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

2013 Fiscal Year Final Research Report

• 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
• Keywords: 薬物代謝

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 Pages: 304-307
  • DOI: 10.1021/tx4004374
  • Peer Reviewed
• [Journal Article] 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 Pages: 147-156
  • DOI: 10.1021/tx4004215
  • 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 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 Pages: 316-324
  • DOI: 10.1016/j.yrtph.2013.01.008
  • Peer Reviewed
• [Journal Article] Clinical evidence of the pharmacokinetics change in thalidomide therapy (2013)
  • Author(s): Nakamura, K., Matsuzawa, N., Ohmori, S., Ando, Y., Yamazaki, H., and Matsunaga, T
  • Journal Title: Drug Metab.Pharmacokinet Volume: 28 Pages: 38-43
  • DOI: 10.2133/dmpk.DMPK-12-RV-089
  • 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 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 Pages: 405-408
  • DOI: 10.1111/j.1742-7843.2011.00823.x
  • Peer Reviewed
• [Journal Article] In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice (2011)
  • Author(s): Yamazaki, H., Suemizu, H., Igaya, S., Shimizu, M., Shibata, N., Nakamura, M., Chowdhury, G. and Guengerich, F. P
  • Journal Title: Chem.Res.Toxicol Volume: 24 Pages: 287–289
  • DOI: 10.1021/tx200005g
  • Peer Reviewed
• [Remarks]
  • URL: http://www.shoyaku.ac.jp/laboratory/doutai.htmlhttp://www.researcherid.com/rid/A-6081-2011