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The functional chacterization of marmoset cytochrome P450 2C enzymes

Research Project

Project/Area Number 15K18934
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionShowa Pharmaceutical University

Principal Investigator

Uehara Shotaro  昭和薬科大学, 薬学部, 特任助教 (10733123)

Co-Investigator(Renkei-kenkyūsha) YAMAZAKI Hiroshi  昭和薬科大学, 薬物動態学研究室, 教授 (30191274)
Research Collaborator UNO Yasuhiro  株式会社新日本科学
Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
KeywordsチトクロムP450 / マーモセット / チロクロムP450 / P450 / Marmoset
Outline of Final Research Achievements

The enzymatic function of marmoset cytochrome P450 2C enzymes was analyzed. Recombinant marmoset P450 2C19 effectively metabolized human P450 2C substrates, S-warfarin, diclofenac, tolbutamide, flurbiprofen, and omeprazole. Marmoset P450 2C19 had high capacity and affinity for S-warfarin 7-hydroxylation that were comparable to those in human liver microsomes, indicating warfarin stereoselectivity similar to findings in humans. The interindividual variability of P450 2C-dependent drug metabolism such as S-warfarin clearance is at least partly accounted for by P450 2C19 variants p.[(Phe7Leu; Ser254Leu; Ile469Thr)] in marmosets. These findings on inter-individual variability and substrate specificity of marmoset P450 enzymes should help to understand apparent species differences in drug metabolism and disposition among marmosets and humans and to extrapolate the preclinical study data obtained using marmosets to humans.

Report

(3 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • Research Products

    (36 results)

All 2017 2016 2015

All Journal Article (20 results) (of which Peer Reviewed: 20 results,  Acknowledgement Compliant: 15 results) Presentation (16 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results)

  • [Journal Article] Marmoset cytochrome P450 4A11, a novel arachidonic acid and lauric acid ω-hydroxylase expressed in liver and kidney tissues.2017

    • Author(s)
      Uehara, S., Uno, Y., Ishii, S., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 印刷中 Issue: 7 Pages: 553-561

    • DOI

      10.1080/00498254.2016.1206673

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Strong induction of cytochrome P450 1A/3A, but not P450 2B, in cultured hepatocytes from common marmosets and cynomolgus monkeys by typical human P450 inducing agents.2017

    • Author(s)
      Uehara, S., Uno, Y., Suzuki, T., Inoue, T., Utoh, M., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab Lett.

      Volume: 印刷中

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Cloning and expression of a novel catechol-<i>O</i>-methyltransferase in common marmosets2017

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Sasaki, E. and Yamazaki H.
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 79 Issue: 2 Pages: 267-272

    • DOI

      10.1292/jvms.16-0459

    • NAID

      130005316105

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Marmoset Cytochrome P450 3A4 Ortholog Expressed in Liver and Small-Intestine Tissues Efficiently Metabolizes Midazolam, Alprazolam, Nifedipine, and Testosterone.2017

    • Author(s)
      Uehara, S., Uno, Y., Nakanishi, K., Ishii, S., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab Dispos.

      Volume: 45 Issue: 5 Pages: 457-467

    • DOI

      10.1124/dmd.116.074898

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Marmoset Flavin-Containing Monooxygenase 3 in the Liver Is a Major Benzydamine and Sulindac Sulfide Oxygenase.2017

    • Author(s)
      Uehara, S., Shimizu, M., Uno, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab Dispos.

      Volume: 45 Issue: 5 Pages: 497-500

    • DOI

      10.1124/dmd.117.075184

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Terfenadine t-butyl hydroxylation catalyzed by human and marmoset cytochrome P450 3A and 4F enzymes in livers and small intestines.2017

    • Author(s)
      Uehara, S., Yuki, Y., Uno, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 印刷中 Issue: 4 Pages: 342-347

    • DOI

      10.1080/00498254.2017.1321811

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] In vivo individual variations in pharmacokinetics of efavirenz in cynomolgus monkeys genotyped for cytochrome P450 2C9.2016

    • Author(s)
      Iwasaki, K., Kitsugi, Y., Ikeda, K., Yoshikawa, T., Hosaka, S., Uehara, S., Uno, Y., Utoh, M., and Yamazaki, H.
    • Journal Title

      Biopharm. Drug Dispos.

      Volume: 37 Issue: 6 Pages: 379-383

    • DOI

      10.1002/bdd.2021

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oxidation of R- and S-omeprazole stereoselectively mediated by liver microsomal cytochrome P450 2C19 enzymes from cynomolgus monkeys and common marmosets.2016

    • Author(s)
      Uehara, S., Kawano, M., Murayama, N., Uno, Y., Utoh, M., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Biochem Pharmacol.

      Volume: 120 Pages: 56-62

    • DOI

      10.1016/j.bcp.2016.09.010

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Utility of non-human primates in drug development: comparison of non-human primate and human drug-metabolizing cytochrome P450 enzymes.2016

    • Author(s)
      Uehara, S., Uno, Y., and Yamazaki, H.
    • Journal Title

      Biochem Pharmacol.

      Volume: 121 Pages: 1-7

    • DOI

      10.1016/j.bcp.2016.06.008

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes, caffeine, warfarin, omeprazole, metoprolol, and midazolam, in common marmosets (Callithrix jacchus).2016

    • Author(s)
      Uehara, S., Inoue, T., Utoh, M., Toda, A., Shimizu, M., Uno, Y., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 46 Issue: 2 Pages: 163-168

    • DOI

      10.3109/00498254.2015.1057270

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Caffeine 7-N-demethylation and C-8-oxidation mediated by liver microsomal cytochrome P450 enzymes in common marmosets.2016

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Suzuki, T., Utoh, M., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 46 Issue: 7 Pages: 573-578

    • DOI

      10.3109/00498254.2015.1096980

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Molecular cloning, tissue distribution, and functional characterization of marmoset cytochrome P450 1A1, 1A2, and 1B1.2016

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab. Dispos.

      Volume: 44 Issue: 1 Pages: 8-15

    • DOI

      10.1124/dmd.115.067561

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Marmoset cytochrome P450 2J2 mainly expressed in small intestines and livers effectively metabolizes human P450 2J2 probe substrates, astemizole and terfenadine.2016

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Okamoto, E., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 印刷中

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] A new marmoset P450 4F12 enzyme expressed in small intestines and livers efficiently metabolizes an anti-histaminic drug ebastine.2016

    • Author(s)
      Uehara, S., Uno, Y., Yuki, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab. Dispos.

      Volume: 印刷中

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Individual differences in metabolic clearance of S-warfarin efficiently mediated by polymorphic marmoset cytochrome P450 2C19 in livers.2016

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Kawano, M., Shimizu, M., Toda, A., Utoh, M., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab. Dispos.

      Volume: 印刷中

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Human plasma concentrations of cytochrome P450 probe cocktails extrapolated from pharmacokinetics in mice transplanted with human hepatocytes and from pharmacokinetics in common marmosets using physiologically based pharmacokinetic modeling2015

    • Author(s)
      Utoh, M., Suemizu, H., Mitsui, M., Kawao, M., Toda, A., Uehara, S., Uno, Y., Shimizu, M., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 46 Issue: 12 Pages: 1049-1055

    • DOI

      10.3109/00498254.2016.1147102

    • Related Report
      2016 Annual Research Report 2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol, and dextromethorphan.2015

    • Author(s)
      Uehara, S., Uno, Y., Hagihira, Y., Murayama, N., Shimizu, M., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Xenobiotica

      Volume: 45 Issue: 9 Pages: 757-765

    • DOI

      10.3109/00498254.2015.1019595

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Activation and deactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes and flavin-containing monooxygenases in common marmosets (Callithrix jacchus).2015

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Murayama, N., Shimizu, M., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab. Dispos.

      Volume: 43 Issue: 5 Pages: 735-742

    • DOI

      10.1124/dmd.115.063594

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Substrate selectivities and catalytic activities of marmoset liver cytochrome P450 2A6 differed from those of human P450 2A6.2015

    • Author(s)
      Uehara, S., Uno, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab. Dispos.

      Volume: 43 Issue: 7 Pages: 969-976

    • DOI

      10.1124/dmd.115.063909

    • Related Report
      2015 Research-status Report
    • Peer Reviewed
  • [Journal Article] Novel marmoset cytochrome P450 2C19 in livers efficiently metabolizes human P450 2C9 and 2C19 substrates, S-warfarin, tolbutamide, flurbiprofen, and omeprazole.2015

    • Author(s)
      Uehara, S., Uno, Y., Inoue, S., Kawano, M., Shimizu, M., Toda, A., Utoh, M., Sasaki, E., and Yamazaki, H.
    • Journal Title

      Drug Metab. Dispos.

      Volume: 43 Issue: 10 Pages: 1408-1416

    • DOI

      10.1124/dmd.115.066100

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] マーモセット、カニクイザルおよびヒト肝によるメトプロロール酸化的代謝の比較2017

    • Author(s)
      石井さくら、上原正太郎、宇野泰広、井上貴史、佐々木えりか、山崎浩史
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター(宮城県 仙台市)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] マーモセット、カニクイザルおよびヒト肝および小腸P450酵素によるテルフェナジンの酸化的代謝2017

    • Author(s)
      結城友香子、上原正太郎、宇野泰広、井上貴史、佐々木えりか、山崎浩史
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター(宮城県 仙台市)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] マーモセットP450 3A 酵素の臓器分布および薬物酸化酵素活性:ヒトP450 3Aとの類似性2017

    • Author(s)
      上原正太郎、中西一志、石井さくら、宇野泰広、井上貴史、佐々木えりか、山崎浩史
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター(宮城県 仙台市)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] 新規マーモセットP450 2F 酵素の同定および機能解析2017

    • Author(s)
      上原正太郎、大塩徹、宇野泰広、井上貴史、佐々木えりか、山崎浩史
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター(宮城県 仙台市)
    • Year and Date
      2017-03-24
    • Related Report
      2016 Annual Research Report
  • [Presentation] Identification and characterization of cytochrome P450 4F enzymes in marmosets.2016

    • Author(s)
      Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
    • Organizer
      11th International ISSX Meeting
    • Place of Presentation
      Busan(Korea)
    • Year and Date
      2016-06-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Pharmacokinetics of efavirenz after intravenous and oral administration of efavirenz to genotyped cynomolgus monkeys.2016

    • Author(s)
      Kazuhide Iwasaki, Yusuke Kitsugi, Kanami Ikeda, Takahiro Yoshikawa, Shotaro Uehara, Yasuhiro Uno, Masahiro Utoh, Hiroshi Yamazaki
    • Organizer
      11th International ISSX Meeting
    • Place of Presentation
      Busan(Korea)
    • Year and Date
      2016-06-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マーモセットあるいはカニクイザル肝細胞を用いた薬物暴露によるチトクロムP450誘導の評価2016

    • Author(s)
      鈴木貴子, 上原正太郎, 村山典恵, 宇野泰広, 矢島加奈子, 鵜藤雅裕, 井上貴史, 佐々木えりか, 山崎浩史
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Research-status Report
  • [Presentation] マーモセット肝のワルファリン酸化的代謝の立体選択性2016

    • Author(s)
      河野未来, 上原正太郎, 石井さくら, 宇野泰広, 井上貴史, 鵜藤雅裕, 佐々木えりか, 山崎浩史
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Research-status Report
  • [Presentation] 新規マーモセットP450 2J酵素の同定および機能解析2016

    • Author(s)
      上原正太郎, 岡本絵里子, 宇野泰広, 井上貴史, 佐々木えりか, 山崎浩史
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Research-status Report
  • [Presentation] マーモセットおよびカニクイザル小腸P450酵素によるエバスチン酸化的代謝2016

    • Author(s)
      上原正太郎, 結城友香子, 宇野泰広, 井上貴史, 佐々木えりか, 山崎浩史
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Research-status Report
  • [Presentation] ヒト肝細胞移植マウスおよびマーモセット生理学的薬物動態モデルを活用したチトクロムP450カクテル基質のヒト血中濃度推移予測2016

    • Author(s)
      清水万紀子, 三井満里奈, 河野未来, 上原正太郎, 宇野泰広, 鵜藤雅裕, 井上貴史, 佐々木えりか, 末水洋志, 山崎浩史
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Research-status Report
  • [Presentation] Cytochrome P450-dependent warfarin and caffeine metabolism in marmosets, monkeys, and humans.2015

    • Author(s)
      Hiroshi Yamazaki, Shotaro Uehara, Yasuhiro Uno, and Erika Sasaki
    • Organizer
      20th North American ISSX Meeting
    • Place of Presentation
      Hilton Orlando Bonnet Creek (Orlando, USA)
    • Year and Date
      2015-10-18
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] マーモセット肝のワルファリン代謝の解析2015

    • Author(s)
      河野未来, 上原正太郎, 宇野泰広, 鵜藤雅裕, 佐々木えりか、山崎浩史
    • Organizer
      第59回日本薬学会関東支部大会
    • Place of Presentation
      日本大学薬学部(千葉県・船橋市)
    • Year and Date
      2015-09-12
    • Related Report
      2015 Research-status Report
  • [Presentation] マーモセット肝のカフェイン代謝経路の解析2015

    • Author(s)
      鈴木貴子, 上原正太郎, 宇野泰広, 鵜藤雅裕, 佐々木えりか, 山崎浩史
    • Organizer
      第59回日本薬学会関東支部大会
    • Place of Presentation
      日本大学薬学部(千葉県・船橋市)
    • Year and Date
      2015-09-12
    • Related Report
      2015 Research-status Report
  • [Presentation] Cytochrome P450-dependent xenobiotic metabolism in marmosets2015

    • Author(s)
      Shotaro Uehara, Hiroshi Yamazaki
    • Organizer
      2nd Symposium of SPU Innovative Project for Pharmaceutical Analyses of Covalent Modification in Biomolecules
    • Place of Presentation
      昭和薬科大学(東京都・町田市)
    • Year and Date
      2015-08-31
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular cloning, expression and functional characterization of marmoset cytochrome P450 2A6.2015

    • Author(s)
      Shotaro Uehara, Yasuhiro Uno, Norie Murayama, Makiko Shimizu, Hiroshi Yamazaki
    • Organizer
      19th International Conference on Cytochrome P450
    • Place of Presentation
      国立オリンピック記念青少年総合センター(東京都・代々木)
    • Year and Date
      2015-06-12
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research

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Published: 2015-04-16   Modified: 2018-03-22  

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