The functional chacterization of marmoset cytochrome P450 2C enzymes

• Project/Area Number: 15K18934
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Showa 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: ¥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.

Research Products

• [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
  • 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
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cloning and expression of a novel catechol-<i>O</i>-methyltransferase in common marmosets (2017)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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 modeling (2015)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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
  • 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
  • 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
• [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
• [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
• [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
• [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
• [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
  • 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
• [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
• [Presentation] Cytochrome P450-dependent xenobiotic metabolism in marmosets (2015)
  • 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
  • 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
  • Int'l Joint Research