Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain
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- Niwa Toshiro
- Department of Chemical Biology, Osaka City University Graduate School of Medicine
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- Okada Kazushi
- Department of Chemical Biology, Osaka City University Graduate School of Medicine Nanobiotechnology Research Center and Department of Bioscience, School of Science and Technology, Kwansei Gakuin University
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- Hiroi Toyoko
- Department of Chemical Biology, Osaka City University Graduate School of Medicine
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- Imaoka Susumu
- Nanobiotechnology Research Center and Department of Bioscience, School of Science and Technology, Kwansei Gakuin University
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- Narimatsu Shizuo
- Laboratories of Health Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
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- Funae Yoshihiko
- Department of Chemical Biology, Osaka City University Graduate School of Medicine
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We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the goal of clarifying whether neurosteroid levels are affected by psychotropic drugs in the brain. PROG or ALLO was incubated with rat CYP2D4 or human CYP2D6 in the presence of typical psychotropic drugs, fluoxetine, imipramine, desipramine, mazindol, and GBR12909, and the 21-hydroxylated metabolites of PROG and ALLO were determined by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. Fluoxetine competitively inhibited CYP2D4-mediated PROG 21-hydroxylation and increased both Km and Vmax values of CYP2D6-mediated PROG 21-hydroxylation. In addition, fluoxetine competitively inhibited ALLO 21-hydroxylation mediated by CYP2D4 and CYP2D6. Imipramine, desipramine, mazindol, and GBR12909 competitively inhibited PROG 21-hydroxylation mediated by CYP2D4 and/or CYP2D6, and all psychotropic drugs inhibited ALLO 21-hydroxylation mediated by CYP2D4 and/or CYP2D6. The inhibition constants (Ki values) of imipramine, desipramine, and mazindol against the 21-hydroxylation of PROG and ALLO by CYP2D6 were lower than those by CYP2D4. These results indicate that psychotropic drugs including fluoxetine affected the metabolism of neurosteroids, such as PROG and ALLO in the brain, suggesting that the regulation of the neurosteroid levels is modified by central nervous system-active drugs that inhibit brain CYP2D isoforms.
収録刊行物
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- Biological & Pharmaceutical Bulletin
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Biological & Pharmaceutical Bulletin 31 (3), 348-351, 2008
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390282679602497920
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- NII論文ID
- 110006623054
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- NII書誌ID
- AA10885497
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- ISSN
- 13475215
- 09186158
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- NDL書誌ID
- 9393030
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
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