Membrane Anchor of Cytochrome P450 Reductase Suppresses the Uncoupling of Cytochrome P450
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- Miyamoto Masayoshi
- Graduate School of Pharmaceutical Sciences, Osaka University
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- Yamashita Taku
- School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University
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- Yasuhara Yuki
- Graduate School of Pharmaceutical Sciences, Osaka University
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- Hayasaki Akinori
- Graduate School of Pharmaceutical Sciences, Osaka University
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- Hosokawa Yukari
- Graduate School of Pharmaceutical Sciences, Osaka University
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- Tsujino Hirofumi
- Graduate School of Pharmaceutical Sciences, Osaka University
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- Uno Tadayuki
- Graduate School of Pharmaceutical Sciences, Osaka University
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抄録
Cytochrome P450 reductase (CPR) is an important redox partner of microsomal CYPs. CPR is composed of a membrane anchor and a catalytic domain that contains FAD and flavin mononucleotide (FMN) as redox centers and mediates electron transfer to CYP. Although the CPR membrane anchor is believed to be requisite for interaction with CYP, its physiological role is still controversial. To clarify the role of the anchor, we constructed a mutant (Δ60-CPR) in which the N-terminal membrane anchor was truncated, and studied its effect on binding properties, electron transfer to CYP2C19, and drug metabolism. We found that Δ60-CPR could bind to and transfer electrons to CYP2C19 as efficiently as WT-CPR, even in the absence of lipid membrane. In accordance with this, Δ60-CPR could mediate metabolism of amitriptyline (AMT) and imipramine (IMP) in the absence of lipids, although activity was diminished. However, Δ60-CPR failed to metabolize omeprazole (OPZ) and lansoprazole (LPZ). To clarify the reason for this discrepancy in drug metabolism, we investigated the uncoupling reaction of the CYP catalytic cycle. By measuring the amount of H2O2 by-product, we found that shunt pathways were markedly activated in the presence of OPZ/LPZ in the Δ60-CPR mutant. Because H2O2 levels varied among the drugs, we conclude that the proton network in the distal pocket of CYP2C19 is perturbed differently by different drugs, and activated oxygen is degraded to become H2O2. Therefore, we propose a novel role for the membrane anchor as a suppressor of the uncoupling reaction in drug metabolism by CYP.
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 63 (4), 286-294, 2015
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
- 1390001204176563584
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- NII論文ID
- 130005061424
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- NII書誌ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 026283603
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- PubMed
- 25832023
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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
- Crossref
- PubMed
- CiNii Articles
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- 抄録ライセンスフラグ
- 使用不可