2016 Fiscal Year Final Research Report
Evaluaion of Human Cytochrome P450 3A Enzymes in Hepatic and Placental Cells by Thalidomide and Relevance to Bioactivation
| Project/Area Number |
26460206
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Showa Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Keywords | サリドマイド |
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| 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.
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| Free Research Field |
薬物代謝学
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