Genomic Cluster and Network Analysis for Predictive Screening for Hepatotoxicity

Abstract

-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.

Metabolomics and biomarker discovery: NMR spectral data of urine and hepatotoxicity by carbon tetrachloride, acetaminophen, and d-galactosamine in rats

“…CCl 4 (1 ml/kg) induced more severe hepatic damage than AAP (2 g/kg) and GalN (0.8 g/kg). The severity of centrilobular liver necrosis and Kupffer cell proliferation, which is consistent with previous data (Fukushima et al 2006;Wills et al 2006) for these compounds, coincides with clinical chemistry which showed evident hepatic changes in plasma levels of ALT and AST. 3.3 NMR Urinary volumes and pH values were not observed to be markedly different among groups.…”

In-depth Identification of Pathways Related to Cisplatin-induced Hepatotoxicity through an Integrative Method Based on an Informatics-assisted Label-free Protein Quantitation and Microarray Gene Expression Approach

“…The ovals represent genes obtained from the microarray data. lated in the carbon tetrachloride-and acetaminophen-treated groups (53). Thus, because many oxidative stress-related proteins/genes were affected by cisplatin, our results confirmed that oxidative stress plays an important role in cisplatin-induced hepatotoxicity.…”

CHANGES OF MICRO-RNA EXPRESSION IN RAT LIVER TREATED BY ACETAMINOPHEN OR CARBON TETRACHLORIDE − REGULATING ROLE OF MICRO-RNA FOR RNA EXPRESSION −

“…There is commonness in the APAP and CCL4 induced toxicity including necrosis or up-regulation of oxidative stress-related genes (Mitchell et al, 1973;Chan et al, 2001;Weber et al, 2003;Nakahira et al, 2003;Fukushima et al, 2006). Therefore, in the microarray analysis, microRNAs commonly changed by APAP and CCL4 were selected.…”