Evaluaion of Human Cytochrome P450 3A Enzymes in Hepatic and Placental Cells by Thalidomide and Relevance to Bioactivation

• Project/Area Number: 26460206
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: Yamazaki Hiroshi 昭和薬科大学, 薬学部, 教授 (30191274)
• Co-Investigator(Kenkyū-buntansha): 村山 典惠 昭和薬科大学, 薬学部, 講師 (90219949) ; 清水 万紀子 昭和薬科大学, 薬学部, 講師 (90307075)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: サリドマイド / P450 3A / 代謝的活性化 / ヒト肝移植マウス / 胎盤 / P450 / CYP3A4

Outline of Final Research Achievements

Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically-based pharmacokinetic model based on data obtained in mice with humanized liver. In vivo non-specific hepatic protein binding parameters of metabolically activated [14C]-5-hydroxythalidomide and subsequent metabolic activation in humanized liver mice can be analyzed by accelerator mass spectrometry. Human placental microsomal fractions showed detectable thalidomide 5-hydroxylation activities. Thalidomide significantly induced P450 3A4/3A5 and pregnane X receptor (PXR) mRNA levels 2- to 3-fold in human placental BeWo cells cultured with a modified medium. Thalidomide also significantly induced midazolam 1´-hydroxylation and thalidomide 5-hydroxylaion activities 3-fold. Taken together, activation of thalidomide to 5-hydroxythalidomide with autoinduction of P450 3A enzymes in human placentas, as well as livers, is suggested in vivo.

Research Products

• [Int'l Joint Research] Vanderbilt University School of Medicine(米国)
• [Int'l Joint Research] Vanderbilt University(米国)
• [Int'l Joint Research] Biopredic Co.(France)
• [Journal Article] Differences in toxicological and pharmacological responses mediated by polymorphic cytochromes P450 and related drug-metabolizing enzymes. (2017)
  • Author(s): Yamazaki, H.
  • Journal Title: Chem. Res. Toxicol. Volume: 30 Issue: 1 Pages: 53-60
  • DOI: 10.1021/acs.chemrestox.6b00286
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity (2017)
  • Author(s): Murayama, N., Kazuki, Y., Satoh, D., Arata, K., Harada, T., Shibata, N., Guengerich, F. P., and Yamazaki, H
  • Journal Title: J. Toxicol. Sci. Volume: 42
  • NAID: 130006865647
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Assessment of protein binding of 5-hydroxythalidomide bioactivated in humanized mice with human P450 3A-chromosome or hepatocytes by two-dimensional electrophoresis/accelerator mass spectrometry (2016)
  • Author(s): Yamazaki, H., Suemizu, H., Kazuki, Y., Oofusa, K., Kuribayashi, S., Shimizu, M., Ninomiya, S., Horie, T., Shibata, N., and Guengerich, F. P.
  • Journal Title: Chem. Res. Toxicol. Volume: 29 Issue: 12 Pages: 1279-1281
  • DOI: 10.1021/acs.chemrestox.6b00136
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model. (2016)
  • Author(s): Kazuki Y, Akita M, Kobayashi K, Osaki M, Satoh D, Ohta R, Abe S, Takehara S, Kazuki K, Yamazaki H, Kamataki T, Oshimura M.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 21419-21419
  • DOI: 10.1038/srep21419
  • Peer Reviewed / Open Access
• [Journal Article] Simulation of human plasma concentrations of thalidomide and primary 5-hydroxylated metabolites explored with pharmacokinetic data in humanized TK-NOG mice (2015)
  • Author(s): Nishiyama, S., Suemizu, H., Shibata, N., Guengerich, F. P., and Yamazaki, H.
  • Journal Title: Chem. Res.Toxicol. Volume: 28 Issue: 11 Pages: 2088-2090
  • DOI: 10.1021/acs.chemrestox.5b00381
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Human HepaRG cells can be cultured in hanging-drop plates for cytochrome P450 induction and function assays (2015)
  • Author(s): Murayama, N., Usui, T., Slawny, N., Chesne, C., and Yamazaki, H
  • Journal Title: Drug Metab.Lett. Volume: 28 Issue: 1 Pages: 268-278
  • DOI: 10.2174/1872312809666150119104806
  • Peer Reviewed / Int'l Joint Research / 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] Zone analysis by two-dimensional electrophoresis with accelerator mass spectrometry of in vivo protein bindings of idiosyncratic hepatotoxicants troglitazone and flutamide bioactivated in chimeric mice with humanized liver (2015)
  • Author(s): Yamazaki,H.; Kuribayashi,S.; Inoue,T.; Honda,T.; Tateno,C.; Oofusa,K.; Ninomiya,S.; Ikeda,T.; Izumi,T.; Horie,T.
  • Journal Title: Toxicol.Res. Volume: 4 Issue: 1 Pages: 106-111
  • DOI: 10.1039/c4tx00068d
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Human urine and plasma concentrations of bisphenol A extrapolated from pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and semi-physiological pharmacokinetic modeling (2015)
  • Author(s): Miyaguchi,T.; Suemizu,H.; Shimizu,M.; Shida,S.; Nishiyama,S.; Takano,R.; Murayama,N.; Yamazaki,H.
  • Journal Title: Regul.Toxicol.Pharmacol. Volume: 72 Issue: 1 Pages: 71-76
  • DOI: 10.1016/j.yrtph.2015.03.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes (2014)
  • Author(s): Suemizu,H.; Sota,S.; Kuronuma,M..; Shimizu,M.; Yamazaki,H.
  • Journal Title: Regul.Toxicol.Pharmacol. Volume: 70 Issue: 2 Pages: 468-473
  • DOI: 10.1016/j.yrtph.2014.08.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of pregnane X receptor (2014)
  • Author(s): Murayama, N., van Beuningen, R., Suemizu, H., Guguen-Guillouzo, C., Shibata, N., Yajima, K., Utoh, M., Shimizu, M., Chesne, C., Nakamura, M., Guengerich, F. P., Houtman, R., and Yamazaki, H
  • Journal Title: Chem.Res.Toxicol Volume: 27 Issue: 2 Pages: 304-307
  • DOI: 10.1021/tx4004374
  • Peer Reviewed
• [Journal Article] 261. Chowdhury G, Shibata N, Yamazaki H., and Guengerich FP. Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analog of thalidomide (2014)
  • Author(s): Chowdhury G, Shibata N, Yamazaki H., and Guengerich FP.
  • Journal Title: Chem. Res.Toxicol. Volume: 27 Issue: 1 Pages: 146-157
  • DOI: 10.1021/tx4004215
  • Peer Reviewed
• [Presentation] Combining mice with humanized liver, mass spectrometry, and physiologically-based pharmacokinetic modeling (2016)
  • Author(s): Hiroshi Yamazaki
  • Organizer: The 31st JSSX Annual Meeting
  • Place of Presentation: キッセイ文化ホール（長野県 松本市）
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] Activation of thalidomide to reactive metabolites by autoinduced human cytochrome P450 3A enzymes with substrate cooperativity (2016)
  • Author(s): Hiroshi Yamazaki, Makiko Shimizu
  • Organizer: The 21st International Symposium on Microsomes and Drug Oxidations
  • Place of Presentation: Davis, California, USA
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] Human and monkey P450 metabolism for human-specific metabolite formation (2016)
  • Author(s): Hiroshi Yamazaki:
  • Organizer: 11th International ISSX Meeting
  • Place of Presentation: 釜山、韓国
  • Year and Date: 2016-06-12
  • Int'l Joint Research / Invited
• [Presentation] Comparison of drug oxidations in humans, primates, and rodents (2016)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 13th Meeting of the Asia Pacific Federation of Pharmacologists （Bangkok)）
  • Place of Presentation: Barkley Hotel (Bangkok, Thai）
  • Year and Date: 2016-02-01
  • Int'l Joint Research / Invited
• [Presentation] ヒト薬物動態予測を目指したサル、マーモセットとヒト肝細胞移植マウスの活用研究 (2015)
  • Author(s): 山崎浩史
  • Organizer: 第38回薬物動態談話会年会 (浜松）
  • Place of Presentation: アクトシティホテル（浜松市）
  • Year and Date: 2015-11-30
  • Invited
• [Presentation] Comparison of drug oxidations in humans, primates, and rodents (2015)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 2015 JSSX / KAPS Joint Session, 30th JSSX Annual Meetign (Tokyo)
  • Place of Presentation: 江戸川区民センター（東京）
  • Year and Date: 2015-11-12
  • Int'l Joint Research / Invited
• [Presentation] ヒトと実験動物との代謝の種差 (2015)
  • Author(s): 山崎浩史
  • Organizer: 第42回日本毒性学会年会 （金沢）
  • Place of Presentation: 金沢日航ホテル（釜沢市）
  • Year and Date: 2015-06-30
  • Invited
• [Presentation] Reactive metabolite formation of drugs by human P450s in chimeric mice with humanized liver (2014)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 19th Notrh American ISSX/ 29th JSSX Annual Meeting
  • Place of Presentation: Hilton San Francisco Union Square Hotel (San Fransico, USA)
  • Year and Date: 2014-10-19 – 2014-10-23
  • Invited
• [Presentation] Metabolic activation and fate of xenobiotics determined by polymorphic drug-metabolizing enzymes (2014)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 19th Notrh American ISSX/ 29th JSSX Annual Meeting
  • Place of Presentation: Hilton San Francisco Union Square Hotel (San Fransico, USA)
  • Year and Date: 2014-10-19 – 2014-10-23
  • Invited
• [Presentation] 医薬品開発におけるヒト代謝物研究の役割 (2014)
  • Author(s): 山崎浩史
  • Organizer: 第41回日本毒性学会年会
  • Place of Presentation: 神戸国際会議場 （神戸市）
  • Year and Date: 2014-07-02 – 2014-07-04
  • Invited
• [Presentation] レボカルニチンを使う透析患者さんの体臭を科学する－個の医療－ (2014)
  • Author(s): 山崎浩史
  • Organizer: 医療薬学フォーラム2014
  • Place of Presentation: 東京ビックサイト （東京都）
  • Year and Date: 2014-06-24 – 2014-06-25
  • Invited
• [Book] Advances in Medicine and Biology, vol 93 (2016)
  • Author(s): Yamazaki, H., Chowdhury, G. and Guengerich, F.P.
  • Total Pages: 8
  • Publisher: Nova Science Publishers, Inc
• [Book] Fifty Years of Cytochrome P450 Research (2014)
  • Author(s): Hiroshi Yamazaki
  • Total Pages: 402
  • Publisher: Springer
• [Remarks] 山崎浩史
  • URL: http://www.shoyaku.ac.jp/research/laboratory/doutai/teacher/96
• [Remarks] ORCid ID (0000-0002-1068-42611)
  • URL: http://orcid.org/0000-0002-1068-4261
• [Remarks] Scopus Author ID: 56049170400
  • URL: http://www.scopus.com/authid/detail.uri?authorId=56049170400
• [Remarks] Researcher ID: A-6081-2011
  • URL: http://www.researcherid.com/rid/A-6081-2011
• [Remarks] 山崎浩史教授の研究業績リスト
  • URL: http://www.shoyaku.ac.jp/labosite/doutai/2015/03/post_6.html
• [Remarks] Yamazaki, Hiroshi
  • URL: http://www.researcherid.com/rid/A-6081-2011