Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress
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- Morita Reiko
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Yafune Atsunori
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Shiraki Ayako
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Itahashi Megu
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University
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- Ishii Yuji
- Division of Pathology, National Institute of Health Sciences
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- Akane Hirotoshi
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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- Nakane Fumiyuki
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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- Suzuki Kazuhiko
- Laboratory of Veterinary Toxicology, Tokyo University of Agriculture and Technology
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- Shibutani Makoto
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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- Mitsumori Kunitoshi
- Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology
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抄録
Orphenadrine (ORPH), an anticholinergic agent, is a cytochrome P450 (CYP) 2B inducer. CYP2B inducers are known to have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of ORPH and to clarify its possible mechanism of action. Male rats were given a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after DEN administration, rats were fed a diet containing ORPH (0, 750, or 1,500 ppm) for 6 weeks. One week after the ORPH-administration rats were subjected to two-thirds partial hepatectomy for the acceleration of hepatocellular proliferation. The number and area of glutathione S-transferase placental form-positive foci significantly increased in the DEN-ORPH groups. Real-time RT-PCR revealed increased mRNA expression levels of Cyp2b1/2, Mrp2 and Cyclin D1 in the DEN-ORPH groups and of Gpx2 and Gstm3 in the DEN-High ORPH group. Microsomal reactive oxygen species (ROS) production and oxidative stress markers such as thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine were increased in the DEN-High ORPH group. Immunohistochemically, constitutively active/androstane receptor (CAR) were clearly localized in the nuclei of hepatocytes in the DEN-ORPH groups. These results suggest that ORPH causes nuclear translocation of CAR resulting in the induction of the liver tumor-promoting activity. Furthermore, oxidative stress resulting from ROS production is also involved in the liver tumor-promoting activity of ORPH.
収録刊行物
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- The Journal of Toxicological Sciences
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The Journal of Toxicological Sciences 38 (3), 403-413, 2013
一般社団法人 日本毒性学会
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詳細情報 詳細情報について
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- CRID
- 1390282679882791680
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- NII論文ID
- 10031158906
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- NII書誌ID
- AN00002808
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- COI
- 1:CAS:528:DC%2BC3sXhtVKhsL%2FM
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- ISSN
- 18803989
- 03881350
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- NDL書誌ID
- 024784036
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- PubMed
- 23665939
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 抄録ライセンスフラグ
- 使用不可