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Influence of chemicals used in consumer products on endocrine-system via activation of nuclear receptors

Research Project

Project/Area Number 16K00559
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Risk sciences of radiation and chemicals
Research InstitutionNihon Pharmaceutical University

Principal Investigator

Kitamura Shigeyuki  日本薬科大学, 薬学部, 客員教授 (40136057)

Co-Investigator(Kenkyū-buntansha) 佐能 正剛  広島大学, 医歯薬保健学研究科(薬), 助教 (00552267)
清水 良  広島国際大学, 薬学部, 講師 (00570491)
杉原 数美  広島国際大学, 薬学部, 教授 (20271067)
藤本 成明  広島大学, 原爆放射線医科学研究所, 准教授 (40243612)
渡部 容子  日本薬科大学, 薬学部, 助教 (60628056)
Project Period (FY) 2016-10-21 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords核内受容体 / 環境化学物質 / 内分泌撹乱 / 生活用品 / シトクロムP450 / 生活関連化学物質 / 内分泌撹乱活性 / 紫外線吸収剤 / リン系難燃剤 / 殺菌剤パラベン / 残留性農薬 / 代謝活性化 / 殺菌料パラベン / 代謝的活性化
Outline of Final Research Achievements

Some chemicals were added into consumer products. It is necessary to conduct the safety assessment of these chemicals. In this study, these chemicals are tested agonistic and antagonistic actions on nuclear receptors using reporter gene assay. Some chemicals such as phthalates, salicylates, parabens, bisphenol A, synthetic musks, UV-filters, brominated flame retardants and pesticides exhibited agonistic and/or antagonistic actions towards estrogen receptor, androgen receptor, thyroid hormone receptor, pregnane X receptor, constitutive androstane receptor and peroxisome proliferator-activate receptor. These chemicals also induced drug-metabolizing enzymes, especially cytochrome P450, via these nuclear receptor activation. Organophosphate flame retardants directly inhibited carboxylesterase in rat livers. In this manner, these chemical may induce endocrine-disrupting actions.

Academic Significance and Societal Importance of the Research Achievements

近年、使用量が増加している生活用品に含まれる化学物質の安全性評価は重要で早急な課題と言える。本研究によって、幾つかの化学物質が核内受容体を介して薬物代謝酵素系に影響することを見出した。このことは薬物以外に、ホルモンや脂質などの内在性物質の代謝にも影響することから、内分泌撹乱作用に繋がる。このような現状において、本研究課題である「生活用品に含まれる化学物質の核内受容体を介した安全性評価」は、社会のニーズに応じたものであり、安全な日常生活を送る上から欠かせないものである。今後、本研究で、危険性を指摘した化学物質に対して、さらなる安全性評価がなされることが望まれる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (34 results)

All 2019 2018 2017 2016

All Journal Article (15 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 15 results,  Open Access: 12 results,  Acknowledgement Compliant: 4 results) Presentation (19 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results)

  • [Journal Article] Profiling of bisphenol A and eight its analogues on transcriptional activity via human nuclear receptors2019

    • Author(s)
      Hiroyuki Kojima, Shinji Takeuchi, Seigo Sanoh, Katsuhiro Okuda, Shigeyuki Kitamura, Naoto Uramaru, Kazumi Sugihara, Kouichi Yoshinari
    • Journal Title

      Toxicology, 413(2),48-55,

      Volume: 413 Pages: 48-55

    • DOI

      10.1016/j.tox.2018.12.001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of benzotriazole ultraviolet stabililizers on rat PXR, CAR and PPARa transcriptional activities2019

    • Author(s)
      Yoko Watanabe, Shoko Hattori, Chieri Emori, Ken Tachibana, Hiroyuki Kojima, Kouichiro Yoshinari, Shigeyuki Kitamura
    • Journal Title

      Fundamental Toxicological Sciences

      Volume: 6 Pages: 57-63

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of the Metabolic Modification of Environmental Chemicals on Endocrine-disrupting Activity2018

    • Author(s)
      Shigeyuki Kitamura
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 138 Issue: 5 Pages: 693-713

    • DOI

      10.1248/yakushi.17-00214

    • NAID

      130006729462

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2018-05-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Study of metabolic activation of the UV-filter octyl methoxycinnamate for endocrine-disrupting activity2018

    • Author(s)
      Yoko Watanabe, Chieri Emori, Naoto Uramaru, Nariaki Fujimoto, Shigeyuki Kitamura
    • Journal Title

      Fundamental Toxicological Sciences

      Volume: 5 Pages: 185-193

    • NAID

      130007525309

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of hepatic thyroid hormone-responsive genes in neonatal rats: Potential targets for thyroid hormone-disrupting chemicals.2018

    • Author(s)
      Fujimoto N., Kitamura S., Uramaru N., Miyagawa S., Iguchi T.
    • Journal Title

      Toxicology Letters

      Volume: 286 Pages: 48-53

    • DOI

      10.1016/j.toxlet.2018.01.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions2018

    • Author(s)
      Naoki Takaoka; Seigo Sanoh; Katsuhiro Okuda; Yaichiro Kotake; Go Sugahara; Ami Yanagi; Yuji Ishida; Chise Tateno;Yoshitaka Tayama; Kazumi Sugihara; Shigeyuki Kitamura; Mami Kurosaki; Mineko Terao; Enrico Garattini; Shigeru Ohta
    • Journal Title

      Biochem. Pharmacol., 154, 28-38. 2018

      Volume: 154 Pages: 28-38

    • DOI

      10.1016/j.bcp.2018.04.017

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Construction of the Database of Rat Repeated-dose Toxicity Tests of Pesticides for the Toxicological Characterization of Hepatocyte Hypertrophy2017

    • Author(s)
      増田茜、増田雅美、中島宏之、小島弘幸、北村繁幸、浦丸直人、保坂卓臣、佐々木崇光、吉成浩一―
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 137 Issue: 5 Pages: 611-622

    • DOI

      10.1248/yakushi.16-00259

    • NAID

      130005631433

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2017-05-01
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Altered expression of Olr59, Ethe1, and Slc10a2 genes in the liver of F344 rats by neonatal thyroid hormone disruption.2017

    • Author(s)
      Matsubara K et al.
    • Journal Title

      J Appl Toxicol

      Volume: - Issue: 9 Pages: 1030-1035

    • DOI

      10.1002/jat.3452

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparative study of hydrolytic metabolism of dimethyl phthalate, dibutyl phthalate and di(2-ethylhexyl) phthalate by microsomes of various rat tissues2017

    • Author(s)
      Ozaki H., Sugihara K., Watanabe Y., Moriguchi K., Uramaru N., Sone T., Ohta S., Kitamura S.
    • Journal Title

      Food and Chemical Toxicology

      Volume: 100 Pages: 217-224

    • DOI

      10.1016/j.fct.2016.12.019

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Developmental changes in drug-metabolizing enzyme expression during metamorphosis of <i>Xenopus tropicalis </i>2017

    • Author(s)
      Mori J., Sanoh S., Kashiwagi K., Hanada H., Shigeta M., Suzuki K., Yamamoto T., Kotake Y., Sugihara K., Kitamura S., Kashiwagi A., Ohta S.
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 42 Issue: 5 Pages: 605-613

    • DOI

      10.2131/jts.42.605

    • NAID

      130006076698

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In vitro metabolism of methiocarb and carbaryl in rats, and its effect on their estrogenic and antiandrogenic activities.2016

    • Author(s)
      Tange S., Fujimoto N., Uramaru N., Wong F. F., Sugihara K., Ohta S., Kitamura S.
    • Journal Title

      Environ Toxicol Pharmacol

      Volume: 41 Pages: 289-297

    • DOI

      10.1016/j.etap.2015.08.014

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Variability of Zalepron 5-oxidase activity in mice and humans, and inhibition by raloxifene.2016

    • Author(s)
      Tanoue C., Sugihara K., Tayama Y., Uramaru N., Watanabe Y., Ohta S., Kitamura S.
    • Journal Title

      Drug Metabolism Letters

      Volume: 10 Issue: 4 Pages: 278-285

    • DOI

      10.2174/1872312810666161227145358

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Estimation of occupational exposure to drugs during tablet crushing.2016

    • Author(s)
      Shizuko Maeda, Eiko Takahashi, Yoshitaka Tayama, Shigeyuki Kitamura, Toyohisa Tsukamoto, Katsushi Miyake, Kazumi Sugihara.
    • Journal Title

      Fundamental Toxicological Sciences

      Volume: 3 Pages: 177-183

    • NAID

      130005158221

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cytochrome P450-inhibitory activity of parabens and phthalates used in consumer products2016

    • Author(s)
      Hitomi Ozaki, Kazumi Sugihara, Yoko Watanabe, Shigeru Ohta, Shigeyuki Kitamura .
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 41 Issue: 4 Pages: 551-560

    • DOI

      10.2131/jts.41.551

    • NAID

      130005165024

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities2016

    • Author(s)
      Chieri Fujino, Yuki Tamura, Satoko Tange, Hiroyuki Nakajima, Seigo Sanoh, Yoko Watanabe, Naoto Uramaru, Hiroyuki Kojima, Kouichi Yoshinari, Shigeru Ohta, Shigeyuki Kitamura
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 41 Issue: 5 Pages: 677-691

    • DOI

      10.2131/jts.41.677

    • NAID

      130005266225

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] ラズベリーケトンの還元的代謝および3T3-L1 細胞の脂肪化抑制2019

    • Author(s)
      浦丸 直人,坂本 佳澄,鈴木 智貴,木根淵 有香,川村 涼,渡部 容子,北村 繁幸,樋口 敏幸
    • Organizer
      日本薬学会139年会 千葉幕張メッセ 2019年3月20-22日
    • Related Report
      2018 Annual Research Report
  • [Presentation] 離乳期におけるラット肝CYPおよびaldehyde oxidaseの変動2019

    • Author(s)
      杉原 数美, 村川 晃大, 荒井 美幸, 田山 剛崇, 清水 良, 北村 繁幸, 太田 茂
    • Organizer
      日本薬学会139年会 千葉幕張メッセ 2019年3月20-22日
    • Related Report
      2018 Annual Research Report
  • [Presentation] Aldehyde oxidase およびCYP2A6 がnicotine 代謝に及ぼす影響2019

    • Author(s)
      田山 剛崇, 西村 さとみ, 杉原 数美, 北村 繁幸, 佐和 章弘, 三宅 勝志
    • Organizer
      日本薬学会139年会 千葉幕張メッセ 2019年3月20-22日
    • Related Report
      2018 Annual Research Report
  • [Presentation] リン系難燃剤のラット肝および小腸カルボキシルエステラーゼに対する阻害効果2018

    • Author(s)
      津越 幸枝,渡部 容子,杉原 数美,北村 繁幸
    • Organizer
      フォーラム2018衛生薬学・環境トキシコロギー アルカス佐世保 2018年9月10-11日
    • Related Report
      2018 Annual Research Report
  • [Presentation] Sex differences of aldehyde oxidases in mouse liverAssessment of inhibitory effects of drugs on mouse and human aldehyde oxidases through in silico, in vitro, and in vivo approaches2018

    • Author(s)
      Kazumi Sugihara, Yoshitaka Tayama, Seigo Sanoh, Shigeyuki Kitamura, Shigeru Ohta
    • Organizer
      2018 International Meeting on 22nd MDO and 33rd JSSX
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Assessment of inhibitory effects of drugs on mouse and human aldehyde oxidases through in silico, in vitro, and in vivo approaches2018

    • Author(s)
      Naoki Takaoka, Seigo Sanoh, Katsuhiro Okuda, Go Sugahara, Ami Yanagi, Yuji Ishida, Chise Tateno, Yoshitaka Tayama, Kazumi Sugihara, Shigeyuki Kitamura, Mami Kurosaki, Mineko Terao, Enrico Garattini, Shigeru Ohta, Yaichiro Kotake
    • Organizer
      2018 International Meeting on 22nd MDO and 33rd JSSX
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ベンズトリアゾール系紫外線吸収剤のPXR, CAR,およびPPARα活性とシトクロムP450活性への影響2017

    • Author(s)
      服部祥子,渡部容子,立花 研,小島弘幸,吉成浩一,北村繁幸
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 臭素化難燃剤PBDE類によるAhRの活性化を介したUGT遺伝子発現誘導機構.内受容体PXRおよびCAR転写活性作用を示す甲状腺ホルモン構造類似環境化学物質のスクリーニング2017

    • Author(s)
      清水 良,浦丸直人,渡部容子, 太田 茂, 北村繁幸, 杉原数美
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] カルバメート系農薬のラットおよびヒトでのin vitro代謝とその核内受容体活性への影響2017

    • Author(s)
      藤野智恵里,渡部容子,浦丸直人,佐能正剛,小島弘幸,吉成浩一,太田 茂,北村繁幸
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] リン系難燃剤のラットカルボキシルエステラーゼ活性に対する阻害効果2017

    • Author(s)
      津越幸枝,渡部容子,杉原数美,北村繁幸
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] リン系難燃剤のラット核内受容体PXR、CARおよびPPARαに対するアゴニスト活性2017

    • Author(s)
      柳川ひらり,渡部容子,小島弘幸,吉成浩一, 北村繁幸
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 合成ムスク類のラットin vivoにおける肝シトクロムP450活性への影響2017

    • Author(s)
      渡部容子,服部祥子,立花 研,佐能正剛,太田 茂,北村繁幸
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 医薬品類による環境汚染と環境因子による毒性変動2017

    • Author(s)
      杉原数美
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 3次元培養およびヒト肝細胞移植キメラマウスを用いた肝臓における薬物代謝、毒性評価2017

    • Author(s)
      佐能正剛
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] フタル酸エステル類とその代謝物が核内受容体およびの転写活性に及ぼす影響2017

    • Author(s)
      佐藤志穂、渡部容子、立花 研、浦丸直人、小島弘幸、吉成浩一、樋口敏幸、北村繁幸
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 薬物代謝酵素アルデヒドオキシダーゼのマウスにおける性差と系統差2017

    • Author(s)
      岸沙也香、村川晃大、平本耕一、清水 良、佐能正剛、太田 茂、北村繁幸、杉原数美
    • Organizer
      第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
    • Related Report
      2017 Research-status Report
  • [Presentation] マウス肝アルデヒドオキシダーゼの性特異的発現機序の検討2017

    • Author(s)
      内藤祐子,田坂真希,富吉博也,濱﨑千尋,清水 良,佐能正剛,太田 茂,北村繁幸、杉原数美
    • Organizer
      第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
    • Related Report
      2017 Research-status Report
  • [Presentation] マウス肝アルデヒド酸化酵素分子種の系統差と性差2017

    • Author(s)
      杉原数美, 平本耕一, 田坂真希, 田山剛崇, 佐能正剛, 太田 茂, 北村繁幸
    • Organizer
      日本薬物動態学会第32回年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 塩素消毒処理による医薬品および生活関連化学物質の毒性変動調査2017

    • Author(s)
      國澤和憲、岡田達司、堂脇美緒、井上沙也香、清水 良、北村繁幸、太田 茂、杉原数美
    • Organizer
      フォーラム2017:衛生薬学・環境トキシコロジー
    • Related Report
      2017 Research-status Report

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Published: 2016-10-24   Modified: 2020-03-30  

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