Utilization of a One-Dimensional Score for Surveying Chemical-Induced Changes in Expression Levels of Multiple Biomarker Gene Sets Using a Large-Scale Toxicogenomics Database

Kiyosawa, Naoki; Shiwaku, Kouji; Hirode, Mitsuhiro; Omura, Ko; Uehara, Takeki; Shimizu, Takuya; Mizukawa, Yumiko; Miyagishima, Toshikazu; Ono, Atsushi; Nagao, Taku; Urushidani, Tetsuro

doi:10.2131/jts.31.433

Cited by 26 publications

(26 citation statements)

References 27 publications

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“…The mononuclear cells were exposed to 100 ng/ml of LPS (from Escherichia coli serotype O111: B4, Sigma). Additionally, cells were also treated with different concentrations (5 mM or 10 mM) of VPA (Sigma) (Kiyosawa et al, 2006;Tamura et al, 2006) at the time of LPS-stimulation. Unstimulated cells and cells treated with 10 mM VPA were used as controls.…”

Section: In Vitro Experimentsmentioning

confidence: 99%

Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo)

Song

Yoon

et al. 2015

Veterinary Immunology and Immunopathology

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Section: In Vitro Experimentsmentioning

confidence: 99%

Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo)

Song

Yoon

et al. 2015

Veterinary Immunology and Immunopathology

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“…TG-GATEs is publicly available and is one of the most comprehensive data sets up to date. 6, 23, 24, 25 …”

Section: Introductionmentioning

confidence: 99%

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity

et al. 2013

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Gene signatures of drug-induced toxicity are of broad interest, but they are often identified from small-scale, single-time point experiments, and are therefore of limited applicability. To address this issue, we performed multivariate analysis of gene expression, cell-based assays, and histopathological data in the TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system) database. Data mining highlights four genes—EGR1, ATF3, GDF15 and FGF21—that are induced 2 h after drug administration in human and rat primary hepatocytes poised to eventually undergo cytotoxicity-induced cell death. Modelling and simulation reveals that these early stress-response genes form a functional network with evolutionarily conserved structure and intrinsic dynamics. This is underlined by the fact that early induction of this network in vivo predicts drug-induced liver and kidney pathology with high accuracy. Our findings demonstrate the value of early gene-expression signatures in predicting and understanding compound-induced toxicity. The identified network can empower first-line tests that reduce animal use and costs of safety evaluation.

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“…To facilitate the analytical procedures for large-scale microarray data, we developed a simple one-dimensional score, named TGP1, which is useful to overview the trend of the changes in expression of multiple biomarker gene lists all at once (Kiyosawa et al, 2006). For each gene list, the signal log ratio was calculated by dividing the mean signal value of the chemical-treated group by that of the corresponding control.…”

Section: Scoring Of the Marker Gene Sets (Tgp1 Score)mentioning

confidence: 99%

“…The former is based on the signal log ratio (Kiyosawa et al, 2006) and is convenient to compare the responsiveness of many drugs to a marker gene list. The disadvantages of this scoring system are that it overestimates the responsiveness when the list contains a gene where the induction is extreme (such as CYP1A1) and it Table 5.…”

Section: 08e-4 9 Starch and Sucrose Metabolism (Rattus Norvegicus)mentioning

confidence: 99%

Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

et al. 2008

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-The present study was conducted as a model case of the toxicogenomics approach for analyzing toxicological mechanisms and toxicity assessments in the early stage of drug development by comparing with classical toxicology data. Methapyrilene (MP) 100 mg/kg produced obvious histopathological changes in liver of rats by single or repeated dose up to 28 days with significant elevation of ALT and AST. In the middle dose groups (30 mg/kg MP), no apparent changes were noted in blood biochemical data by single dosing or repeated dosing up to one week, and no obvious histopathological changes were observed except a slight hypertrophy in the hepatocytes. Comprehensive gene expression changes were analyzed using Affymetrix GeneChip ® and differentially expressed probe sets were statistically extracted. These contained many genes related to "glutathione metabolism", "apoptosis", "MAPK signaling pathway" and "regulation of cell cycle", which were all thought to be involved in the development of presently observed phenotypes. In the high dose groups, TGP1 scores (developed in our system in order to overview the responsiveness of drugs to multiple marker gene lists) for these categories were markedly increased from the early time point after single dose and kept their high expression throughout the repeated dose period. In the middle dose groups, the increment of the scores were noted not only at the time points when apparent pathological changes emerged, but also at the earlier stage of repeated dosing and even after single dosing. We conclude that toxicogenomics would enable a more sensitive assessment at the earlier time point than classical toxicology evaluation.

show abstract

Utilization of a One-Dimensional Score for Surveying Chemical-Induced Changes in Expression Levels of Multiple Biomarker Gene Sets Using a Large-Scale Toxicogenomics Database

Cited by 26 publications

References 27 publications

Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo)

Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo)

Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity

Gene expression profiling of methapyrilene-induced hepatotoxicity in rat

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