Delta9-Tetrahydrocannabinol, a major component of marijuana, disrupts estrogen-signaling through estrogen receptor beta

• Project/Area Number: 25460182
• 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: Hiroshima International University
• Principal Investigator: Takeda Shuso 広島国際大学, 薬学部, 准教授 (00460379)
• 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: テトラヒドロカンナビノール / 薬物型大麻草 / 内分泌かく乱 / ERβ / 乳がん / 大麻主成分 / 大麻 / エストロゲン受容体

Outline of Final Research Achievements

Is Δ9-tetrahydrocannabinol (Δ9-THC) an anti-estrogenic chemical? Since Δ9-THC is used both recreationally and medicinally for the treatment of pain and nausea in cancer patients undergoing chemotherapy in the United States and other countries, it is important to investigate the mechanistic basis of Δ9-THC’s 17β-estradiol (E2) signaling disruption. By using estrogen receptor α (ERα)-positive human breast cancer cell line MCF-7, we report here that Δ9-THC’s growth suppressive effects on MCF-7 cells are drastically seen in the presence of E2, and that Δ9-THC inhibits E2-stimulated ERα activation, leading to cell growth. Mechanistically, by performing several lines of biochemical analyses, it is demonstrated that i) Δ9-THC up-regulates ERβ, being recognized as a repressor of ERα function and ii) Δ9-THC function as an activator for the ERβ to interfere with ERα. The data here suggest that anti-estrogenic Δ9-THC disrupts E2/ERα signaling via the second type of ER, ERβ.

Research Products

• [Journal Article] Fipronil, an insecticide, acts as an anti-estrogen via the concomitant down-regulation of ERα and PES1 (2016)
  • Author(s): Okazaki, H., Kohro-Ikeda, E., Takeda, S., Ishii, H., Furuta, E., Matsuo, S., Matsumoto, M., Takiguchi, M., and Aramaki, H.
  • Journal Title: Fundamental Toxicological Sciences Volume: 3 Issue: 1 Pages: 33-37
  • DOI: 10.2131/fts.3.33
  • NAID: 130005129242
  • ISSN: 2189-115X
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HU-210, a synthetic analog of ∆⁹-THC, is not a modifier of estrogen signaling in MCF-7 human breast cancer cells (2016)
  • Author(s): Okazaki, H., Takeda, S., Ishii, H., Matsuo, S., Furuta, E., Watanabe, K., and Aramaki
  • Journal Title: Fundamental Toxicological Sciences Volume: 3 Issue: 2 Pages: 55-61
  • DOI: 10.2131/fts.3.55
  • NAID: 130005133714
  • ISSN: 2189-115X
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells. (2014)
  • Author(s): Takeda, S., Ikeda, E., Su, S., Harada, M., Okazaki, H., Yoshioka, Y., Nishimura, H., Ishii, H., Kakizoe, K., Taniguchi, A., Tokuyasu, M., Himeno, T., Watanabe, K., Omiecinski, C.J., and Aramaki, H.
  • Journal Title: Toxicology Volume: 326 Pages: 18-24
  • DOI: 10.1016/j.tox.2014.09.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells (2014)
  • Author(s): Takeda, S., Okazaki, H., Ikeda, E., Abe, S., Yoshioka,Y., Watanabe, K., and Aramaki, H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 39 Issue: 5 Pages: 711-716
  • DOI: 10.2131/jts.39.711
  • NAID: 130004690957
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Δ⁹-Tetrahydrocannabinol Targeting Estrogen Receptor Signaling: The Possible Mechanism of Action Coupled with Endocrine Disruption (2014)
  • Author(s): Takeda, S.(an invited review)
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 37 Issue: 9 Pages: 1435-1438
  • DOI: 10.1248/bpb.b14-00226
  • NAID: 130004684788
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Medicinal Chemistry and Pharmacology Focused on Cannabidiol, a Major Component of the Fiber-Type <i>Cannabis</i> (2013)
  • Author(s): Shuso Takeda (単著)
  • Journal Title: YAKUGAKU ZASSHI Volume: 133 Issue: 10 Pages: 1093-1101
  • DOI: 10.1248/yakushi.13-00196
  • NAID: 130004427986
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2013-10-01
  • Peer Reviewed
• [Journal Article] Δ9-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor β (ERβ) (2013)
  • Author(s): S. Takeda, K. Yoshida, H. Nishimura, M. Harada, S. Okajima, H. Miyoshi, Y. Okamoto, T. Amamoto, K. Watanabe, C.J. Omiecinski, H. Aramaki
  • Journal Title: Chemical Research in Toxicology Volume: 26 Issue: 7 Pages: 1073-1079
  • DOI: 10.1021/tx4000446
  • Peer Reviewed
• [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解析 (2015)
  • Author(s): 姫野太一、池田恵理子、岡崎裕之、徳安美紀、谷口彩、石井宏幸、垣添和弘、竹田修三、原口浩一、渡辺和人、荒牧弘範
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学ほか(神戸市)
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 新世代ビスフェノールBPAFによるエストロゲンシグナルへの影響 (2014)
  • Author(s): 垣添和弘、岡崎裕之、池田恵理子、徳安美紀、石井宏幸、姫野太一、谷口彩、吉岡靖史、竹田修三、原口浩一、荒牧弘範
  • Organizer: 第31回日本薬学会九州支部会
  • Place of Presentation: 第一薬科大学(福岡)
  • Year and Date: 2014-12-26 – 2014-12-27
• [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): 石井宏幸、池田恵理子、竹田修三、岡崎裕之、姫野太一、谷口彩、吉岡靖史、西村肇、渡辺和人、荒牧弘範
  • Organizer: 第31回日本薬学会九州支部会
  • Place of Presentation: 第一薬科大学(福岡)
  • Year and Date: 2014-12-26 – 2014-12-27
• [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、岡崎裕之、竹田修三、渡辺和人、荒牧弘範
  • Organizer: 第21回日本時間生物学会
  • Place of Presentation: 九州大学医学部百年講堂(福岡市)
  • Year and Date: 2014-11-08 – 2014-11-09
• [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、岡崎裕之、池田恵理子、石井宏幸、垣添和弘、姫野太一、谷口彩、吉岡靖史、竹田修三、原口浩一、渡辺和人、瀧口益史、荒牧弘範
  • Organizer: フォーラム2014：衛生薬学・環境トキシコロジー
  • Place of Presentation: つくば国際会議場(つくば市)
  • Year and Date: 2014-09-19 – 2014-09-20
• [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FA2Hの発現 (2014)
  • Author(s): 吉岡靖史、池田恵理子、竹田修三、石井宏幸、西村肇、渡辺和人、荒牧弘範
  • Organizer: フォーラム2014：衛生薬学・環境トキシコロジー
  • Place of Presentation: つくば国際会議場(つくば市)
  • Year and Date: 2014-09-19 – 2014-09-20
• [Presentation] ERβの発現誘導能を示す環境化学物質の網羅的解析 (2014)
  • Author(s): 池田 恵理子, 竹田 修三, 姫野 太一, 徳安 美紀, 西村 肇, 吉岡 靖史, 原口 浩一, 渡辺 和人, 荒牧 弘範
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本市(熊本市総合体育館)
• [Presentation] Δ9-テトラヒドロカンナビノールによるERβ発現誘導を介したエストロゲン/ERα機能抑制 (2013)
  • Author(s): 吉田 和貴, 竹田 修三, 西村 肇, 池田 恵理子, 渡辺 和人, 荒牧 弘範
  • Organizer: フォーラム2013：衛生薬学・環境トキシコロジー
  • Place of Presentation: 福岡市(九州大学医学部百年講堂)
• [Book] 日本医事新報 質疑応答: 医療用大麻とは (2014)
  • Author(s): 竹田修三(単著)
  • Total Pages: 2
  • Publisher: 日本医事新報社