Metabolism of major phytocannabinoids in human brain and lung microsomes and its toxicological implication

• Project/Area Number: 25460176
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: Hokuriku University
• Principal Investigator: Watanabe Kazuhito 北陸大学, 薬学部, 教授 (30113038)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 大麻成分 / テトラヒドロカンナビノール / カンナビジオール / カンナビノール / 脳 / 肺 / 代謝 / 細胞毒性 / ヒト脳ミクロソーム / ヒト肺ミクロソーム / ヒト胎盤ミクロソーム / ﾃﾄﾗﾋﾄﾞﾛｶﾝﾅﾋﾞﾉｰﾙ / ｶﾝﾅﾋﾞｼﾞｵｰﾙ / ｶﾝﾅﾋﾞﾉｰﾙ / ｼﾄｸﾛﾑP450 / ﾋﾄ脳ﾐｸﾛｿｰﾑ / ﾋﾄ肺ﾐｸﾛｿｰﾑ / ﾋﾄ胎盤ﾐｸﾛｿｰﾑ / CYP19 / アナンアミド加水分解 / シトクロムP450 / 酸化的代謝

Outline of Final Research Achievements

Metabolic interactions of major phytocannabinoids (tetrahydrocannabinol, THC; cannabidiol, CBD; cannabinol, CBN) with microsomes from human brain, lung and placenta were investigated as part of toxicological study of these cannabinoids on extrahepatic tissues and following points were clarified: (1 & 2) metabolism of cannabinoids with human brain and lung microsomes. (3) metabolism of cannabinoids with human placenta microsomes and CYP19. (4) microsomal aldehyde oxygenase (MALDO) activity in human brain and lung microsomes for 11-oxo-THC. (5) inhibitory effects of cannabinoids on hydrolysis of anandamide and 2-arachinoylglycerol with human brain and lung microsomes. (6) Cytotoxicity of THC metabolites to mouse lung macrophage J774-1 cells.

Research Products

• [Journal Article] 大麻文化科学考 その26 － 危険ドラッグ・デザイナードラッグとしての合成ンナビノイド関連化合物 (2016)
  • Author(s): 渡辺和人、宇佐見則行、木村敏行、山本郁男
  • Journal Title: 北陸大学紀要 Volume: 40 Pages: 1-9
  • Peer Reviewed / Open Access
• [Journal Article] Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells (2015)
  • Author(s): Yamaori S, Kinugasa Y, Jiang R, Takeda S, Yamamoto I, Watanabe K
  • Journal Title: Life Sci. Volume: 136 Pages: 87-93
  • DOI: 10.1016/j.lfs.2015.07.007
  • NAID: 120007100188
  • Peer Reviewed / Open Access
• [Journal Article] Δ9-THC modulation of fatty acid 2-hydroxylase (FAH2) gene expression: posible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells (2014)
  • Author(s): S. Takeda et al.
  • Journal Title: Toxicology Volume: 326 Pages: 18-24
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Structural requirements for potent direct inhibition oh human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety (2014)
  • Author(s): Yamaori et al.
  • Journal Title: Chem. Biol. Interact. Volume: 215 Pages: 62-68
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells (2014)
  • Author(s): S. Takeda et al.
  • Journal Title: J. Toxicol. Sci. Volume: 39 Pages: 711-716
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characterization of the structural determinants required for potent mechanism-based inhibition of human cytochrome P450 1A1 by cannabidiol (2014)
  • Author(s): Yamaori S, Okushima Y, Yamamoto I, Watanabe K
  • Journal Title: Chem. Biol. Interact. Volume: 215 Pages: 62-68
  • DOI: 10.1016/j.cbi.2014.03.007
  • NAID: 120007100189
  • Peer Reviewed
• [Journal Article] Human brain microsomes: their abilities to metabolize tetrahydrocannabinols and cannabinol (2013)
  • Author(s): K. Watanabe et al.
  • Journal Title: Forensic Toxicology Volume: 31 Issue: 2 Pages: 307-311
  • DOI: 10.1007/s11419-013-0181-x
  • Peer Reviewed
• [Journal Article] Δ8-Tetrahydrocannabinol induces cytotoxicity in macrophage J774-1 cells: involvement of cannabinoid receptor 2 and p38 MAPK (2013)
  • Author(s): S. Yamaori et al.,
  • Journal Title: Toxicology Volume: 314 Issue: 2-3 Pages: 254-261
  • DOI: 10.1016/j.tox.2013.10.007
  • Peer Reviewed
• [Journal Article] Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19 (2013)
  • Author(s): Rongrong Jiang
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 28 Issue: 4 Pages: 332-338
  • DOI: 10.2133/dmpk.DMPK-12-RG-129
  • NAID: 130004463321
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed
• [Journal Article] Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety (2013)
  • Author(s): S. Yamaori et al.
  • Journal Title: Biological & Pharmaceutical Bulletin Volume: 36 Pages: 1197-1203
  • Peer Reviewed
• [Presentation] 発芽過程における大麻草種子 mRNAの発現変化 (2015)
  • Author(s): 北村雅史、地中 啓、中村 耕、荒金眞佐子、渡辺和人、佐々木陽平
  • Organizer: 日本法科学技術学会第21回学術集会
  • Place of Presentation: 柏の葉カンファレンスセンター（柏市、千葉県）
  • Year and Date: 2015-11-12
• [Presentation] Potency and mechanism of CYP2J2 inhibition by major phytocannabinoids (2015)
  • Author(s): S. Yamaori, Y. Nagata, S. Ohmori, I. Yamamoto and K. Watanabe
  • Organizer: 20th North American ISSX Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-10-18
  • Int'l Joint Research
• [Presentation] Metabolism of major phytocannabinoids by human placenta microsomes and CYP19 (2015)
  • Author(s): K. Watanabe et al.
  • Organizer: TIAFT2015
  • Place of Presentation: Firenze, Italy
  • Year and Date: 2015-08-30 – 2015-09-05
• [Presentation] Metabolism of major phytocannabinoids by human placenta microsomes and CYP19 (2015)
  • Author(s): K. Watanabe, K. Inoue, M. Murai, N. Usami, S. Yamaori and I. Yamamoto
  • Organizer: TIAFT 2015, the 53rd Annual Meeting of the International Association of Forensic Toxicologists
  • Place of Presentation: Firenze, Italy
  • Year and Date: 2015-08-30
  • Int'l Joint Research
• [Presentation] Inducibility of CYP enzymes by cannabidiol (2015)
  • Author(s): K. Watanabe et al.
  • Organizer: ICRS2015
  • Place of Presentation: Wolfville, Canada
  • Year and Date: 2015-06-28 – 2015-07-02
• [Presentation] Inducibility of CYP enzymes by cannabidiol (2015)
  • Author(s): K.Watanabe, S. Yamaori, R. Jiang, Y. Kinugasa, Y. Okushima and I. Yamamoto
  • Organizer: 25th Annual Symposium of the ICRS
  • Place of Presentation: Wolfville, Canada
  • Year and Date: 2015-06-28
  • Int'l Joint Research
• [Presentation] 合成カンナビノイドの歴史的経緯 (2015)
  • Author(s): 渡辺和人
  • Organizer: 日本法中毒学会第34年会
  • Place of Presentation: 福岡市
  • Year and Date: 2015-06-26 – 2015-06-27
  • Invited
• [Presentation] 大麻主成分のDuquenois反応－呈色物質の質量分析による構造解析 (2015)
  • Author(s): 渡辺和人ほか
  • Organizer: 日本法中毒学会第34年会
  • Place of Presentation: 福岡市
  • Year and Date: 2015-06-26 – 2015-06-27
• [Presentation] 合成カンナビノイドの歴史的経緯（シンポジウム：合成カンナビノイドを考える） (2015)
  • Author(s): 渡辺和人
  • Organizer: 日本法中毒学会第34年会
  • Place of Presentation: 九州大学医学部百年講堂（福岡市）
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] ﾋﾄCYP19による主要カンナビノイドの代謝 (2015)
  • Author(s): 渡辺和人ほか
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-03-28
• [Presentation] エストロゲン受容体ERβ誘導能を示す化合物の網羅的解析と生体機能への影響評価 (2015)
  • Author(s): 姫野太一ほか
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-03-27
• [Presentation] 大麻主成分Δ9-THCによるPPARαを介したFA2Hの発現制御メカニズムの解明 (2014)
  • Author(s): 石井弘幸ほか
  • Organizer: 第31回日本薬学会九州支部会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-12-01
• [Presentation] 大麻主成分Δ9-THCのマウス概日時計機構に与える影響 (2014)
  • Author(s): 池田恵理子ほか
  • Organizer: 第21回日本時間生物学会学術大会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-11-01
• [Presentation] Evaluation of luciferin-4A O-demethylase activity as a CYP4A11 marker in human liver and kidney microsomes (2014)
  • Author(s): S. Yamaori et al.
  • Organizer: 19th ISSX and 29th JSSX
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-10-13 – 2014-10-23
• [Presentation] PPARαにアゴニスト作用を示さないΔ9-テトラヒドロカンナビノールによるPPARαの活性化と制御下遺伝子FAH2の発現 (2014)
  • Author(s): 吉岡靖史ほか
  • Organizer: フォーラム2014:衛生薬学環境トキシコロジー
  • Place of Presentation: つくば市
  • Year and Date: 2014-09-19 – 2014-09-20
• [Presentation] 大麻主成分Δ9-THCによる子宮機能障害: ERα機能破綻と細胞外マトリックス分解酵素の発現誘導 (2014)
  • Author(s): 姫野太一ほか
  • Organizer: フォーラム2014:衛生薬学環境トキシコロジー
  • Place of Presentation: つくば市
  • Year and Date: 2014-09-19 – 2014-09-20
• [Presentation] 新世代ビスフェノール(ビスフェノールAF)によるERβを介したシグナル毒性 (2014)
  • Author(s): 徳安美紀ほか
  • Organizer: フォーラム2014:衛生薬学環境トキシコロジー
  • Place of Presentation: つくば市
  • Year and Date: 2014-09-19 – 2014-09-20
• [Presentation] ヒト脳ミクロソームによる主要カンナビノイドの代謝 (2014)
  • Author(s): 渡辺和人ほか
  • Organizer: フォーラム2014:衛生薬学環境トキシコロジー
  • Place of Presentation: つくば市
  • Year and Date: 2014-09-19 – 2014-09-20
• [Presentation] Characterization of structural requirement for potent mechanism-based inhibition of hhuman CYP1A1 by cannabidiol (2014)
  • Author(s): K. Watanabe et al.
  • Organizer: ICRS2014
  • Place of Presentation: Baveno, Italy
  • Year and Date: 2014-06-28 – 2014-07-03
• [Presentation] Characterization of structural requirements for potent mechanism-based inhibition of human CYP1A1 by cannabidiol (2014)
  • Author(s): K. Watanabe et al.
  • Organizer: The 24th Annual International Cannabinoid Research Society Symposium on Cannabinoids
  • Place of Presentation: Baveno, Italy
• [Presentation] ダナゾールのヒトCYP3A活性に対する影響 (2014)
  • Author(s): 山折 大ほか
  • Organizer: 医療薬学フォーラム2014/第22回クリニカルファーマシーシンポジウミウム
  • Place of Presentation: 東京都
• [Presentation] Structural requirement for potent direct inhibition of human CYP1A1 by cannabidiol (2013)
  • Author(s): S. Yamaori et al.
  • Organizer: The 23rd Annual International Cannabinoid Research Society Symposium on Cannabinoids
  • Place of Presentation: Vancouver, Canada
• [Presentation] ヒト脳および肺Microsomal Aldehyde Oxygenase (MALDO) による11-oxo-tetrahydrocannabinol の代謝
  • Author(s): 渡辺和人ほか
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本市
• [Presentation] Inhibitory effects of major phytocannabinoids on human cytochrome P450s and its toxicological significance in drug interactions
  • Author(s): K. Watanabe
  • Organizer: Symposium of Preventive Pharmacy, 2013 Spring Annual Convention of Pharmaceutical Society of Korea
  • Place of Presentation: Suncheon, Korea
  • Invited
• [Book] Cannabinoids as potent inhibitors of human CYP1 enzymes, in The Handbook of Cannabis and Relaterd Pathologies (2016)
  • Author(s): 203)K. Watanabe, S. Yamaori, K. Masuda, T. Katsu, S. Narimatsu, and I. Yamamotｏ
  • Total Pages: 10
  • Publisher: Ｅｌｓｅｖｉｅｒ