Gene Expression Analysis of Acetaminophen-induced Liver Toxicity in Rat
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Acetaminophen
Liver Regeneration
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There have been many studies investigating the genomic biomarker and/or molecular mechanism of nephrotoxicity using microarray. However, most of these researches were carried out by studying gene expression changes at one specific time point. As gene expression varies with time and disease stage, the current study investigated the time-series pattern of gene expression in a rat model using a typical nephrotoxic compound. Rats were administrated with 80 mg/kg gentamycin or saline by intramuscular injection for 14 consecutive days followed by a 28-d recovery. Rats were scarified on D2, D4, D8, D15 and Recovery Day (R29), when kidneys were obtained for whole-genome microarray analysis and histological examination. Urine was collected at each necropsy for kidney injury molecular-1 (KIM-1) analysis. The KIM-1 detection and histological examination confirmed the nephrotoxicity. After differentially expression genes (DEGs) identification, there were 4360 and 4323 regulated genes for females and males, respectively. However, few overlapping expression genes co-regluated at each time point were found. By principle component analysis (PCA) and hierarchical cluster, the gene expression patterns were observed to be apparently associated with the disease stage. GO Annotation showed (1) immune response and related process, response to wounding, cell locomotion on D2; (2) cell death and apoptosis was also noted on D4; (3) processes of organic acid or carboxylic acid, apoptosis or cell death on D8 and D15; (4) processes of cell cycle, mitosis, division cell cycle on R29. In conclusion, the authors mapped the time-series gene expression patterns at the initiation, development and recovery stage of gentamycin-induced nephrotoxicity.
Nephrotoxicity
Gene chip analysis
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CCL4
Liver Regeneration
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The KFDA (Korea Food & Drug Administration) has performed a collaborative toxicogenomics project since 2003. Its aim is to construct a toxicology database of 12 compounds administered to mice at initial phase. We chose 6-MP (6-mercaptopurine) which has been used in the treatment of childhood leukemia. It was administered at low (0.224 mg/kg) and at high (2.24 mg/kg) dose (5 mice per group) intraperitonealy to the postnatal 6 weeks mice, then the serum and liver were collected at the indicated time (6, 24 and 72 h) after scarification. Serum biochemical markers for liver toxicity were measured and histopathologic studies also were carried out. The gene expression profiling was carried out by using Applied Biosystems 1700 Full Genome Expression Mouse. By self-organization maps (SOM), we identified groups with unique gene expression patterns, some of them are supposed to be related to 6-MP induced toxicity, including lipid metabolism abnormality, inflammatory response, oxidative stress, ATP depletion and cell death. The potential toxic effects appearing as gene expression changes are dependent of the time of 6-MP but independent of the dosage of it. This study would contribute to establishment of international database as well as national one about hepatotoxicity.
Toxicogenomics
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Steatosis
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A common animal model of chemical hepatocarcinogenesis was used to demonstrate the utility of genomic and proteomic data to identifyearly biomarkers for conventional toxicological endpoints in toxicological studies. N-nitrosomorpholine was applied to young adult male Wistar rats for 7 weeks followed by an exposure-free period of up to 43 weeks. A second group of untreated animals served as control. Five animals in each treatment group were sacrificed at 9 time points during and after exposure. Gene and protein expression of liver tissue homogenates were analyzed by Affymetrix Rat Genome Chips (RG-U34A) and 2D electrophoresis based proteomics. Proteomic analysis was performed in two laboratories. Proteins were separated using 2D electrophoresis (pH 3-10) and gel images were analyzed to obtain intensity values for each spot. Statistical evaluation using linear model analysis and Wilcoxon rank sum tests resulted in candidate genes and proteins differentially expressed between treated and control animals at early and late intervention time points. Time course of change in expression of deregulated proteins was compared to the related gene expression profiles. One focus of the study was to determine biomarkers for carcinogenicity characterized by pronounced differential expression at late stages of hepatocarcinogenesis. Among others, glutathione S-transferase P (GSTp) was identified by both approaches. To validate this finding, GSTp-stained liver sections of all animals were evaluated morphometrically and the area fractions of GSTp-positive foci of altered hepatocytes were determined. A strong correlation between area fraction of foci and both, gene and protein expression as well as between gene and protein expression could be demonstrated.
Proteome
Difference gel electrophoresis
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Objective: To investigate the changes of the gene expression profile of rat liver tissue injured by co-administration of isoniazid( INH) and rifampicin( RFP) using cDNA microarrays. Methods: Twenty Wistar rats were divided into 2 groups( 10 in each group),and administrated( ig) with the combination of INH( 400mg·kg- 1) and RFP( 100 mg·kg- 1) or equal-volume saline,respectively,for 14 days. The gene expression profiles were detected by cDNA microarrays. The differentially expressed genes significantly correlated with liver injury were screened and analyzed. The mechanisms of liver injury caused by co-administration of INH and RFP were specifically analyzed at level of gene expression based on the biological functions of those differentially expressed genes. Results: Totally 55 differentially expressed genes were found in the rats with the combination of INH and RFP. Among them,36 genes were up-regulated,while the other 19 genes were down-regulated. These differential-ly expressed genes were functionally related to the changes in CYP450-related genes,and the genes relevant to the metabolism of three substances( glucose,protein,and lipid),liver function and antioxidation. Conclusion: The combination of INH and RFP causes the remarkable changes of the gene expression profiles in rat liver,which is important for further elucidating the mechanisms of liver injury caused by co-administration of INH and RFP.
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Thioacetamide
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Hepatotoxin
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Liver Regeneration
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