| Project/Area Number |
10672115
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | KOBE GAKUIN UNIVERSITY |
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Principal Investigator |
IGARASHI Kazuo KOBE GAKUIN UNIVERSITY, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80098467)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Haloperidol / Neurotoxicity / Pyridinium metabolite / P450 / Peroxidase / Brain enzyme / 脳内酵素系 / 脳内代謝 |
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| Research Abstract |
This study was undertaken to examine the metabolic enzyme system in brain involved in the formation neurotoxic pyridinium metabolite (HPPィイD1+ィエD1) derived from antipsychotic agent haloperiodol (HP). In vitro oxidations of HP and its dehydrated product HPTP to HPPィイD1+ィエD1 were investigated using various brain preparations. The mitochondorial fraction proved to be most active. Although HPTP appeared to be a better substrate than HP in rat brain, its conversion to HPPィイD1+ィエD1 was not NADPH dependent suggesting that it is not catalyzed by cytochrome P450. In addition, we attempted inhibition experiments using the MAO inhibitors clorgyline and deprenyl. Moderate and concentration dependent inhibition was observed with clorgyline (an MAO-A selective inhibitor). This result suggests that brain MAO-A may contribute to HPPィイD1+ィエD1 formation from HPTP. In order to examine the possibility of peroxide-supported P450 catalysis of HP to HPPィイD1+ィエD1, we conducted incubations using cumene hydroperoxide (CuOOH). The conversion of HP to HPPィイD1+ィエD1 increased by about 3 times in the presence of CuOOH. Moreover, the study using enzyme preparations of horseradish peroxidase or myeroperoxidase indicated that these enzymes were catalyzed in the conversion of HP to HPPィイD1+ィエD1. Consequently, we conclude that HP and HPTP are converted to the neurotoxic pyridinium metabolite HPPィイD1+ィエD1 not by chemical processes but rather by peroxidase in brain.
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