Basic study for appropriate use of clinical medicine: functional interaction of drug metabolizing enzymes and its significance in vivo
| Project/Area Number |
25293039
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
Ishii Yuji 九州大学, 薬学研究科(研究院), 准教授 (90253468)
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| Co-Investigator(Renkei-kenkyūsha) |
YAMADA Hideyuki 九州大学, 大学院薬学研究院, 教授 (40142351)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2013: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
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| Keywords | 薬物代謝 / グルクロン酸抱合 / P450 / UGT / タンパク質間相互作用 / CYP / 機能的相互作用 / シトクロムP450 |
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| Outline of Final Research Achievements |
Cumulative evidence suggests that there is protein-protein interaction between cytochromes P450 (P450s, CYPs) and UDP-glucuronosyltransferases (UGTs). In this project, we obtained evidence as follows: 1) The activity of CYP3A4 was significantly suppressed by coexpressing UGT2B7. A series of studies suggested that both hydrophobic domains located near the C terminus and within UGT2B7 are needed for interaction with CYP3A4. 2) CYP3A4 enhances wild-type UGT1A7(*1)-catalyzed glucuronidation. In sharp contrast, CYP3A4 suppresses the activity of UGT1A7*4 that carries a W208R mutation. Therefore, it is suggested that residue 208 of UGT1A7 is crucial for the responsiveness to CYP3A4-dependent modulation. Further, interaction between UGT1A7*1/*4 and CYP3A4 was observed in living cells by fluorescence resonance energy transfer (FRET) analysis. Mutual modulation of UGT and CYP3A4 helps our better understanding of inter-individual differences of CYP3A4 as well as UGT.
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Report
(4 results)
Research Products
(28 results)
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[Journal Article] Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants2014
Author(s)
Ishii Y, Koba H, Kinoshita K, Oizaki T, Iwamoto Y, Takeda S, Miyauchi Y, Nishimura Y, Egoshi N, Taura F, Morimoto S, Ikushiro S, Nagata K, Yamazoe Y, Mackenzie PI, Yamada H
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Journal Title
Drug Metabolism and Disposition
Volume: 42
Issue: 2
Pages: 229-238
DOI
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Peer Reviewed
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[Presentation] CYTOCHROME P450 3A4 RESTORES THE CATALYTIC PROPERTY OF UDP-GLUCURONOSYLTRANSFERASE 1A1*6, ONE OF THE ALLELIC VARIANTS WHICH ARE CONCERNED FOR CAUSING GILBERT SYNDROME2013
Author(s)
Kousuke Kinoshita, Toshiya Oizaki, Yuki Iwamoto, Yuu Miyauchi, Shin-ichi Ikushiro, Yasushi Yamazoe, Kiyoshi Nagata, Peter I. Mackenzie, Hideyuki Yamada, and Yuji Ishii
Organizer
28th Annual meeting of Japanese Society for the Study of Xenobiotics
Place of Presentation
東京 タワーホール船堀
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