Identification of potential genomic biomarkers for early detection of chemically induced cardiotoxicity in rats.
Cardiotoxicity represents one of the most serious side effects of new drugs. It is essential for pharmaceutical companies to detect potential cardiotoxicity of candidate drugs in non-clinical studies during the early stages of drug development. In this study, we aimed to detect potential genomic biomarkers of rat cardiotoxicity using a toxicogenomics approach. In order to achieve this, we induced cardiac lesions in rats following treatment with the three prototypical cardiotoxic compounds isoproterenol, doxorubicin and carbofuran. We then undertook histopathological examination and microarray analysis at 8 or 24h after single dosing. Using statistical and cluster analysis, we extracted 36 probe sets commonly up-regulated by the three cardiotoxic compounds. GO analysis revealed that these genes were functionally associated with either chemotaxis, tissue regeneration, positive regulation of cell proliferation, cellular organization and morphogenesis events in accordance with the degeneration of myocardium and inflammation observed in the histopathology analysis. Most of selected genes showed transient up-regulation at different time point for each compound. However, among these genes, Spp1, Fhl1, Timp1, Ccl7 and Reg3b revealed a sustained up-regulation with high expression levels at both time points for all three compounds. In conclusion, even though definitive validation studies are required for the establishment of their usefulness and reliability, these identified genes may prove to be the most promising candidate genomic biomarkers of cardiotoxicity in rats.
Mori
Yoko
Y
Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
Kondo
Chiaki
C
Tonomura
Yutaka
Y
Torii
Mikinori
M
Uehara
Takeki
T
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002235:Carbofuran / Q000633:toxicity; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics*; D054715:Cardiotoxins / Q000633:toxicity; D054410:Chemokine CCL7 / Q000096:biosynthesis / Q000235:genetics; D016000:Cluster Analysis; D004317:Doxorubicin / Q000633:toxicity; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007545:Isoproterenol / Q000633:toxicity; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D000073718:Pancreatitis-Associated Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics
D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; D054715:Cardiotoxins; C515452:Ccl7 protein, rat; D054410:Chemokine CCL7; D037181:Lectins, C-Type; D009124:Muscle Proteins; D000073718:Pancreatitis-Associated Proteins; D012333:RNA, Messenger; C506897:Spp1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin; D004317:Doxorubicin; D007545:Isoproterenol; D002235:Carbofuran