| Project/Area Number |
02453140
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
HIROBE Masaaki Tokyo University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20012594)
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| Co-Investigator(Kenkyū-buntansha) |
HIGUCHI Tsunehiko Tokyo University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (50173159)
MASHINO Tadahiko Tokyo University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (90165697)
OHTA Shigeru Tokyo University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (60160503)
NAGANO Tetsuo Tokyo University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (20111552)
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| Project Period (FY) |
1990 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 1992: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1991: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1990: ¥6,700,000 (Direct Cost: ¥6,700,000)
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| Keywords | Cytochrome P-450 / Cytochrome P-450 Model / Porphyrin / Drug Metabolism / Oxidation / チトクロームP-450 / アルカン水酸化 / 芳香環水酸化 / Ru-ポルフィリン / チトクロームc / チトクロ-ムP450 / 西洋ワサビペルオキシデ-ス / チトクロ-ムc / 鉄ポルフィリン / 脱カルボン酸反応 / チトクロ-ムPー450化学モデル / 比較代謝化学 / ミクロペルオキシダ-ゼ / チトクロ-ムPー420 / 活性代謝物 / S軸配位子 |
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| Research Abstract |
Cytochrome P-450 plays an important role in metabolizing biomolecules and xenobiotics, and the mechanism of its catalytic activities has been the subject of extensive investigation. Recently many attempts have been made to reproduce the reactivity in chemical systems with a simple metalloporphyrin. We have achieved the synthesis of many effective P-450 mimics and clarified their functions with the aim of developing artificial enzymes having high similarity to the native P-450 system for investigation of drug metabolism.
Here we present the results of our studies for three years.
(1) The stable iron porphyrin ligated by alkyl thiolate showed enormously accelerated heterolytic O-O bond cleavage of peracids even in hydrophobic solvents. The heterolytic cleavage gives Fe^<5+>-oxenoid type active species which is thought to be a strong oxidant.
(2) Modified cytochrome c, immobilized cytochrome c and microperoxidase-11, catalyzed some P-450-like substrate oxidations. The reaction mechanisms of these N- and S-oxidations were similar to those of P-450itself.
(3) Ru-porphyrin/2,6-disubstituted pyridine N-oxide system was developed for olefin epoxidation. In the presence of acid, this system effectively catalyzed a oxidation of unactivated alkane and turn over number of the catalyst was 18800.
(4) Many P-450 model systems were tested for ability to metabolize various drugs compared with the native P-450 system and coupling reactions of aniline derivatives, beta-oxo formation of piperidine derivatives, and oxidative decarboxylation of phenylacetic acid derivatives were found to be new P-450 dependent metabolic pathways. These results clearly show that P-450 model is useful for identification of minor/new/unstable metabolites.
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