Extraction of peroxisome proliferator-activated receptor alpha agonist-induced lipid metabolism-related and unrelated genes in rat liver and analysis of their genomic location

摘要

Although peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists are obviously hepatocarcinogenic in rodents, they have been widely used for dyslipidemia and proven to be safe for clinical use without respect to the species difference. It is established that PPAR alpha acts as a part of the transcription factor complex, but its precise mechanism is still unknown. Using the data of Toxicogenomics Database, reliable genes responsive to PPAR alpha agonists, clofibrate, fenofibrate and WY-14,643, in rat liver, were extracted from both in vivo and in vitro data, and sorted by their fold increase. It was found that there were many genes responding to fibrates exclusively in vivo. Most of the in vivo specific genes appear to be unrelated to lipid metabolism and are not upregulated in the kidney. Fifty-seven genes directly related to cell proliferation were extracted from in vivo data, but they were not induced in vitro at all. Analysis of PPAR-responsive elements could not explain the observed difference in induction. To evaluate possible interaction between neighboring genes in gene expression, the correlation of the fold changes of neighboring genes for 22 drugs with various PPAR alpha agonistic potencies were calculated for the genes showing more than 2.5 fold induction by 3 fibrates in vivo, and their genomic location was compared with that of the human orthologue. In the present study, many candidates of genes other than lipid metabolism were selected, and these could be good starting points to elucidate the mechanism of PPAR alpha agonist-induced rodent-specific toxicity.