Role of pregnane X receptor in the preventive effect of Boiogito against experimentally induced cholestatic liver injury

• Project/Area Number: 26460903
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: University of Toyama
• Principal Investigator: Watanabe Shiro 富山大学, 和漢医薬学総合研究所, 准教授 (00222406)
• Co-Investigator(Kenkyū-buntansha): 藤田 恭輔 富山大学, 和漢医薬学総合研究所, 助教 (70707538)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胆汁酸 / トランスポーター / 水酸化 / 硫酸抱合化 / CAR / VDR / 核内受容体 / FXR / 胆汁うっ滞性肝疾患 / リトコール酸 / 肝臓 / 小腸 / 吸収 / 排泄 / 代謝 / cyp3a11 / BSEP / MRP3 / OSTβ

Outline of Final Research Achievements

Lithocholic acid (LCA) was orally given to mice to induce cholestatic liver injury. The co-administration of Boiogito (BOT) with LCA was shown to ameliorate LCA-induced liver injury and cholestasis. These effects were associated with the attenuation of the elevation in hepatic content of LCA. BOT administration could increase the expression levels of mRNA as well as proteins of cytochrome P450 2b10 (Cyp2b10) and sulfotransferase 2a1 (sult2a1) in liver. These results suggest that BOT can prevent cholestasis through the acceleration of the degradation of LCA in liver. The induction of the above bile acid metabolizing enzymes is known to be mediated by the activation of a set of several nuclear receptors such as pregnane X receptor (PXR), constitutive androstane receptor (CAR) as well as vitamin D receptor (VDR). Further studies are necessary to explore the role of these receptors in the preventive effect of BOT on LCA-induced cholestatic liver injury.

Research Products

• [Journal Article] Ursodeoxycholic acid suppresses lipogenesis in mouse liver: possible role of the decrease in β-muricholic acid, a farnesoid X receptor antagonist. (2017)
  • Author(s): Fujita K., Iguchi Y., Une M., Watanabe S.
  • Journal Title: Lipids Volume: 52 Issue: 4 Pages: 335-344
  • DOI: 10.1007/s11745-017-4242-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Changes in liver lipidomics associated with sodium cholate-induced liver injury and its prevention by boiogito, a Japanese herbal medicine, in mice (2016)
  • Author(s): Watanabe S, Fujita K, Tsuneyama K, Nose M.
  • Journal Title: Trad Kampo Med Volume: 3 Issue: 1 Pages: 9-19
  • DOI: 10.1002/tkm2.1032
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel method for determining peroxisomal fatty acid β-oxidation. (2016)
  • Author(s): Masashi Morita, Shun Matsumoto, Airi Okazaki, Kaito Tomita, Shiro Watanabe, Kosuke Kawaguchi, Daishiro Minato, Yuji Matsuya, Nobuyuki Shimozawa, Tsuneo Imanaka.
  • Journal Title: J Inherit Metab Dis Volume: 39 Issue: 5 Pages: 725-731
  • DOI: 10.1007/s10545-016-9952-y
  • Peer Reviewed
• [Journal Article] Dipasperoside B, a new trisiridoid glucoside from Dipsacus asper. (2016)
  • Author(s): Li F., Tanaka K., Watanabe S., Tezuka Y.
  • Journal Title: Nat. Prod. Commun. Volume: 11 Pages: 891-894
  • Peer Reviewed
• [Journal Article] Brain microsomal fatty acid elongation is increased in abcd1-deficient mouse during active myelination phase. (2015)
  • Author(s): Morita M, Kawamichi M, Shimura Y, Kawaguchi K, Watanabe S, Imanaka T.
  • Journal Title: Metab Brain Dis Volume: 30 Issue: 6 Pages: 1359-1367
  • DOI: 10.1007/s11011-015-9701-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia. (2015)
  • Author(s): Niu Y, Li F, Inada C, Tanaka K, Watanabe S, Fujiwara H, Sasaki-Hamada S, Oka J, Matsumoto K.
  • Journal Title: J Pharm Biomed Anal. Volume: 104 Pages: 21-30
  • DOI: 10.1016/j.jpba.2014.11.019
  • Peer Reviewed
• [Journal Article] Role of transient receptor potential vanilloid 4 activation in indomethacin-induced intestinal damage (2014)
  • Author(s): Yamawaki H., Mihara H., Suzuki N., Nishizono H., Uchida K., Watanabe S., Tominaga M., Sugiyama T.
  • Journal Title: Am. J. Physiol. Gastrointest. Liver Physiol. Volume: 307 Issue: 1 Pages: G33-G40
  • DOI: 10.1152/ajpgi.00105.2013
  • Peer Reviewed
• [Journal Article] Dietary hyodeoxycholic acid exerts hypolipidemic effects by reducing farnesoid X receptor antagonist bile acids in mouse enterohepatic tissues. (2014)
  • Author(s): Watanabe S, Fujita K.
  • Journal Title: Lipids Volume: 49 Issue: 10 Pages: 963-973
  • DOI: 10.1007/s11745-014-3947-y
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 防己黄耆湯のリトコール酸誘導胆汁うっ滞モデルマウスに対する改善効果. (2017)
  • Author(s): 藤田恭輔, 渡辺志朗. 2017, 3, 24-27, 仙台
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
• [Presentation] ヒオデオキシコール酸の投与はTSODマウスの肝臓における炎症・線維化を促進する． (2017)
  • Author(s): 渡辺志朗、藤田恭輔、西田建志、井村譲二、常山幸一
  • Organizer: TSODマウス研究会情報交換会
  • Place of Presentation: つくば市
• [Presentation] ヒオデオキシコール酸のデキストラン硫酸ナトリウム誘発大腸炎に対する改善効果. (2016)
  • Author(s): 藤田恭輔, 杉山和恵, 西川将司, 上田浩, 渡辺志朗.
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] Ursodeoxycholic acid suppresses lipogenesis and reduces lipid contents in mouse liver possibly by reducing β-muricholic acid, a farnesoid X receptor antagonist. (2016)
  • Author(s): Shiro Watanabe, Kyosuke Fujita
  • Organizer: The first international symposium on Toyama-Asia-Africa Pharmaceutical network
  • Place of Presentation: 富山
  • Year and Date: 2016-09-12
  • Int'l Joint Research
• [Presentation] リトコール酸誘導胆汁うっ滞モデルマウスにおける肝傷害ならびに胆汁酸蓄積に対する防己黄耆湯の軽減効果． (2016)
  • Author(s): 渡辺志朗、辻哲也、藤田恭輔
  • Organizer: 第33回和漢医薬学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2016-08-27
• [Presentation] TSODマウスの肝炎に及ぼすヒオデオキシコール酸の効果 (2015)
  • Author(s): 藤田恭輔、常山幸一、渡辺志朗
  • Organizer: 日本薬学会北陸支部第127回例会
  • Place of Presentation: 富山市
  • Year and Date: 2015-11-15
• [Presentation] ヒオデオキシコール酸はTSODマウスにおける肝炎症反応を促進する (2015)
  • Author(s): 藤田恭輔、常山幸一、渡辺志朗
  • Organizer: 第38回胆汁酸研究会
  • Place of Presentation: 横浜市
  • Year and Date: 2015-11-07
• [Presentation] 大柴胡湯の抗肥満作用に関する研究 (2015)
  • Author(s): 小西明伸、荒 哲也，山崎寛生、渡辺志朗、藤田恭輔
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-02
• [Presentation] 胆汁酸負荷による肝障害に対する防已黄耆湯の軽減効果 (2015)
  • Author(s): 渡辺志朗、藤田恭輔
  • Organizer: 第14回日本臨床中医薬学会学術大会
  • Place of Presentation: 富山市
  • Year and Date: 2015-09-29
• [Presentation] 豚胆主要成分ヒオデオキシコール酸が肥満モデルマウスに与える影響 (2015)
  • Author(s): 藤田恭輔、常山幸一、辻 哲也、渡辺志朗
  • Organizer: 第32回和漢医薬学会学術大会
  • Place of Presentation: 富山市
  • Year and Date: 2015-08-22
• [Presentation] マウスにおけるヒオデオキシコール酸とウルソデオキシコール酸の脂質低下作用の比較 (2014)
  • Author(s): 渡辺志朗，藤田恭輔
  • Organizer: 第36回胆汁酸研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-29
• [Presentation] ヒオデオキシコール酸およびウルソデオキシコール酸の肝臓中トリグリセリド含量低下作用 (2014)
  • Author(s): 藤田恭輔、松川征也、井上俊、渡辺志朗
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 大柴胡湯の抗肥満作用の検討 (2014)
  • Author(s): 林忠紘、荒哲也、和田篤敬、藤田恭輔、渡辺志朗
  • Organizer: 日本生薬学会第61年会
  • Place of Presentation: 福岡
  • Year and Date: 2014-09-13 – 2014-09-14
• [Presentation] 脂肪酸構成の網羅的分析によるコール酸誘発性肝障害とその防已黄耆湯による軽減の機構解析 (2014)
  • Author(s): 渡辺志朗，藤田恭輔
  • Organizer: 第31回和漢医薬学会学術大会
  • Place of Presentation: 千葉
  • Year and Date: 2014-08-30 – 2014-08-31
• [Presentation] Chemical profiling of endogenous and exogenous markers of chitosan in an animal model of diabetes (2014)
  • Author(s): Niu Yimin, Li Feng, Hironori Fujiwara, Ken Tanaka, Shiro Watanabe, Sachie Sasak-Hamada, Jun-Ichiro Oka, Kinzo Matsumoto
  • Organizer: 第31回和漢医薬学会学術大会
  • Place of Presentation: 千葉
  • Year and Date: 2014-08-30 – 2014-08-31