The functional characterization of cytochrome P450 enzymes from preclinical species

• Project/Area Number: 17K15520
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Central Institute for Experimental Animals
• Principal Investigator: Uehara Shotaro 公益財団法人実験動物中央研究所, 実験動物研究部, 研究員 (10733123)
• Research Collaborator: SUEMIZU Hiroshi ; YAMAZAKI Hiroshi ; UNO Yasuhiro
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥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 / 薬物代謝 / 薬物代謝における動物種差 / シトクロムP450 / P450 3A4 / P450 2D6 / P450 2C19 / プロゲステロン / プロパフェノン / CYP2B6 / ヒト肝キメラマウス

Outline of Final Research Achievements

Common marmosets (Callithrix jacchus) are attracting attention as non-human primate models in preclinical studies for drug development. Marmoset cytochrome P450 (P450) forms exhibited high degree of amino acid sequence identity (more than 85% in most of P450 orthologs) toward human P450 orthologs, and catalyzed typical human P450 substrates. In addition, the role of P450 3A and 2C enzymes for progesterone oxidation was similar to the case of human P450s. These results in this study suggested marmosets were potentially suitable animal models for drug metabolism and pharmacokinetics studies.

Academic Significance and Societal Importance of the Research Achievements

医薬品開発において医薬候補化合物の有効性や安全性は実験動物を用いて評価される。薬物の安全性および毒性を予測するための薬物動態研究では、げっ歯類から非ヒト霊長類まで様々な実験動物が用いられる。本研究では、主要な薬物代謝酵素チトクロムP450の特性に着目し、小型霊長類マーモセットがヒト薬物動態を精度よく予測するために有用な動物種である可能性を示唆した。薬物動態研究にマーモセットを有効活用することで、より安全で有効性の高い医薬品の開発が加速することが期待される。

Research Products

• [Journal Article] Survey of Drug Oxidation Activities in Liver and Intestine Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model. (2019)
  • Author(s): Uehara S, Oshio T, Nakanishi K, Tomioka E, Suzuki M, Inoue T, Uno Y, Sasaki E, Yamazaki H.
  • Journal Title: Curr Drug Metab. Volume: 20 Issue: 2 Pages: 103-113
  • DOI: 10.2174/1389200219666181003143312
  • Peer Reviewed
• [Journal Article] Marmoset Cytochrome P450 2B6, a Propofol Hydroxylase Expressed in Liver. (2019)
  • Author(s): Oshio T, Uehara S, Uno Y, Inoue T, Sasaki E, and Yamazaki H.
  • Journal Title: Xenobiotica Volume: 49 Issue: 3 Pages: 265-269
  • DOI: 10.1080/00498254.2018.1439204
  • Peer Reviewed
• [Journal Article] Expression and inducibility of cytochrome P450s in human hepatocytes isolated from chimeric mice with humanized livers. (2019)
  • Author(s): Uehara S, Higuchi Y, Yoneda N, Yamazaki H, and Suemizu H.
  • Journal Title: Xenobiotica Volume: 49 Issue: 6 Pages: 678-687
  • DOI: 10.1080/00498254.2018.1495346
  • Peer Reviewed
• [Journal Article] Polymorphisms of cytochrome P450 2B6 (CYP2B6) in cynomolgus and rhesus macaques. (2019)
  • Author(s): Uno Y, Uehara S, and Yamazaki H. Polymorphisms of cytochrome P450 2B6 (CYP2B6) in cynomolgus and rhesus macaques.
  • Journal Title: J Med Primatol. Volume: 印刷中 Issue: 4 Pages: 232-237
  • DOI: 10.1111/jmp.12336
  • Peer Reviewed
• [Journal Article] Regioselective hydroxylation of an antiarrhythmic drug, propafenone, mediated by rat liver cytochrome P450 2D2 differs from that catalyzed by human P450 2D6. (2019)
  • Author(s): Uehara S, Murayama N, Yamazaki H, and Suemizu H.
  • Journal Title: Xenobiotica Volume: 印刷中 Issue: 11 Pages: 1323-1331
  • DOI: 10.1080/00498254.2018.1564401
  • Peer Reviewed
• [Journal Article] Molecular cloning and tissue distribution of a novel marmoset ABC transporter. (2018)
  • Author(s): Uehara S, Uno Y, Inoue T, Sasaki E, and Yamazaki H.
  • Journal Title: Biopharm Drug Dispos. Volume: 39 Issue: 1 Pages: 59-63
  • DOI: 10.1002/bdd.2111
  • Peer Reviewed
• [Journal Article] Effects of aging and rifampicin pretreatment on the pharmacokinetics of human cytochrome P450 probes caffeine, warfarin, omeprazole, metoprolol and midazolam in common marmosets genotyped for cytochrome P450 2C19. (2018)
  • Author(s): Toda A, Uehara S, Inoue T, Utoh M, Kusama T, Shimizu M, Uno Y, Mogi M, Sasaki E, and Yamazaki H.
  • Journal Title: Xenobiotica Volume: 48 Issue: 7 Pages: 720-726
  • DOI: 10.1080/00498254.2017.1353716
  • Peer Reviewed
• [Journal Article] Marmoset pulmonary cytochrome P450 2F1 oxidizes biphenyl and 7-ethoxycoumarin and hepatic human P450 substrates. (2018)
  • Author(s): Uehara S, Uno Y, Oshio T, Inoue T, Sasaki E, and Yamazaki H.
  • Journal Title: Xenobiotica Volume: 48 Issue: 7 Pages: 656-662
  • DOI: 10.1080/00498254.2017.1354138
  • Peer Reviewed
• [Journal Article] Progesterone hydroxylation by cytochromes P450 2C and 3A enzymes in marmoset liver microsomes. (2018)
  • Author(s): Nakanishi K, Uehara S, Uno Y, Inoue T, Sasaki E, and Yamazaki H.
  • Journal Title: Xenobiotica Volume: 48 Issue: 8 Pages: 757-763
  • DOI: 10.1080/00498254.2017.1363444
  • Peer Reviewed
• [Journal Article] Association with polymorphic marmoset cytochrome P450 2C19 of in vivo hepatic clearances of chirally separated R-omeprazole and S-warfarin using individual marmoset physiologically based pharmacokinetic models. (2018)
  • Author(s): Kusama T, Toda A, Shimizu M, Uehara S, Inoue T, Uno Y, Utoh M, Sasaki E, and Yamazaki H.
  • Journal Title: Xenobiotica Volume: 48 Issue: 10 Pages: 1072-1077
  • DOI: 10.1080/00498254.2017.1393121
  • Peer Reviewed
• [Journal Article] Molecular characterization and polymorphisms of butyrylcholinesterase in cynomolgus macaques. (2018)
  • Author(s): Uno Y, Uehara S, Mahadhi HMD, Ohura K, Hosokawa M, Imai T.
  • Journal Title: J Med Primatol. Volume: 47 Issue: 3 Pages: 185-191
  • DOI: 10.1111/jmp.12342
  • Peer Reviewed
• [Journal Article] In vivo and in vitro diclofenac 5-hydroxylation mediated primarily by cytochrome P450 3A enzymes in common marmoset livers genotyped for P450 2C19 variants. (2018)
  • Author(s): Nakanishi K, Uehara S, Kusama T, Inoue T, Shimura K, Kamiya Y, Murayama N, Shimizu M, Uno Y, Sasaki E, and Yamazaki H.
  • Journal Title: Biochem Pharmacol. Volume: 152 Pages: 272-278
  • DOI: 10.1016/j.bcp.2018.04.002
  • Peer Reviewed
• [Journal Article] Cytochrome P450 1A1, 2C9, 2C19, and 3A4 Polymorphisms Account for Interindividual Variability of Toxicological Drug Metabolism in Cynomolgus Macaques. (2018)
  • Author(s): Uno Y, Uehara S, Murayama N, and Yamazaki H.
  • Journal Title: Chem Res Toxicol. Volume: 31 Issue: 12 Pages: 1373-1381
  • DOI: 10.1021/acs.chemrestox.8b00257
  • Peer Reviewed
• [Journal Article] Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans. (2018)
  • Author(s): Uno Y, Uehara S, Yamazaki H.
  • Journal Title: Biochem Pharmacol. Volume: 153 Pages: 184-195
  • DOI: 10.1016/j.bcp.2017.12.015
  • Peer Reviewed
• [Journal Article] Progesterone hydroxylation by cytochromes P450 2C and 3A enzymes. (2018)
  • Author(s): Nakanishi K, Uehara S, Uno Y, Inoue T, Sasaki E, Yamazaki H.
  • Journal Title: Xenobiotica Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Marmoset Cytochrome P450 2B6, a Propofol Hydroxylase Expressed in Liver. (2018)
  • Author(s): Oshio T., Uehara, S., Uno, Y., Inoue, T., Sasaki, E., and Yamazaki, H.
  • Journal Title: Xenobiotica Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Hepatic expression of cytochrome P450 enzymes in non-human primate species. (2017)
  • Author(s): Uehara, S., Uno, Y., and Yamazaki, H.
  • Journal Title: J Med Primatol. Volume: 46 Issue: 6 Pages: 347-351
  • DOI: 10.1111/jmp.12288
  • Peer Reviewed
• [Presentation] 生理学的薬物動態モデルとヒト肝移植マウスを用いた短長鎖フタル酸ジエステル類のヒト尿中予測排泄速度の差異 (2019)
  • Author(s): 三浦智徳, 吉沢愛映, 水野紗和, 上原正太郎, 神矢佑輔, 村山典恵, 清水万紀子, 末水洋志, 山崎浩史
  • Organizer: 日本薬学会第139年会
• [Presentation] グルクロン酸抱合活性の種差を考慮したフタル酸ジブチル経口投与後の生理学的薬物動態モデルによるヒト体内動態予測 (2019)
  • Author(s): 水野紗和，三浦智徳，吉沢愛映，上原正太郎，神矢佑輔，村山典恵，清水万紀子，末水洋志，山崎浩史
  • Organizer: 日本薬学会第139年会
• [Presentation] 医薬品等の抱合反応を触媒するマーモセット肝グルタチオンS-転移酵素分子種 (2019)
  • Author(s): 田中佐季，村山典恵，加藤雅巳，上原正太郎，上原正太郎，宇野泰広，山崎浩史
  • Organizer: 日本薬学会第139年会
• [Presentation] マーモセット肝UDP-グルクロン酸転移酵素 (UGT) 触媒機能のサルとヒトとの比較 (2019)
  • Author(s): 河村秀，村山典恵，小野関駿佑，上原正太郎，石井祐，上原正太郎，宇野泰広，生城真，山崎浩史
  • Organizer: 日本薬学会第139年会
• [Presentation] EXPRESSION AND INDUCTION ABILITY OF CYTOCHROME P450 IN HUMAN HEPATOCYTES HARVESTED FROM CHIMERIC MICE WITH HUMANIZED LIVER. (2018)
  • Author(s): Uehara S, Higuchi Y, Yoneda N, Yamazaki H, and Suemizu H
  • Organizer: 22nd North American ISSX Meeting
• [Presentation] Activities of UDP-glucuronosyltransferase 1A/2B enzymes in marmoset liver microsomes: comparison with cynomolgus macaques and humans (2018)
  • Author(s): Murayama N, Uehara S, Ishii Y, Onozeke S, Kawamura S, Ikushiro S, Uno Y, Yamazaki H
  • Organizer: 2018MDO/JSSX
• [Presentation] Expression and inducibility of cytochrome P450 in human hepatocytes from humanized-liver TK-NOG mice. (2018)
  • Author(s): Uehara S, Higuchi Y, Yoneda N, Yamazaki H, and Suemizu H
  • Organizer: 2018MDO/JSSX