Thalidomide increases cytochrome P450 activity and drug metabolism in liver through direct activation of nuclear receptor CAR and PXR

• Project/Area Number: 23590200
• 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): SHIMIZU Makiko 昭和薬科大学, 薬学部, 講師 (90307075) ; MURAYAMA Norie 昭和薬科大学, 薬学部, 講師 (90219949)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 薬物代謝 / サリドマイド / P450 3A4 / 酵素誘導 / ヒト型薬物代謝 / ヒト肝移植キメラマウス / 反応性代謝物 / グルタチオン付加体

Research Abstract

We demonstrated heterotropic cooperativity of human cytochrome P450 (P450) 3A4/5 by the teratogen thalidomide using a model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver displayed enhanced midazolam clearance upon pre-treatment with orally administered thalidomide, presumably because of human P450 3A induction. Thalidomide enhanced levels of P450 3A4/2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes indirectly suggesting activation of gene transcription factors. Thalidomide and its human proportionate metabolite 5-hydroxythalidomide displayed significant modulation of coregulator interaction with CAR and PXR ligand-binding domains similar to established agonists for these receptors. These results collectively suggest that thalidomide could act as a ligand for PXR and CAR and cause enzyme induction. The possibilities of drug interactions during thalidomide therapy in humans should be evaluated further.

Research Products

• [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
• [Journal Article] The human hepatic cell line HepaRG cells, possible cell source for steady generation of humanized liver TK-NOG mice (2014)
  • Author(s): Higuchi, Y., Kawai, K., Yamazaki, H., Nakamura, M., Bree, F., Guillouzo, C., and Suemizu, H.
  • Journal Title: Xenobiotica Volume: 27 Issue: 2 Pages: 146-157
  • DOI: 10.3109/00498254.2013.836257
  • Peer Reviewed
• [Journal Article] In vivo drug interactions of the teratogen thalidomide with midazolam: Heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice (2013)
  • Author(s): Yamazaki, H., Suemizu, H., Murayama, N., Utoh, M., Shibata, N., Nakamura, M., and Guengerich, F. P.
  • Journal Title: Chem.Res.Toxicol. Volume: 26 Issue: 3 Pages: 486-489
  • DOI: 10.1021/tx400008g
  • Peer Reviewed
• [Journal Article] Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling (2013)
  • Author(s): Tsukada, A., Suemizu, H., Murayama, N., Takano, R., Shimizu, M., Nakamura, M., and Yamazaki, H
  • Journal Title: Regul.Toxicol.Pharmacol Volume: 65 Issue: 3 Pages: 316-324
  • DOI: 10.1016/j.yrtph.2013.01.008
  • Peer Reviewed
• [Journal Article] Clinical Evidence of Pharmacokinetic Changes in Thalidomide Therapy (2013)
  • Author(s): Nakamura K, Matsuzawa N, Ohmori S, Ando Y, Yamazaki H, Matsunaga T
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 28 Issue: 1 Pages: 38-43
  • DOI: 10.2133/dmpk.DMPK-12-RV-089
  • NAID: 130004463295
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed
• [Journal Article] The <i>CYP3A4</i> intron 6 C>T polymorphism (<i>CYP3A4*22</i>) is associated with reduced CYP3A4 protein level and function in human liver microsomes (2013)
  • Author(s): Okubo, M., Murayama, N., Shimizu, M., Shimada, T., Guengerich, F. P., and Yamazaki, H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 38 Issue: 3 Pages: 349-354
  • DOI: 10.2131/jts.38.349
  • NAID: 10031158900
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed
• [Journal Article] In vivo formation of dihydroxylated and glutathione conjugate metabolites derived from thalidomide and 5-hydroxythalidomide in humanized TK-NOG mice (2012)
  • Author(s): Yamazaki, H., Suemizu, H., Shimizu, M., Igaya, S., Shibata, N., Nakamura, N., Chowdhury, G., and Guengerich, F.P
  • Journal Title: Chem Res Toxicol Volume: 25 Issue: 2 Pages: 274-276
  • DOI: 10.1021/tx300009j
  • Peer Reviewed
• [Journal Article] Different metabolites of human hepatotoxic pyrazolopyrimidine derivative 5-n-butyl-pyrazolo[1,5-a]pyrimidine produced by human, rat, and monkey cytochrome P450 1A2 and liver microsomes (2012)
  • Author(s): Kuribayashi, S., Uno, Y., Naito, S., and Yamazaki, H
  • Journal Title: Basic Clin.Pharmacol.Toxicol Volume: 110 Issue: 4 Pages: 405-408
  • DOI: 10.1111/j.1742-7843.2011.00823.x
  • Peer Reviewed
• [Journal Article] A rapid multiplex PCR assay that can reliably discriminate the cytochrome P450 2D6 whole-gene deletion allele from 2D6*10 alleles. (2012)
  • Author(s): Okubo, M., Murayama, N., Miura, J., Shimizu, M., and Yamazakik, H
  • Journal Title: Clinica Chimica Acta Volume: 413 Issue: 19-20 Pages: 1675-1677
  • DOI: 10.1016/j.cca.2012.05.013
  • Peer Reviewed
• [Journal Article] Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation (2012)
  • Author(s): Hosoi, Y., Uno, Y., Murayama, N., Fujino, H., Shukuya, M., Iwasaki, K., Shimizu, M., Utoh, M., and Yamazaki, H.
  • Journal Title: Biochem. Pharmacol. Volume: 84 Issue: 12 Pages: 1691-1695
  • DOI: 10.1016/j.bcp.2012.09.026
  • Peer Reviewed
• [Journal Article] Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs (2012)
  • Author(s): Mogi, M., Toda, A., Iwasaki, K., Kusumoto, S., Takahara, H., Shimizu, M., Murayama, N., Izumi, H., Utoh, M., and Yamazaki, H.
  • Journal Title: The Journal of Toxicological Sciences Volume: 37 Issue: 6 Pages: 1157-1164
  • DOI: 10.2131/jts.37.1157
  • NAID: 130004447016
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed
• [Journal Article] In Vivo Formation of a Glutathione Conjugate Derived from Thalidomide in Humanized uPA-NOG (2011)
  • Author(s): Yamazaki, H., Suemizu, H.(8名・2番目)
  • Journal Title: Mice Chem Res Toxicol Volume: 24 Issue: 3 Pages: 287-289
  • DOI: 10.1021/tx200005g
  • Peer Reviewed
• [Journal Article] Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants (2011)
  • Author(s): Akiyoshi, T. Saito, T., Murase, S., Miyazaki, M. Murayama, N., Yamazaki, H., Guengerich, F. P., Nakamura, K., Yamamoto, K., and Ohtani, H
  • Journal Title: Drug Metab. Dispos Volume: 39 Issue: 4 Pages: 724-728
  • DOI: 10.1124/dmd.110.036780
  • Peer Reviewed
• [Journal Article] Mechanism-based inhibition of cytochrome P450 (CYP) 2A6 by chalepensin in recombinant systems, in human liver microsomes and mice in vivo (2011)
  • Author(s): Ueng, Y.-F., Chen, C.-C., Chung, Y.-T, Liu, T.-Y., Chang, Y.-P., Lo, W.-S., Murayama, N., Yamazaki, H., Soucek, P., Chau, G.-Y., Chi, C.-W., Chen, R.-M., Li D.T.
  • Journal Title: Brit.J.Pharmacol. Volume: 163 Issue: 6 Pages: 1250-1262
  • DOI: 10.1111/j.1476-5381.2011.01341.x
  • Peer Reviewed
• [Presentation] P450 Based DDI and Clinical Significance: Genotyping and Phenotyping (2013)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 4th Joint Workshop of the International Society for the Study of Xenobiotics (ISSX) and the Chinese Society for the Study of Xenobiotics (CSSX)
  • Place of Presentation: 河南大学, Henan, China
  • Invited
• [Presentation] Comparison of Estimates of “Normal” Exposure through Diet to Internal Dosimetry Generated at NOEL and LOEL Doses in Animal Toxicity Studies (2013)
  • Author(s): Hiroshi Yamazaki
  • Organizer: ICCA-LRI and NCATS Workshop
  • Place of Presentation: La Posada de Santa, Santa Fe, NM, USA
  • Invited
• [Presentation] DRUG OXIDATIONS AND INTERACTIONS MEDIATED BY MOKEY AND HUMAN CYTOCHROME P450 ENZYEMS (2013)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 18th International Conference on Cytochrome P450 ~Biochemistry, Biophysics, Biotechnology~
  • Place of Presentation: Washington University, Seatle, WA, USA
  • Invited
• [Presentation] Acrylonitrile concentrations hypothetically modeled in humans (2013)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 13th International Congress of Toxicology
  • Place of Presentation: COEX in Seoul, Seoul, Korea
  • Invited
• [Presentation] Utility of Microminipig for in vitro and in vivo drug metabolizing activities (2012)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 第85回日本薬理学会年会(招待講演)
  • Place of Presentation: 京都国際会議場 （京都市）
• [Presentation] Reactive metabolite formation from thalidomide mediated by human cytochrome P450 3A enzymes and in chimeric mice with humanized liver (2011)
  • Author(s): Hiroshi Yamazaki
  • Organizer: 17th International Conference on Cytochrome P450 ~Biochemistry, Biophysics, Biotechnology~(招待講演)
  • Place of Presentation: Manchester大学 （Manchester, UK)
• [Presentation] Human Drug metabolites and interactions mediated by polymorphic drug-metabolizing enzymes (2011)
  • Author(s): Hiroshi Yamazaki
  • Organizer: The 26th JSSX Annual Meeting(招待講演)
  • Place of Presentation: 広島国際会議場 （広島市）
• [Presentation] 正常動物を用いたヒト薬物代謝予測-ミニブタおよびサルの有用性 (2011)
  • Author(s): 山崎浩史
  • Organizer: 第58回日本実験動物学会総会(招待講演)
  • Place of Presentation: 江戸川区民センター （東京都）
• [Presentation] トキシコキネティクス、特に薬物代謝酵素特性の面からみたマイクロミニピッグ (2011)
  • Author(s): 山崎浩史
  • Organizer: 第38回日本トキシコロジー学会学術年会(招待講演)
  • Place of Presentation: 横浜国際会議場 (横浜市）
• [Presentation] P450を介した相互作用 (2011)
  • Author(s): 山崎浩史
  • Organizer: 第32回日本臨床薬理学会年会(招待講演)
  • Place of Presentation: アクトシティ浜松市 （浜松市）
• [Presentation] OLINDAを用いた放射線内部被ばく評価 (2011)
  • Author(s): 山崎浩史
  • Organizer: 第3回医薬品開発支援機構（APDD) シンポジウム－我が国における14C-MD臨床試験の実施手順 - NEDOプロジェクトの成果を踏まえて -(招待講演)
  • Place of Presentation: 慶應義塾大学薬学部 （東京都）
• [Presentation] mpact of human drug-metabolizing enzymes in drug development
  • Author(s): Hiroshi Yamazaki
  • Organizer: 2013 JSSX / KPS Joint Session, Korean Pharmacetical Society
  • Place of Presentation: Osong Medical Innovation Foudation CV Center, Osong, Chungchungbuk-do, Korea
  • Invited
• [Presentation] ヒト肝試料を活用した薬物代謝研究
  • Author(s): 山崎浩史
  • Organizer: 第33回日本臨床薬理学会年会
  • Place of Presentation: 沖縄コンベンションセンター（宜野湾市）
  • Invited
• [Presentation] Human Drug metabolites bioactivated by cytochrome P450 enzymes
  • Author(s): Hiroshi Yamazaki
  • Organizer: The 27th JSSX Annual Meeting
  • Place of Presentation: 江戸川区民センター（江戸川区）
  • Invited
• [Presentation] マイクロミニピッグ肝薬物代謝酵素活性のヒトとの比較
  • Author(s): 山崎浩史
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Invited
• [Presentation] Species, Ethnic, and Individual Differences in Human Drug-metabolizing Cytochrome P450 Enzymes
  • Author(s): Hiroshi Yamazaki
  • Organizer: 50th Anniversary Symposium on Cytochrome P450
  • Place of Presentation: 九州大学医学部（福岡市）
  • Invited
• [Presentation] Drug Metabolism in Chimeric Mice with Humanized Liver
  • Author(s): Hiroshi Yamazaki
  • Organizer: The North Jersey ACS Drug Metabolism Discussion Group, 2012 Spring Symposium
  • Place of Presentation: Crowne Plaza Hotel Somerset-Bridgewater, Somerset, New Jersey , USA,
  • Invited
• [Book] 新衛生化学・公衆衛生学 (2011)
  • Author(s): 山崎浩史 他
  • Total Pages: 461
  • Publisher: 南江堂
• [Remarks]
  • URL: http://www.shoyaku.ac.jp/laboratory/doutai.htmlhttp://www.researcherid.com/rid/A-6081-2011