Gene expression profiling in rat liver treated with various hepatotoxic-compounds inducing coagulopathy
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概要
- 論文の詳細を見る
A large-scale transcriptome database of rat liver (TG-GATEs) has been established by the Toxicogenomics Project in Japan. In the present study, we focused on 8 hepatotoxic compounds within TG-GATEs, i.e., clofibrate, omeprazole, ethionine, thioacetamide, benzbromarone, propylthiouracil, Wy-14,643 and amiodarone, which induced coagulation abnormalities. Aspirin was selected as a reference compound that directly causes coagulation abnormality, but not through liver toxicity. In blood chemical examinations, for all the coagulopathic compounds there was little elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), suggesting no severe cell death by treatment with the compounds. We extracted 344 probe sets from the data for these 8 typical drugs, which induced this phenotype at any time from 3 to 28 days of repeated administration. Principal component analysis using these probe sets clearly separated dose- and time-dependent clusters of the treated groups from their controls, except aspirin and propylthiouracil, both of which were considered to cause coagulopathy not due to their hepatotoxicity but due to their direct effects on the blood coagulation system. Reviewing the extracted genes, changes in lipid metabolism were found to be dominant. Genes related to blood coagulation were generally down-regulated by these drugs except that vitamin K epoxide reductase complex subunit 1 (Vkorc 1) like 1, a paralogous gene of Vkorc 1, was up-regulated. As expected, expression changes of these genes were least prominent in aspirin or propylthiouracil-treated liver. We concluded that these probe sets could be a good starting point in developing mechanism-based biomarkers for diagnosis or prognosis of hepatotoxicity-related coagulation abnormalities in the early stage of drug development.
- 日本トキシコロジー学会の論文
- 2009-06-01
著者
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Ohno Yasuo
第一三共安全性研究所
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Ohno Yasuo
National Institute of Health Sciences
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Nagao Taku
Food Safety Commission Of Japan
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Nagao Taku
Laboratory Of Pharmacology & Toxicology Graduate School Of Pharmaceutical Sciences The Universit
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Nagao Taku
Laboratory Of Pharmacology And Toxicology Graduate School Of Pharmaceutical Sciences The University
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Ono Atsushi
Toxicogenomics Project National Institute Of Biomedical Innovation:national Institute Of Health Scie
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Kiyosawa Naoki
Toxicogenomics Project National Inst. Of Biomedical Innovation
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Kiyosawa Naoki
Toxicogenomics Project National Institute Of Biomedical Innovation
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Miwa Satoko
Exploratory Toxicology & Dmpk Research Laboratories Tanabe Seiyaku Co. Ltd.
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MIYAGISHIMA Toshikazu
Toxicogenomics Project, National Institute of Biomedical Innovation
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URUSHIDANI Tetsuro
Toxicogenomics Project, National Institute of Biomedical Innovation
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Suzuki Takamasa
Toxicogenomics Project National Institute Of Biomedical Innovation
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Urushidani Tetsuro
Toxicogenomics Project National Institute Of Biomedical Innovation:department Of Pathophysiology Dos
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Urushidani Tetsuro
Laboratory Of Pharmacology & Toxicology Graduate School Of Pharmaceutical Sciences The Universit
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Miyagishima Toshikazu
Toxicogenomics Project National Institute Of Biomedical Innovation
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Uehara Takeki
Toxicogenomics Project National Institute Of Biomedical Innovation
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OMURA Ko
Toxicogenomics Project, National Institute of Biomedical Innovation
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HIRODE Mitsuhiro
Toxicogenomics Project, National Institute of Biomedical Innovation
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Omura Ko
Toxicogenomics Project National Institute Of Biomedical Innovation
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Shimuzu Toshinobu
Toxicogenomics Project, National Institute of Biomedical Innovation
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Ohno Yasuo
Toxicogenomics Project, National Institute of Biomedical Innovation
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Ohno Yasuo
Toxicogenomics Project National Institute Of Biomedical Innovation:national Institute Of Health Scie
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Hirode Mitsuhiro
Toxicogenomics Project National Institute Of Biomedical Innovation
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Ono Atsushi
Toxicogenomics Project National Institute Of Biomedical Innovation:national Institute Of Health Scie
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Urushidani Tetsuro
Toxicogenomics Project National Institute Of Biomedical Innovation
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