Mechanism of carbohydrate toxicity induction and its association with transcription factors involved in expression of xenobiotics-metabolizing enzymes

• Project/Area Number: 19590151
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: University of Shizuoka
• Principal Investigator: MIWA Masao University of Shizuoka, 薬学部, 名誉教授 (10046287)
• Co-Investigator(Kenkyū-buntansha): 菅谷 純子 静岡県立大学, 薬学部, 教授 (30098131)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 解毒酵素 / 転写調節因子 / 転写調節 / 糖毒性 / 核内受容体

Research Abstract

高脂肪食摂食等による栄養状態や糖尿病等の病態時に薬物代謝能が変化し、薬物(代謝物)による酸化ストレスの原因となり薬物副作用が惹起されることを提唱してきた。高カロリー食摂餌で亢進する血清TGレベル、肝TGおよび総コレステロール含量、門脈血グルコースレベル、転写因子SREBP1cやFatty acid synthase mRNAレベルが酵素合成イヌリン摂取により抑制され、肝臓に運搬される糖レベルの低下が抗肥満効果に結びついたと推察された。さらに高脂肪・高糖質食摂餌ラット肝臓における核内CAR、PPARαの発現亢進がUGT1A1、UGT1A6の発現を誘導し、薬物動態に影響をおよぼすことを見いだした。

Research Products

• [Journal Article] Up-regulation of CAR expression through Elk-1 in HepG2 and SW480 cells by serum starvation stress (2009)
  • Author(s): Makoto Osabe, Junko Sugatani, Akiko Takemura, Masatoshi Kurosawa, Yasuhiro Yamazaki, Akira Ikari, Masao Miwa
  • Journal Title: FEBS Letters 583(5)[IF 3.263] Pages: 885-889
• [Journal Article] Comparison of enzymatically synthesized inulin, resistant maltodextrin and clofibrate effects on biomarkers of metabolic disease in rats fed a high-fat and high sucrose (cafeteria) diet (2008)
  • Author(s): J. Sugatani, M. Osabe, T. Wada, K. Yamakawa, Y. Yamazaki, T. Takahashi, A. Ikari, M. Miwa
  • Journal Title: Eur. J. Nutr 47(4)[IF2.356] Pages: 192-200
• [Journal Article] Expression of CAR in SW480 and HepG2 cells during G1 is associated with cell proliferation (2008)
  • Author(s): M. Osabe, J. Sugatani, A. Takemura, Y. Yamazaki, A. Ikari, N. Kitamura, M. Negishi, M. Miwa
  • Journal Title: Biochem. Biophys. Res. Commun 369(4)[IF 2.855] Pages: 1027-1033
• [Journal Article] TRPM6 expression and cell proliferation are up-regulated by phosphorylation of ERK1/2 in renal epithelial cells (2008)
  • Author(s): A. Ikari, C. Okude, H. Sawada, Y. Yamazaki, J. Sugatani, M. Miwa
  • Journal Title: Biochem. Biophys. Res. Commun 369(4)[IF 2.855] Pages: 1129-1133
• [Journal Article] Surface localization of the nuclear receptor CAR in influenza A virus-infected cells (2008)
  • Author(s): T. Takahashi, Y. Moriyama, A. Ikari, J. Sugatani T. Suzuki, M. Miwa
  • Journal Title: Biochem. Biophys. Res. Commun 368(3)[IF 2.855] Pages: 550-555
• [Journal Article] PPP1R16A, the membrane subunit of protein phosphatase 1b, signals nuclear translocation of the nuclear receptor CAR (2008)
  • Author(s): T. Sueyoshi, R. Moore, J. Sugatani Y. Matsumura, M. Negishi
  • Journal Title: Mol. Pharmacol 73(4)[IF 4.469] Pages: 1113-1121
• [Journal Article] Constitutive androstane receptor and peroxisome proliferator-activated receptor a are activated in liver of male rats fed a high-fat and high-sucrose diet and the hepatic expression of UGT1A1 and UGT1A6 is enhanced (2008)
  • Author(s): M. Osabe, J. Sugatani, T. Fukuyama, S. Ikushiro, A. Ikari, M. Miwa
  • Journal Title: Drug Metab. Dispos 36(2)[IF 3.638] Pages: 294-302
• [Journal Article] Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs : implication of defects in the UGT1A1 gene promoter (2008)
  • Author(s): J. Sugatani, K. Mizushima, M. Osabe, K. Yamakawa, S. Kakizaki, H. Takagi, M. Mori, A. Ikari, M. Miwa
  • Journal Title: Naunyn Schmiedebergs Arch. Pharmacol 377(4-6)[IF 2.779] Pages: 597-605
• [Journal Article] Claudin-16 is directly phosphorylated by protein kinase a independently of a vasodilator-stimulated phosphoprotein-mmediated pathway (2008)
  • Author(s): A. Ikari, M. Ito, C. Okude, H. Sawada, H. Harada, M. Degawa, H. Sakai, T. Takahashi, J. Sugatani, M. Miwa
  • Journal Title: J. Cell Physiol 214(1)[IF3.638] Pages: 221-229
• [Journal Article] Activation of a polyvalent cation-sensing receptor decreases magnesium transport via claudin-16 (2008)
  • Author(s): A. Ikari, C. Okude, H. Sawada, Y. Sasaki, Y. Yamazaki, J. Sugatani, M. Degawa, M. Miwa
  • Journal Title: Biochim. Biophys. Acta 1778(1)[IF 3.587] Pages: 283-290
• [Journal Article] Downregulation of TRPM6-mediated magnesium influx by cyclosporine A (2008)
  • Author(s): A, Ikari, C. Okude, H. Sawada, T. Takahashi, J. Sugatani, M. Miwa
  • Journal Title: Naunyn Schmiedebergs Arch. Pharmacol 377(4-6)[IF 2.779] Pages: 333-343
• [Journal Article] Constitutive androstane receptor and peroxisome proliferator-activated receptor a are activated in liver of male rats fed ahigh-fat and high-sucrose diet and the hepatic expression of UGT1A1 and UGT1A6 is enhanced. (2008)
  • Author(s): M. Osabe, J. Sugatani, T. Fukuyama, S. Ikushiro, A. Ikari, M. Miwa.
  • Journal Title: Drug Metab. Dispos. 36 Pages: 294-302
  • Peer Reviewed
• [Journal Article] Comparison of enzymatically synthesized inulin, resisitant maltodextrin and clofibrate effects on biomarkers of metabolic disease in rats fed a high-fat and high sucrose (cafeteria) diet. (2008)
  • Author(s): J. Sugatani, M. Osabe, T. Wada, K. Yamakawa, Y. Yamazaki, T. Takahashi, A. Ikari, M. Miwa
  • Journal Title: Eurp. J. Nutr. 47 Pages: 192-200
  • Peer Reviewed
• [Journal Article] Expression of CAR in SW480 and HepG2 cells during G1 is associated with cell proliferation. (2008)
  • Author(s): Osabe M., et. al.
  • Journal Title: Biochem. Biophys. Res. Commun. 369 Pages: 1027-1033
  • Peer Reviewed
• [Journal Article] Constitutive androstane receptor and peroxisome proliferator activated receptor a are activated in liver of male rats fed a high-fat and high-sucrose diet and the hepatic expression of UGT1A1 and UGT1A6 is enhanced. (2008)
  • Author(s): Osabe M., et. al.
  • Journal Title: Drug Metab. Dispos. 36 Pages: 294-302
  • Peer Reviewed
• [Presentation] 酵素合成イヌリンと抗高脂血症薬併用による抗肥満作用と薬物代謝酵素発現に及ぼす影響の解析 (2009)
  • Author(s): 定光慧、今西正樹、長部誠、和田正、山崎泰広、五十里彰、菅谷純子
  • Organizer: 日本薬学会第129年会(講演要旨集3)
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] 酵素合成イヌリンと抗高脂血症薬併用による抗肥満作用と薬物代謝酵素発現に及ぼす影響の解析 (2009)
  • Author(s): 定光慧, 今西正樹, 長部誠, 和田正, 山崎泰広, 五十里彰, 菅谷純子
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-28
• [Presentation] メタボリックシンドロームと薬物代謝 : 酵素合成イヌリン摂取による脂肪肝形成時に認められる肝機能障害抑制効果 (2008)
  • Author(s): 菅谷純子
  • Organizer: 第13回静岡健康・長寿学術フォーラム「元気な血管で健康な長寿を-老いは血管に始まる」、グランシップ
  • Place of Presentation: 静岡
  • Year and Date: 2008-11-07
• [Presentation] メタボリツクシンドロームと薬物代謝 : 酵素合成イヌリン摂取による脂肪肝形成時に認められる肝機能障害抑制効果 (2008)
  • Author(s): 菅谷純子
  • Organizer: 第13回静岡健康・長寿学術フォーラム
  • Place of Presentation: 静岡
  • Year and Date: 2008-11-07
• [Presentation] 高カロリー食摂取ラットにおける肝コレステロールトランスポーターAbcg5/8発現変動の解析 (2008)
  • Author(s): 山崎泰広、長部誠、松井久美子、鎌田修二、近江明大、竹村明子、五十里彰、菅谷純子、三輪匡男
  • Organizer: 日本薬学会第128年会(講演要旨集3)
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-27
• [Presentation] 酵素合成法によるイヌリンの抗肥満作用機構の解析 (2008)
  • Author(s): 菅谷純子、和田正、長部誠、鎌田修二、近江明大、石川智子、山崎泰広、五十里彰、三輪匡男
  • Organizer: 日本薬学会第128年会(講演要旨集3)(59)
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-27
• [Presentation] Comparison of enzymatically synthesized inulin, clofibrate and fluvastatin effects on biomarkers of metabolic disease and drug metabolism in rats fed standard and cafeteria diets (2008)
  • Author(s): Junko Sugatani, Makoto Osabe, Satoshi Sadamitsu, Masaki Imanishi, Yasuhiro Yamazaki, Akira Ikari, Masao Miwa
  • Organizer: 1^<st> International conference on health and longevity sciences, Yaku-shoku Dogen、'Medicine and food, sharing a common origin
  • Place of Presentation: University of Shizuoka
• [Presentation] Comparison of enzymatically synthesized inulin, clofibrate and fluvastatin effects on biomarkers of metabolic disease and drug metabolism in rats fed standard and cafeteria diets (2008)
  • Author(s): J. Sugatani, M. Osabe, S. Sadamitsu, M. Imanishi, Y. Yamazaki, A. Ikari, M. Miwa
  • Organizer: 1^<st> International conference on health and longevity sciences, Yaku-shoku Dogen、'Medicine and food, sharing a common origin
  • Place of Presentation: 静岡
• [Presentation] 脂肪肝形成モデル動物の薬物動態-アセトアミノフェングルクロン酸抱合反応の亢進 (2007)
  • Author(s): 長部誠、菅谷純子、福山知哲、山崎泰広、五十里彰、三輪匡男
  • Organizer: 第1回次世代を担う若手医療薬科学シンポジウム
  • Year and Date: 2007-12-15
• [Presentation] 脂肪肝形成モデル動物の薬物動態-アセトアミノフェングルクロン酸抱合反応の亢進 (2007)
  • Author(s): 長部誠、菅谷純子、福山知哲、山崎康広、五十里彰、三輪匡男
  • Organizer: 第1回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-12-15
• [Presentation] 高カロリー食の摂取により脂肪肝を形成したラット肝臓のグルクロン酸抱合酵素UGT1A1、UGT1A6の発現亢進は核内受容体CAR、PPARaの活性化に起因するBMB2007 (2007)
  • Author(s): 水嶋康介、菅谷純子、長部誠、福山知哲、山崎泰広、五十里彰、三輪匡男
  • Organizer: 第80回日本生化学会大会(332)
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] 高カロリー食の摂取により脂肪肝を形成したラット肝臓のグルクロン酸抱合酵素UGT1A1、UGT1A6の発現亢進は核内受容体CAR、PPARαの活性化に起因する (2007)
  • Author(s): 水嶋康介、菅谷純子、長部誠、福山知哲、山崎康広、五十里彰、三輪匡男
  • Organizer: 第80回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] 高栄養状態で長期に飼育したラットの肝薬物代謝酵素/トランスポーターの発現変動について (2007)
  • Author(s): 菅谷純子
  • Organizer: 第10回P450研究会、第2回UGT研究会合同開催
  • Place of Presentation: 富山
  • Year and Date: 2007-07-21
• [Presentation] 高脂肪高糖質食で飼育したラット肝薬物代謝酵素/トランスポーターの発現変動について (2007)
  • Author(s): 長部誠、菅谷純子、福山知哲、山崎泰広、高橋忠伸、五十里彰、三輪匡男
  • Organizer: 第53回日本薬学会東海支部総会・大会(講演要旨集)(28)
  • Place of Presentation: 名古屋
  • Year and Date: 2007-07-07
• [Presentation] Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet : Association with the suppression of hepatic cytochrome P450 and HNF4a expression (2007)
  • Author(s): Makoto Osabe, Junko Sugatani, Tadashi Wada, Tadanobu Takahashi, Akira Ikari, Masao Miwa
  • Organizer: The 5th International Symposium on Receptor Mechanisms, Signal Transduction and Drug Effects, International Receptor Symposium
  • Place of Presentation: Shizuoka, Japan
• [Book] 加水分解酵素3.1.4.39-3.1.4.51、4.6.1.14「酵素ハンドブック(第3版)」(八木達彦、福井俊郎、一島英治、鏡山博行、虎谷哲夫編集) (2008)
  • Author(s): 菅谷純子, 三輪匡男
  • Publisher: 朝倉書店
• [Book] 酵素ハンドブック(第3版) (2008)
  • Author(s): 菅谷純子, 三輪匡男
  • Publisher: 朝倉書店