Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain(Biochemistry)
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概要
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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 K_m and V_<max> 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 (K_i, 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.
- 2008-03-01
著者
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NAKAMURA Seikou
Kyoto Pharmaceutical University
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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
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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, Kw
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NARIMATSU Shizuo
Laboratories of Health Chemistry,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
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FUNAE Yoshihiko
Department of Chemical Biology, Osaka City University Graduate School of Medicine
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中村 紳一郎
Specialty Chemicals Research Center Shin-etsu Chemical Co. Ltd.
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Hiroi Toyoko
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 R
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Nakamura S
Toyama Univ. Toyama Jpn
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FUNAE Yoshihiko
Osaka City University School of Medicine
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Nakamura S
Specialty Chemicals Research Center Shin-etsu Chemical Co. Ltd.
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Funae Y
Osaka City Univ. Medical School Osaka Jpn
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Funae Yoshihiko
Department Of Chemical Biology Osaka City University Graduate School Of Medicine
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Funae Y
Osaka City University Medical School
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Funae Yoshihiko
Department Of Chemical Biology Osaka City University Medical School
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Nakamura Satoko
Osaka University Of Pharmaceutical Sciences
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Narimatsu Shizuo
Laboratories Of Health Chemistry Graduate School Of Medicine Dentistry And Pharmaceutical Sciences O
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Narimatsu Shizuo
Laboratories Health Chemistry Faculty Of Pharmaceutical Sciences Okayama University
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Imaoka S
Nanobiotechnology Research Center And Department Of Bioscience School Of Science And Technology Kwan
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Imaoka Susumu
Nanobiotechnology Res. Center And Dep. Of Bioscience School Of Sci. And Technol. Kwansei Gakuin Univ
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Imaoka Susumu
Department Of Bioscience And Nanobiotechnology Research Center School Of Science And Technology Kwan
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Niwa Toshiro
Department Of Chemical Biology Osaka City University Graduate School Of Medicine
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Narimatsu Shizuo
Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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Nakamura S
Laboratories Of Health Chemistry Graduate School Of Medicine Dentistry And Pharmaceutical Sciences O
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Okada Kazushi
Department of Bioscience, Nanobiotechnology Research Center, School of Science and Technology, Kwansei Gakuin University
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