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)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Medical pharmacy
|
Research Institution | Showa Pharmaceutical University |
Principal Investigator |
|
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 *help |
¥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.
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Report
(4 results)
Research Products
(34 results)
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[Journal Article] Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of pregnane X receptor2014
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
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Journal Title
Chem.Res.Toxicol
Volume: 27
Issue: 2
Pages: 304-307
DOI
Related Report
Peer Reviewed
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[Journal Article] The human hepatic cell line HepaRG cells, possible cell source for steady generation of humanized liver TK-NOG mice2014
Author(s)
Higuchi, Y., Kawai, K., Yamazaki, H., Nakamura, M., Bree, F., Guillouzo, C., and Suemizu, H.
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Journal Title
Xenobiotica
Volume: 27
Issue: 2
Pages: 146-157
DOI
Related Report
Peer Reviewed
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[Journal Article] In vivo drug interactions of the teratogen thalidomide with midazolam: Heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice2013
Author(s)
Yamazaki, H., Suemizu, H., Murayama, N., Utoh, M., Shibata, N., Nakamura, M., and Guengerich, F. P.
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Journal Title
Chem.Res.Toxicol.
Volume: 26
Issue: 3
Pages: 486-489
DOI
Related Report
Peer Reviewed
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[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 modeling2013
Author(s)
Tsukada, A., Suemizu, H., Murayama, N., Takano, R., Shimizu, M., Nakamura, M., and Yamazaki, H
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Journal Title
Regul.Toxicol.Pharmacol
Volume: 65
Issue: 3
Pages: 316-324
DOI
Related Report
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[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 microsomes2013
Author(s)
Okubo, M., Murayama, N., Shimizu, M., Shimada, T., Guengerich, F. P., and Yamazaki, H.
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Journal Title
The Journal of Toxicological Sciences
Volume: 38
Issue: 3
Pages: 349-354
DOI
NAID
ISSN
0388-1350, 1880-3989
Related Report
Peer Reviewed
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[Journal Article] In vivo formation of dihydroxylated and glutathione conjugate metabolites derived from thalidomide and 5-hydroxythalidomide in humanized TK-NOG mice2012
Author(s)
Yamazaki, H., Suemizu, H., Shimizu, M., Igaya, S., Shibata, N., Nakamura, N., Chowdhury, G., and Guengerich, F.P
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Journal Title
Chem Res Toxicol
Volume: 25
Issue: 2
Pages: 274-276
DOI
Related Report
Peer Reviewed
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[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 microsomes2012
Author(s)
Kuribayashi, S., Uno, Y., Naito, S., and Yamazaki, H
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Journal Title
Basic Clin.Pharmacol.Toxicol
Volume: 110
Issue: 4
Pages: 405-408
DOI
Related Report
Peer Reviewed
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[Journal Article] Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7-hydroxylation2012
Author(s)
Hosoi, Y., Uno, Y., Murayama, N., Fujino, H., Shukuya, M., Iwasaki, K., Shimizu, M., Utoh, M., and Yamazaki, H.
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Journal Title
Biochem. Pharmacol.
Volume: 84
Issue: 12
Pages: 1691-1695
DOI
Related Report
Peer Reviewed
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[Journal Article] Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs2012
Author(s)
Mogi, M., Toda, A., Iwasaki, K., Kusumoto, S., Takahara, H., Shimizu, M., Murayama, N., Izumi, H., Utoh, M., and Yamazaki, H.
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Journal Title
The Journal of Toxicological Sciences
Volume: 37
Issue: 6
Pages: 1157-1164
DOI
NAID
ISSN
0388-1350, 1880-3989
Related Report
Peer Reviewed
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[Journal Article] Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants2011
Author(s)
Akiyoshi, T. Saito, T., Murase, S., Miyazaki, M. Murayama, N., Yamazaki, H., Guengerich, F. P., Nakamura, K., Yamamoto, K., and Ohtani, H
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Journal Title
Drug Metab. Dispos
Volume: 39
Issue: 4
Pages: 724-728
DOI
Related Report
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[Journal Article] Mechanism-based inhibition of cytochrome P450 (CYP) 2A6 by chalepensin in recombinant systems, in human liver microsomes and mice in vivo2011
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.
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Journal Title
Brit.J.Pharmacol.
Volume: 163
Issue: 6
Pages: 1250-1262
DOI
Related Report
Peer Reviewed
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