Genomic cluster and network analysis for predictive screening for hepatotoxicity.
The present study was undertaken to estimate the usefulness of genomic approaches to predict hepatotoxicity. Male rats were treated with acetaminophen (APAP), carbon tetrachloride (CCL), amiodarone (AD) or tetracycline (TC) at toxic doses. Their livers were extracted 6 or 24 hr after the dosings and were used for subsequent examinations. At 6 hr there were no histological changes noted in any of the groups except for the CCL group, but at 24 hr, such changes were noted in all but the AD group. Regarding genomic analysis, we performed hierarchical cluster analysis using S-plus software. The individual microarray data were clearly classified into 5 treatment-related clusters at 24 hr as well as at 6 hr, even though no morphological changes were noted at 6 hr. In the gene expression analysis using GeneSpring, transcription factor and oxidative stress- and lipid metabolism-related genes were markedly affected in all treatment groups at both time points when compared with the corresponding control values. Finally, we investigated gene networks in the above-affected genes by using Ingenuity Pathway Analysis software. Down-regulation of lipid metabolism-related genes regulated by SREBP1 was observed in all treatment groups at both time points, and up-regulation of oxidative stress-related genes regulated by Nrf2 was observed in the APAP and CCL treatment groups. From the above findings, for the application of genomic approaches to predict hepatotoxicity, we considered that cluster analysis for classification and early prediction of hepatotoxicity and network analysis for investigation of toxicological biomarkers would be useful.
Fukushima
Tamio
T
Drug Safety Research & Development, Nagoya Laboratories, Pfizer Japan Inc, Aichi, Japan. tamio.fukushima@pfizer.com
Kikkawa
Rie
R
Hamada
Yoshimasa
Y
Horii
Ikuo
I
D000082:Acetaminophen / Q000633:toxicity*; D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D016000:Cluster Analysis; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013752:Tetracycline / Q000633:toxicity*
D000082:Acetaminophen; D002251:Carbon Tetrachloride; D013752:Tetracycline; D000638:Amiodarone