IN VIVO HEPATOTOXICITY STUDY OF RATS IN COMPARISON WITH IN VITRO HEPATOTOXICITY SCREENING SYSTEM
スポンサーリンク
概要
- 論文の詳細を見る
For the establishment of a high throughput screening system using primary cell cultures, investigation of elucidated toxicities to assess the correlation between in vitro and in vivo hepatotoxicity is necessary in the safety evaluation of the compound. In the previous study, we reported the usability of rat primary cultured hepatocytes for establishment of high throughput screening system. To confirm the reliability of rat primary hepatocytes culture screening system, we conducted a single-dose in vivo study with relatively high dose of hepatotoxicant in rats using 4 reference compounds (acetaminophen, amiodarone, tetracycline, carbon tetrachloride), and investigated histopathological changes and expression of oxidative stress-related proteins by immunohistochemistry. We also carried out a proteomics analysis for estimating the reliable and sensitive biomarkers. Histopathologically, compound-specific hepatotoxicity was detected at 24 hr after administration in all compounds except amiodarone, which is known to induce phospholipidosis. Immunohistochemically, oxidative stress-related proteins were increased within 6 hr after administration in all treated groups. Proteomics analysis revealed several protein biomarkers related to oxidative stress and mitochondrial metabolism-regulation, which had been previously detected by proteomics analysis in in vitro screening system. Oxidative stress-related proteins were considered as useful biomarkers of hepatotoxicity; since they were detected by immunohistochemistry and proteomics analysis prior to appearance of compound-specific histopathological changes detected by light microscopy. Considering the relevance of in vitro system to in vivo system from the aspect of new biomarkers related to the toxicogenomics/toxicoproteomics, in vitro primary cell culture system would be sufficient to detect hepatotoxicity in the early stage of drug discovery.
- 日本トキシコロジー学会の論文
- 2006-02-24
著者
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HORII Ikuo
Worldwide Safety Sciences, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Japan
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Yamamoto Toshinori
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Yamamoto T
Showa Univ. Tokyo Jpn
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Yamamoto Toshinori
Department Of Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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Fujikawa Masaaki
worldwide safety sciences
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Yamada Hiroshi
worldwide safety sciences
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Horii Ikuo
Showa Univ. (department Of Biochemical Toxicology School Of Pharmaceutical Sciences)
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Horii I
Drug Safety Research And Development Pfizer Global Research And Development Nagoya Laboratories. Pfi
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Horii Ikuo
Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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YAMAMOTO Toshinori
Worldwide Safety Sciences, Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc.
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KIKKAWA Rie
Worldwide Safety Sciences, Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc.
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HAMADA Yoshimasa
Worldwide Safety Sciences, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Inc.
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Kikkawa Rie
Worldwide Safety Sciences Pfizer Global Research And Development Nagoya Laboratories Pfizer Inc.
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Kikkawa Rie
Worldwide Safety Sciences Global Research & Development Nagoya Laboratories Pfizer Inc.
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Yamada Hiroshi
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Kikkawa Rie
Pfizer Global Research & Development Toxicology Nagoya Laboratoreis
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Horii Ikuo
Worldwide Safety Sciences Pgrd Nagoya Laboratories Pfizer Inc.
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Fujikawa Masaaki
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Fujikawa Masaaki
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Japan
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Yamamoto Toshinori
Departments Of Clinical Pharmacy And Pharmacognosy School Of Pharmaceutical Sciences Showa Universit
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Horii Ikuo
Worldwide Safety Sciences
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Horii Ikuo
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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Hamada Yoshimasa
Worldwide Safety Sciences Global Research & Development Nagoya Laboratories Pfizer Japan Inc.
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Fujikawa Masaaki
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Japan
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Horii Ikuo
Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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Yamada Hiroshi
Worldwide Safety Sciences Pfizer Global Research And Development Nagoya Laboratories Pfizer Japan In
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Yamamoto Toshinori
Department Of Pharmacology Medical College Of Oita
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Hamada Yoshimasa
Worldwide Safety Sciences Global Research & Development Nagoya Laboratories Pfizer Inc.
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Fujikawa Masaaki
World Wide Safety Sciences
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