction in beta-oxidation pathways was substantially greater in the rodent than the primate.
Cariello
Neal F
NF
GlaxoSmithKline Inc., Safety Assessment, Research Triangle Park, North Carolina 27709, USA. Neal.F.Cariello@gsk.com
Romach
Elizabeth H
EH
Colton
Heidi M
HM
Ni
Hong
H
Yoon
Lawrence
L
Falls
J Greg
JG
Casey
Warren
W
Creech
Donald
D
Anderson
Steven P
SP
Benavides
Gina R
GR
Hoivik
Debie J
DJ
Brown
Roger
R
Miller
Richard T
RT
D000818:Animals; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D058607:Fibric Acids; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000819:agonists*; D020025:Peroxisome Proliferators / Q000493:pharmacokinetics / Q000633:toxicity*; D013045:Species Specificity; D014158:Transcription, Genetic / Q000187:drug effects*
D005227:Fatty Acids; D058607:Fibric Acids; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D002995:Clofibric Acid; C019304:ciprofibrate